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Many diseases are now associated with aberrant epigenetics and gene expression changes. Epigenetics can be modified by factors like diet. One dietary factor, folic acid, is consumed in various forms including supplements, energy drinks, and fortified grains. It was hypothesized high levels of folic acid would affect gene expression and enzyme activity of chromatin modifying enzymes as well as dendritic spine densities in a commonly utilized neuron model, the SHSY5Y cell. Decreased MBD2 and MECP2 were discovered upon treatment of SHSY5Y cells with a 2x folic acid dose. Corresponding decreases in dendritic spines were apparent in the 2x folic acid treated cells as well. Activity of DNMTs and H3K4 HMTs was altered. Further, H3K4me1, H3K4me3, H3K9Ac, and global DNA methylation were decreased in the 2x folic acid treated cells. Further studies are warranted to determine if the effects of excess folic acid are detrimental to organismal physiology. Keywords: Epigenetics, Folic acid, Dendritic spines, DNA methylation, Gene expression, Histone modifications

Objective: To examine the extent to which Veterans Health Administration (VHA) Patient-Aligned Care Team (PACT) members have a shared understanding/ agreement upon and enact responsibilities within the team., Background: The PACT model focuses on team-based care management. However, lack of a shared understanding of team-based care management roles and responsibilities makes system-wide implementation a challenge., Methods: Quantitative and qualitative analysis of national survey data collected in 2022 from primary care personnel working in a VHA-affiliated primary care facility., Results: Significant discrepancies exist in responses about what core team members say they do and what others perceive they should be doing, indicating either a lack of agreement, knowledge, or training about what core team members should do., Conclusions: Successful implementation of a team-based model requires adequate support and training for teamwork including shared mental models to work according to their clinical competency. Clear guidance and communication of expectations are critical for role clarity., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To understand whether team member support reduces team leader stress., Method: In Phase 1, we used hierarchical linear modeling with survey data and administrative records from 45 Veterans Health Administration teams (73 providers and 228 associated members) to investigate how teamwork support mitigates leader stress. In Phase 2, we adopted a parallel/simultaneous mixed methods design, utilizing open- and closed-ended responses from 267 additional Veterans Health Administration providers. With the mixed methods design we first analyzed open-ended responses using directed content analysis and hypothesis coding. Next, we transformed our codes into counts and compared them with closed-ended responses to understand whether teamwork support allows leaders to engage in work aligned with their qualifications., Results: As predicted, providers' role conflict corresponded with decreased performance under low teamwork support, but this negative relationship was attenuated with high teamwork support as such support allows leaders to focus on tasks they are uniquely qualified to perform., Conclusions: These findings emphasize the facilitative nature of teams in supporting leaders: followers provide teamwork support that helps leaders navigate role conflict by allowing leaders to work on tasks consistent with their qualifications.

In recent years, there has been a growing interest in the relationship between microorganisms in the surrounding environment and cancer cells. While the tumor microenvironment predominantly comprises cancer cells, stromal cells, and immune cells, emerging research highlights the significant contributions of microbial cells to tumor development and progression. Although the impact of the gut microbiome on treatment response in lung cancer is well established, recent investigations indicate complex roles of lung microbiota in lung cancer. This article focuses on recent findings on the human lung microbiome and its impacts in cancer development and progression. We delve into the characteristics of the lung microbiome and its influence on lung cancer development. Additionally, we explore the characteristics of the intratumoral microbiome, the metabolic interactions between lung tumor cells, and how microorganism-produced metabolites can contribute to cancer progression. Furthermore, we provide a comprehensive review of the current literature on the lung microbiome and its implications for the metastatic potential of tumor cells. Additionally, this review discusses the potential for therapeutic modulation of the microbiome to establish lung cancer prevention strategies and optimize lung cancer treatment.

Background: Recent studies have uncovered the near-ubiquitous presence of microbes in solid tumors of diverse origins. Previous literature has shown the impact of specific bacterial species on the progression of cancer. We propose that local microbial dysbiosis enables certain cancer phenotypes through provisioning of essential metabolites directly to tumor cells., Methods: 16S rDNA sequencing of 75 patient lung samples revealed the lung tumor microbiome specifically enriched for bacteria capable of producing methionine. Wild-type (WT) and methionine auxotrophic (metA mutant) E. coli cells were used to condition cell culture media and the proliferation of lung adenocarcinoma (LUAD) cells were measured using SYTO60 staining. Further, colony forming assay, Annexin V Staining, BrdU, AlamarBlue, western blot, qPCR, LINE microarray and subcutaneous injection with methionine modulated feed were used to analyze cellular proliferation, cell-cycle, cell death, methylation potential, and xenograft formation under methionine restriction. Moreover, C 14 -labeled glucose was used to illustrate the interplay between tumor cells and bacteria., Results/discussion: Our results show bacteria found locally within the tumor microenvironment are enriched for methionine synthetic pathways, while having reduced S-adenosylmethionine metabolizing pathways. As methionine is one of nine essential amino acids that mammals are unable to synthesize de novo, we investigated a potentially novel function for the microbiome, supplying essential nutrients, such as methionine, to cancer cells. We demonstrate that LUAD cells can utilize methionine generated by bacteria to rescue phenotypes that would otherwise be inhibited due to nutrient restriction. In addition to this, with WT and metA mutant E. coli, we saw a selective advantage for bacteria with an intact methionine synthetic pathway to survive under the conditions induced by LUAD cells. These results would suggest that there is a potential bi-directional cross-talk between the local microbiome and adjacent tumor cells. In this study, we focused on methionine as one of the critical molecules, but we also hypothesize that additional bacterial metabolites may also be utilized by LUAD. Indeed, our radiolabeling data suggest that other biomolecules are shared between cancer cells and bacteria. Thus, modulating the local microbiome may have an indirect effect on tumor development, progression, and metastasis., (© 2023. The Author(s).)

The growth and metastasis of solid tumours is known to be facilitated by the tumour microenvironment (TME), which is composed of a highly diverse collection of cell types that interact and communicate with one another extensively. Many of these interactions involve the immune cell population within the TME, referred to as the tumour immune microenvironment (TIME). These non-cell autonomous interactions exert substantial influence over cell behaviour and contribute to the reprogramming of immune and stromal cells into numerous pro-tumourigenic phenotypes. The study of some of these interactions, such as the PD-1/PD-L1 axis that induces CD8 + T cell exhaustion, has led to the development of breakthrough therapeutic advances. Yet many common analyses of the TME either do not retain the spatial data necessary to assess cell-cell interactions, or interrogate few (<10) markers, limiting the capacity for cell phenotyping. Recently developed digital pathology technologies, together with sophisticated bioimage analysis programs, now enable the high-resolution, highly-multiplexed analysis of diverse immune and stromal cell markers within the TME of clinical specimens. In this article, we review the tumour-promoting non-cell autonomous interactions in the TME and their impact on tumour behaviour. We additionally survey commonly used image analysis programs and highly-multiplexed spatial imaging technologies, and we discuss their relative advantages and limitations. The spatial organization of the TME varies enormously between patients, and so leveraging these technologies in future studies to further characterize how non-cell autonomous interactions impact tumour behaviour may inform the personalization of cancer treatment.​., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Cohn, Forder, Marshall, Vucic, Stewart, Noureddine, Lockwood, MacAulay, Guillaud and Lam.)

Lung tumors frequently metastasize to the brain. Brain metastasis (BM) is common in advanced cases, and a major cause of patient morbidity and mortality. The precise molecular mechanisms governing BM are still unclear, in part attributed to the rarity of BM specimens. In this work, we compile a unique transcriptomic dataset encompassing RNA-seq, microarray, and single-cell analyses from BM samples obtained from patients with lung adenocarcinoma (LUAD). By integrating this comprehensive dataset, we aimed to enhance understanding of the molecular landscape of BM, thereby facilitating the identification of novel and efficient treatment strategies. We identified 102 genes with significantly deregulated expression levels in BM tissues, and discovered transcriptional alterations affecting the key driver 'hub' genes CD69 (a type II C-lectin receptor) and GZMA (Granzyme A), indicating an important role of the immune system in the development of BM from primary LUAD. Our study demonstrated a BM-specific gene expression pattern and revealed the presence of dendritic cells and neutrophils in BM, suggesting an immunosuppressive tumor microenvironment. These findings highlight key drivers of LUAD-BM that may yield therapeutic targets to improve patient outcomes.

Liquid biopsies have emerged as a promising tool for the detection of metastases as well as local and regional recurrence in lung cancer. Liquid biopsy tests involve analyzing a patient's blood, urine, or other body fluids for the detection of biomarkers, including circulating tumor cells or tumor-derived DNA/RNA that have been shed into the bloodstream. Studies have shown that liquid biopsies can detect lung cancer metastases with high accuracy and sensitivity, even before they are visible on imaging scans. Such tests are valuable for early intervention and personalized treatment, aiming to improve patient outcomes. Liquid biopsies are also minimally invasive compared to traditional tissue biopsies, which require the removal of a sample of the tumor for further analysis. This makes liquid biopsies a more convenient and less risky option for patients, particularly those who are not good candidates for invasive procedures due to other medical conditions. While liquid biopsies for lung cancer metastases and relapse are still being developed and validated, they hold great promise for improving the detection and treatment of this deadly disease. Herein, we summarize available and novel approaches to liquid biopsy tests for lung cancer metastases and recurrence detection and describe their applications in clinical practice.

Lung cancer detection and monitoring are hampered by a lack of sensitive biomarkers, which results in diagnosis at late stages and difficulty in tracking response to treatment. Recent developments have established liquid biopsies as promising non-invasive methods for detecting biomarkers in lung cancer patients. With concurrent advances in high-throughput sequencing technologies and bioinformatics tools, new approaches for biomarker discovery have emerged. In this article, we survey established and emerging biomarker discovery methods using nucleic acid materials derived from bodily fluids in the context of lung cancer. We introduce nucleic acid biomarkers extracted from liquid biopsies and outline biological sources and methods of isolation. We discuss next-generation sequencing (NGS) platforms commonly used to identify novel biomarkers and describe how these have been applied to liquid biopsy. We highlight emerging biomarker discovery methods, including applications of long-read sequencing, fragmentomics, whole-genome amplification methods for single-cell analysis, and whole-genome methylation assays. Finally, we discuss advanced bioinformatics tools, describing methods for processing NGS data, as well as recently developed software tailored for liquid biopsy biomarker detection, which holds promise for early diagnosis of lung cancer.

Lung cancer and chronic obstructive pulmonary disease (COPD) often co-occur, and individuals with COPD are at a higher risk of developing lung cancer. While the underlying mechanism for this risk is not well understood, its major contributing factors have been proposed to include genomic, immune, and microenvironment dysregulation. Here, we review the evidence and significant studies that explore the mechanisms underlying the heightened lung cancer risk in people with COPD. Genetic and epigenetic changes, as well as the aberrant expression of non-coding RNAs, predispose the lung epithelium to carcinogenesis by altering the expression of cancer- and immune-related genes. Oxidative stress generated by tobacco smoking plays a role in reducing genomic integrity, promoting epithelial-mesenchymal-transition, and generating a chronic inflammatory environment. This leads to abnormal immune responses that promote cancer development, though not all smokers develop lung cancer. Sex differences in the metabolism of tobacco smoke predispose females to developing COPD and accumulating damage from oxidative stress that poses a risk for the development of lung cancer. Dysregulation of the lung microenvironment and microbiome contributes to chronic inflammation, which is observed in COPD and known to facilitate cancer initiation in various tumor types. Further, there is a need to better characterize and identify the proportion of individuals with COPD who are at a high risk for developing lung cancer. We evaluate possible novel and individualized screening strategies, including biomarkers identified in genetic studies and exhaled breath condensate analysis. We also discuss the use of corticosteroids and statins as chemopreventive agents to prevent lung cancer. It is crucial that we optimize the current methods for the early detection and management of lung cancer and COPD in order to improve the health outcomes for a large affected population.

Objective: The aim of this study was to analyze the perceptions of core team members implementing patient-centered medical home (PCMH) within the Veterans Health Administration regarding delegation of work., Background: Significant overlap exists in the performance of work tasks among PCMH team members (primary care providers, RNs, clinical associates, clerks), and scant literature exists on appropriate delegation within PCMH teams., Methods: This study conducted used a quantitative and qualitative analysis of 4254 respondents to a 2018 survey., Results: Primary care providers rely heavily on team members, and nurses report being relied upon at high levels. Lack of role clarity and a perceived need for a team leader were concerns voiced by participants., Conclusions: Findings indicated a need for clear guidance on roles and responsibilities within the team. Patient-centered medical home team members need information about the scope of practice of each professional group to allow providers to function at the top of their scope of practice and ensure effective delegation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Nasopharyngeal carcinoma (NPC) is unique among head and neck cancers for its strong causative association with Epstein Barr-Virus and high levels of immune infiltration that play a role in pathogenesis. As such, immunotherapy for the treatment of NPC is a promising area of research in the pursuit of improving patient outcomes. Understanding the tumour immune microenvironment (TIME) of NPC is the key to developing targeted immunotherapies and stratifying patients to determine optimal treatment regimens. Recent research has uncovered distinct characteristics of the TIME in NPC as well as important differences between the different disease subtypes; however, reviewing the state of the field reveals a further need for the application of novel techniques like multiplexed hyperspectral imaging and mass cytometry. These techniques can be used to identify spatial, compositional, and functional aspects of the TIME in NPC such as immune cell sociology, novel immune populations, and differences in immune-related signalling pathways in NPC in order to identify clinically relevant characteristics for targeted immunotherapy development and biomarker discovery., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Dysregulation of ubiquitin-proteasome pathway genes through copy number alteration, promoter hypomethylation, and miRNA deregulation is involved in cancer development and progression. Further characterizing alterations in these genes may uncover novel drug targets across a range of diseases in which druggable alterations are uncommon, including hepatocellular carcinoma (HCC). We analyzed 377 HCC and 59 adjacent non-malignant liver tissue samples, focusing on alterations to component genes of the widely studied CRL2 pVHL E3 ubiquitin ligase complex. mRNA upregulation of the component genes was common, and was correlated with DNA hypomethylation and copy number increase, but many tumours displayed overexpression that was not explained by either mechanism. Interestingly, we found 66 miRNAs, including 39 previously unannotated miRNAs, that were downregulated in HCC and predicted to target one or more CRL2 pVHL components. Several miRNAs, including hsa-miR-101-3p and hsa-miR-139-5p, were negatively correlated with multiple component genes, suggesting that miRNA deregulation may contribute to CRL2 pVHL overexpression. Combining miRNA and mRNA expression, DNA copy number, and methylation status into one multidimensional survival analysis, we found a significant association between greater numbers of alterations and poorer overall survival for multiple component genes. While the intricacies of CRL2 pVHL complex gene regulation require additional research, it is evident that multiple causes for the deregulation of these genes must be considered in HCC, including non-traditional mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Minatel, Cohn, Pewarchuk, Barros-Filho, Sage, Stewart, Marshall, Telkar, Martinez, Reis, Robinson and Lam.)

The placenta is a vital organ formed during pregnancy, and being the interface between the mother and fetus, it is paramount that placental functioning is strictly controlled. Gene expression in the placenta is finely tuned-with aberrant expression causing placental pathologies and inducing stress on both mother and fetus. Gene regulation is brought upon by several mechanisms, and small non-coding RNAs (sncRNAs) have recently been appreciated for their contribution in gene repression. Their dysregulation has been implicated in a range of somatic and inherited disorders, highlighting their importance in maintaining healthy organ function. Their specific roles within the placenta, however, are not well understood, and require further exploration. To this end, we summarize the mechanisms of microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), and transfer RNAs (tRNAs), their known contributions to human placental health and disease, the relevance of sncRNAs as promising biomarkers throughout pregnancy, and the current challenges faced by placental sncRNA studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Telkar, Stewart, Pewarchuk, Cohn, Robinson and Lam.)

MicroRNAs (miRNAs) play vital roles in the regulation of normal developmental pathways. However, cancer cells can co-opt these miRNAs, and the pathways that they regulate, to drive pro-tumourigenic phenotypes. Characterization of the miRNA transcriptomes of fetal organs is essential for identifying these oncofetal miRNAs, but it has been limited by fetal sample availability. As oncofetal miRNAs are absent from healthy adult lungs, they represent ideal targets for developing diagnostic and therapeutic strategies. We conducted small RNA sequencing of a rare collection of 25 human fetal lung (FL) samples and compared them to two independent cohorts ( n = 140, n = 427), each comprised of adult non-neoplastic lung (ANL) and lung adenocarcinoma (LUAD) samples. We identified 13 oncofetal miRNAs that were expressed in FL and LUAD but not in ANL. These oncofetal miRNAs are potential biomarkers for LUAD detection (AUC = 0.963). Five of these miRNAs are derived from the imprinted C14MC miRNA cluster at the 14q32 locus, which has been associated with cancer development and abnormal fetal and placental development. Additionally, we observed the pulmonary expression of 44 previously unannotated miRNAs. The sequencing of these fetal lung samples also provides a baseline resource against which aberrant samples can be compared.

Background: Learning healthcare systems have invested heavily in training primary care staff to provide care using patient-centered medical home models, but less is known about how to effectively lead such teams to deliver high quality care. Research is needed to better understand which healthcare leadership skills are most utilized or in need of development through additional training., Method: Semi-structured telephone interviews with healthcare leaders familiar with Patient-Aligned Care Teams (PACT) implementation in the U.S. Department of Veterans Affairs (VA). We interviewed sixteen (N = 16) physician, nursing, and administrative leaders at VA facilities located in the upper Midwestern United States. Content analysis of interviews transcripts using template techniques., Results: Participants described instrumental challenges that they perceived hindered leadership effectiveness, including the supervisory structure; pace of change; complexity of the clinical data infrastructure; an over-reliance on technology for communication; and gaps in available leadership training. Factors perceived as facilitating effective leadership included training in soft skills, face-to-face communication, and opportunities for formal training and mentorship. A cross-cutting theme was the importance of developing "soft skills" for effective PACT leadership., Conclusions: Although formal leadership training and development were perceived as beneficial, healthcare leaders familiar with PACT implementation in the VA described a mismatch between the skills and knowledge PACT leaders need to succeed and the training available to them. Closing this gap could improve retention of skilled and knowledgeable healthcare leaders, thereby reducing the costs associated with training and leading to improvements in healthcare delivery.

Purpose: To assess differences in Patient Aligned Care Team (PACT) performance between rural and urban primary care clinics within the Veterans Health Administration (VHA)., Methods: An Explanatory Sequential Mixed Methods design was conducted using VHA administrative data to assess performance of a national sample of 891 VHA primary care clinics. Generalized Estimating Equations with repeated measures were used to estimate associations between rurality and process-oriented endpoints including: chronic disease management through telehealth; use of telephone visits, group visits or secured messaging; same-day access; continuity with primary care provider; and postdischarge follow-up. Qualitative data collected during on-site visits with 5 clinics were used to provide insights into PACT processes from the perspectives of staff in rural and urban clinics., Findings: After adjusting for patient- and practice-level characteristics, clinics located in large rural or small/isolated rural areas demonstrated difficulty enhancing access through use of telephone visits, group visits, or secured messaging and completing postdischarge follow-up calls, compared to urban clinics. Qualitative analysis indicated that staff from both rural and urban clinics reported similar barriers implementing these PACT processes. Both patient and staff behaviors and preferences impact implementation of these processes. Distance to care and access to high-speed Internet were also reported as barriers., Conclusions: This study contributes to the understanding of PACT performance in rural settings by highlighting ways contextual and behavioral factors relate to performance. Increasing implementation of patient-centered medical home (PCMH) models, such as PACT, will require additional attention to the complex relationships between the practice and surrounding context., (© 2020 National Rural Health Association.)

Background: Long non-coding RNAs (lncRNAs) have long been implicated in cancer-associated phenotypes. Recently, a class of lncRNAs, known as cis -acting, have been shown to regulate the expression of neighboring protein-coding genes and may represent undiscovered therapeutic action points. The chromatin architecture modification gene HMGA1 has recently been described to be aberrantly expressed in lung adenocarcinoma (LUAD). However, the mechanisms mediating the expression of HMGA1 in LUAD remain unknown. Here we investigate the deregulation of a putative cis -acting lncRNA in LUAD, and its effect on the oncogene HMGA1 ., Methods: LncRNA expression was determined from RNA-sequencing data of tumor and matched non-malignant tissues from 36 LUAD patients. Transcripts with significantly deregulated expression were identified and validated in a secondary LUAD RNA-seq dataset (TCGA). SiRNA-mediated knockdown of a candidate cis -acting lncRNA was performed in BEAS-2B cells. Quantitative real-time PCR was used to observe the effects of lncRNA knockdown on the expression of HMGA1., Results: We identified the lncRNA RP11.513I15.6, which we refer to as HMGA1- lnc , neighboring HMGA1 to be significantly downregulated in both LUAD cohorts. Conversely, we found HMGA1 significantly overexpressed in LUAD and anticorrelated with HMGA1- lnc . In vitro experiments demonstrated siRNA-mediated inhibition of HMGA1- lnc in immortalized non-malignant lung epithelial cells resulted in a significant increase in HMGA1 gene expression., Conclusion: Our results suggest that HMGA1- lnc is a novel cis -acting lncRNA that negatively regulates HMGA1 gene expression in lung cells. Further characterization of this regulatory mechanism may advance our understanding of the maintenance of lung cancer phenotypes and uncover a novel therapeutic intervention point for tumors driven by HMGA1 ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Stewart, Sage, Enfield, Marshall, Cohn and Lam.)

Objective: The aim of this study was to analyze perceptions and experiences of clinicians implementing the patient-centered medical home (PCMH)., Background: The PCMH model focuses on several important concepts, including team-based care management as well as care coordination and continuity among providers and across settings of care., Methods: A qualitative analysis of data collected in 2016 from primary care personnel through a national survey was conducted., Results: Four themes were found consistent with care management and care coordination: the importance of teamwork and optimized team member roles, need for adequate prioritization of care management and care coordination, need to refine tools and resources supporting care management and care coordination, and challenges with managing and coordinating care with and across complex systems., Conclusions: Successful implementation requires adequate support for teamwork and ensuring team members can work according to their clinical competency. Nurses practicing in expanded roles need clear role guidelines and adequate time to function in these roles.

The tumour immune microenvironment is a crucial mediator of lung tumourigenesis, and characterizing the immune landscape of patient tumours may guide immunotherapy treatment regimens and uncover novel intervention points. We sought to identify the landscape of tumour-infiltrating immune cells in the context of long non-coding RNA (lncRNAs), known regulators of gene expression. We examined the lncRNA profiles of lung adenocarcinoma (LUAD) tumours by interrogating RNA sequencing data from microdissected and non-microdissected samples (BCCRC and TCGA). Subsequently, analysis of single-cell RNA sequencing data from lung tumours and flow-sorted healthy peripheral blood mononuclear cells identified lncRNAs in immune cells, highlighting their biological and prognostic relevance. We discovered lncRNA expression patterns indicative of regulatory relationships with immune-related protein-coding genes, including the relationship between AC008750.1 and NKG7 in NK cells. Activation of NK cells in vitro was sufficient to induce AC008750.1 expression. Finally, siRNA-mediated knockdown of AC008750.1 significantly impaired both the expression of NKG7 and the anti-tumour capacity of NK cells. We present an atlas of cancer-cell extrinsic immune cell-expressed lncRNAs, in vitro evidence for a functional role of lncRNAs in anti-tumour immune activity, which upon further exploration may reveal novel clinical utility as markers of immune infiltration.

Purpose: Patient engagement has been broadly defined as the process of actively involving and supporting patients in health care and treatment decision making. The aim of this study was to identify organizational factors that are associated with greater use of patient engagement care practices in Veterans Health Administration primary care clinics., Methods: We conducted a cross-sectional analysis of data from the 2016 Patient-Aligned Care Team (PACT) national survey of direct care clinicians (primary care clinicians, registered nurses, and clinical associates). Exploratory factor analysis was used to group conceptually related patient engagement survey items into 3 subscales: planning and goal setting; motivational interviewing; and organizational strategies to promote self-management. Our independent variables included literature-based factors reported to promote team-based care and interdisciplinary collaboration in primary care. We used generalized estimating equations with multivariate logistic regression analysis to identify independent correlates of high performance on each patient engagement domain (top 25th vs bottom 25th percentile)., Results: A total of 2,478 direct care clinicians from 609 clinics completed all patient engagement items in the PACT survey. For all patient engagement sub-scales, respondents at high-performing clinics were more likely to report having regular team meetings to discuss performance improvement and having leadership responsible for implementing PACT. For 2 of 3 patient engagement subscales, high performance was also associated with having fully staffed PACT teams (≥3 team members per primary care clinician) and role clarity., Conclusions: Several desirable organizational and contextual factors were associated with high performance of patient engagement care practices. Strategies to improve the organizational functioning of primary care teams may enhance patient engagement in care., (© 2020 Annals of Family Medicine, Inc.)

Head and neck squamous cell carcinoma (HNSCC) has a poor survival rate mainly due to late stage diagnosis and recurrence. Despite genomic efforts to identify driver mutations and changes in protein-coding gene expression, developing effective diagnostic and prognostic biomarkers remains a priority to guide disease management and improve patient outcome. Recent reports of previously-unannotated microRNAs (miRNAs) from multiple somatic tissues have raised the possibility of HNSCC-specific miRNAs. In this study, we applied a customized in-silico analysis pipeline to identify novel miRNAs from raw small-RNA sequencing datasets from public repositories. We discovered 146 previously-unannotated sequences expressed in head and neck samples that share structural properties highly characteristic of miRNAs. The combined expression of the novel miRNAs revealed tissue and context-specific patterns. Furthermore, comparison of tumor with non-malignant tissue samples ( n = 43 pairs) revealed 135 of these miRNAs as differentially expressed, most of which were overexpressed or exclusively found in tumor samples. Additionally, a subset of novel miRNAs was significantly associated with HPV infection status and patient outcome. A prognostic-model combining novel and known miRNA was developed (multivariate Cox regression analysis) leading to an improved death and relapse risk stratification (log rank p < 1e-7). The presence of these miRNAs was corroborated both in an independent dataset and by RT-qPCR analysis, supporting their potential involvement in HNSCC. In this study, we report the discovery of 146 novel miRNAs in head and neck tissues and demonstrate their potential biological significance and clinical relevance to head and neck cancer, providing a new resource for the study of HNSCC., (Copyright © 2019 Rock, Minatel, Marshall, Guisier, Sage, Barros-Filho, Stewart, Garnis and Lam.)

Recent studies have uncovered microRNAs (miRNAs) that have been overlooked in early genomic explorations, which show remarkable tissue- and context-specific expression. Here, we aim to identify and characterize previously unannotated miRNAs expressed in gastric adenocarcinoma (GA). Raw small RNA-sequencing data were analyzed using the miRMaster platform to predict and quantify previously unannotated miRNAs. A discovery cohort of 475 gastric samples (434 GA and 41 adjacent nonmalignant samples), collected by The Cancer Genome Atlas (TCGA), were evaluated. Candidate miRNAs were similarly assessed in an independent cohort of 25 gastric samples. We discovered 170 previously unannotated miRNA candidates expressed in gastric tissues. The expression of these novel miRNAs was highly specific to the gastric samples, 143 of which were significantly deregulated between tumor and nonmalignant contexts ( p -adjusted < 0.05; fold change > 1.5). Multivariate survival analyses showed that the combined expression of one previously annotated miRNA and two novel miRNA candidates was significantly predictive of patient outcome. Further, the expression of these three miRNAs was able to stratify patients into three distinct prognostic groups ( p = 0.00003). These novel miRNAs were also present in the independent cohort (43 sequences detected in both cohorts). Our findings uncover novel miRNA transcripts in gastric tissues that may have implications in the biology and management of gastric adenocarcinoma.

Introduction: The sponging of microRNAs by a long non-coding RNA (lncRNA) away from their coding gene targets is a conceptually-simple, yet biologically-complex method of lncRNA-mediated gene regulation. Currently, predictions of genes that participate in sponge-based regulation are largely based on sequence homology alone, which may not adequately reflect the cellular environment in which lncRNA:miRNA pairs interact. The vast number of potential interactions generated by these predictions impedes the identification of functional gene regulatory relationships, which necessitates an approach that considers biological context. XIST, the female-specific lncRNA canonically involved in silencing the X chromosome, has been suggested by many studies to act as a miRNA sponge. The sex-specificity of XIST provides the opportunity to study the biological feasibility of proposed XIST-miRNA interactions. Here we take a comprehensive approach by considering factors that affect possible regulation through XIST-miRNA sponging., Results: To identify the most feasible candidates in a particular tissue (lung adenocarcinomas), we considered protein-coding genes that (1) were positively correlated with XIST expression within sexes, (2) were targeted by miRNAs shared with XIST, and (3) expressed in lung adenocarcinoma. This revealed a robust set of 124 genes potentially positively regulated by XIST through the sequestration of 804 shared miRNAs. We then used the basic sex-specific nature of XIST to compare the changes in miRNA-target gene relationships in endogenously high-XIST and low-XIST systems to discover a high-confidence set of only 13 miRNA-gene pairs. As XIST is expressed exclusively in the nucleus, we validated the nuclear presence of several of these high-confidence miRNAs using RT-qPCR, confirming the co-localization required for XIST to interact with these species., Conclusions: We use a biology-driven approach to identify genes defended from miRNA-based inhibition by the lncRNA XIST. Importantly, we identify that only a small subset of miRNAs predicted by sequence homology alone have the capacity to mediate the XIST-target gene axis, as they are enriched in the nucleus and able to co-localize with XIST for sponging. Our results reinforce the necessary consideration of biological features in future studies of lncRNA:miRNA interactions., Competing Interests: The authors have declared that no competing interests exist.

Background: Though much is known about the benefits attributed to medical scribes documenting patient visits (e.g., reducing documentation time for the provider, increasing patient-care time, expanding the roles of licensed and non-licensed personnel), little attention has been paid to how care workers enact scribing as a part of their existing practice. The purpose of this study was to perform an ethnographic process evaluation of an innovative medical scribing practice with primary care teams in Veterans Health Administration (VHA) clinics across the United States. The aim of our study was to understand barriers and facilitators to implementing a scribing practice in primary care., Methods: At three to six months after medical scribing was introduced, we used semi-structured interviews and direct observations during site visits to five sites to describe the intervention, understand if the intervention was implemented as planned, and to record the experience of the teams who implemented the intervention. This manuscript only reports on semi-structured interview data collected from providers and scribes. Initial matrix analysis based on categories outlined in the evaluation plan informed subsequent deductive coding using the social-shaping theory Normalization Process Theory., Results: Through illustrating the slow accumulation of interactions and knowledge that fostered cautious momentum of teams working to normalize scribing practice in VHA primary care clinics, we show how the practice had 1) an organizing effect, as it centered a shared goal (the creation of the note) between the provider, scribe, and patient, and 2) a generative effect, as it facilitated care workers developing relationships that were both interpersonally and inter-professionally valuable. Based on our findings, we suggest that a scribing practice emphasizes the complementarity of existing professional roles, which thus leverage the interactional possibilities already present in the primary care team. Scribing, as a skill, forged moments of interprofessional fit. Scribing, in practice, created opportunities for interpersonal connection., Conclusions: Our research suggests that individuals will notice different benefits to scribing based on their professional expectations and organizational roles related to documenting patient visits.

Transcriptome sequencing has led to the widespread identification of long non-coding RNAs (lncRNAs). Subsequently, these genes have been shown to hold functional importance in human cellular biology, which can be exploited by tumors to drive the hallmarks of cancer. Due to the complex tertiary structure and unknown binding motifs of lncRNAs, there is a growing disparity between the number of lncRNAs identified and those that have been functionally characterized. As such, lncRNAs deregulated in cancer may represent critical components of cancer pathways that could serve as novel therapeutic intervention points. Pseudogenes are non-coding DNA sequences that are defunct relatives of their protein-coding parent genes but retain high sequence similarity. Interestingly, certain lncRNAs expressed from pseudogene loci have been shown to regulate the protein-coding parent genes of these pseudogenes in trans particularly because of this sequence complementarity. We hypothesize that this phenomenon occurs more broadly than previously realized, and that aberrant expression of lncRNAs overlapping pseudogene loci provides an alternative mechanism of cancer gene deregulation. Using RNA-sequencing data from two cohorts of lung adenocarcinoma, each paired with patient-matched non-malignant lung samples, we discovered 104 deregulated pseudogene-derived lncRNAs. Remarkably, many of these deregulated lncRNAs (i) were expressed from the loci of pseudogenes related to known cancer genes, (ii) had expression that significantly correlated with protein-coding parent gene expression, and (iii) had lncRNA protein-coding parent gene expression that was significantly associated with survival. Here, we uncover evidence to suggest the lncRNA-pseudogene-protein-coding gene axis as a prominent mechanism of cancer gene regulation in lung adenocarcinoma, and highlights the clinical utility of exploring the non-coding regions of the cancer transcriptome.

Multiple team membership is common in today's team-based organizations, but little is known about its relationship with collective effectiveness across teams. We adopted a microfoundations framework utilizing existing individual- and team-level research to develop a higher-level perspective on multiple team membership's relationship with performance of entire units of teams. We tested our predictions with data collected from 849 primary care units of the Veterans Health Administration serving over 4.2 million patients. In this context, we found multiple team membership is negatively associated with unit performance, and this negative relationship is exacerbated by task complexity. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

In this article, we report a qualitative case study, in which we examined enablers and barriers related to the development, implementation, and sustainability of a comprehensive school physical activity program (CSPAP) aligned with the Health Optimizing Physical Education (HOPE) curriculum model at a middle school. Literature on program-diffusion and school-university partnerships guided data collection and analysis. Data sources included semi-structured interviews with the program implementation team (n = 9) and the school's health and physical education teachers (n = 7); a focus group interview with students; documents (e.g., lesson plans), and observations. Constant comparison techniques were used to code and draw out themes from the data. Findings revealed the extensive effort needed for program implementation and highlighted the importance of strong external support mechanisms, conducting needs assessments, and training teachers to market physical activity programming. Partnerships may provide critical support for schools in their efforts to generate and sustain CSPAPs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Despite advancements in therapeutic strategies, diagnostic and prognostic molecular markers of kidney cancer remain scarce, particularly in patients who do not harbour well-defined driver mutations. Recent evidence suggests that a large proportion of the human noncoding transcriptome has escaped detection in early genomic explorations. Here, we undertake a large-scale analysis of small RNA-sequencing data from both clear cell renal cell carcinoma (ccRCC) and nonmalignant samples to generate a robust set of miRNAs that remain unannotated in kidney tissues. We find that these novel kidney miRNAs are also expressed in renal cancer cell lines. Moreover, these sequences are differentially expressed between ccRCC and matched nonmalignant tissues, implicating their involvement in ccRCC biology and potential utility as tumour-specific markers of disease. Indeed, we find some of these miRNAs to be significantly associated with patient survival. Finally, target prediction and subsequent pathway analysis reveals that miRNAs previously unannotated in kidney tissues may target genes involved in ccRCC tumourigenesis and disease biology. Taken together, our results represent a new resource for the study of kidney cancer and underscore the need to characterize the unexplored areas of the transcriptome.

Chronic exposure to arsenic affects more than 200 million people worldwide, and has been associated with many adverse health effects, including cancer in several organs. There is accumulating evidence that arsenic biotransformation, a step in the elimination of arsenic from the human body, can induce changes at a genetic and epigenetic level, leading to carcinogenesis. At the genetic level, arsenic interferes with key cellular processes such as DNA damage-repair and chromosomal structure, leading to genomic instability. At the epigenetic level, arsenic places a high demand on the cellular methyl pool, leading to global hypomethylation and hypermethylation of specific gene promoters. These arsenic-associated DNA alterations result in the deregulation of both oncogenic and tumour-suppressive genes. Furthermore, recent reports have implicated aberrant expression of non-coding RNAs and the consequential disruption of signaling pathways in the context of arsenic-induced carcinogenesis. This article provides an overview of the oncogenomic anomalies associated with arsenic exposure and conveys the importance of non-coding RNAs in the arsenic-induced carcinogenic process.

International implementation of the patient-centered medical home (PCMH) model for delivering primary care has dramatically increased in the last decade. A majority of research on PCMH's impact has emphasized the care provided by clinically trained staff. In this article, we report our ethnographic analysis of data collected from Department of Veterans Affairs staff implementing PACT, the VA version of PCMH. Teams were trained to use within-team delegation, largely accomplished through attention to clinical licensure, to differentiate staff in providing efficient, patient-centered care. In doing so, PACT may reinforce a clinically defined culture of care that countermands PCMH ideals. Such competing rubrics for care are brought into relief through a focus on the care work performed by clerks. Ethnographic analysis identifies clerks' care as a kind of emotional dirty work, signaling important areas for future anthropological study of the relationships among patient-centered care, stigma, and clinical authority., (© 2016 by the American Anthropological Association.)

Background: A particularly useful model for examining implementation of quality improvement interventions in health care settings is the PARIHS (Promoting Action on Research Implementation in Health Services) framework developed by Kitson and colleagues. The PARIHS framework proposes three elements (evidence, context, and facilitation) that are related to successful implementation., Purposes: An evidence-based program focused on quality enhancement in health care, termed TeamSTEPPS (Team Strategies and Tools to Enhance Performance and Patient Safety), has been widely promoted by the Agency for Healthcare Research and Quality, but research is needed to better understand its implementation. We apply the PARIHS framework in studying TeamSTEPPS implementation to identify elements that are most closely related to successful implementation., Methodology/approach: Quarterly interviews were conducted over a 9-month period in 13 small rural hospitals that implemented TeamSTEPPS. Interview quotes that were related to each of the PARIHS elements were identified using directed content analysis. Transcripts were also scored quantitatively, and bivariate regression analysis was employed to explore relationships between PARIHS elements and successful implementation related to planning activities., Findings: The current findings provide support for the PARIHS framework and identified two of the three PARIHS elements (context and facilitation) as important contributors to successful implementation., Practice Implications: This study applies the PARIHS framework to TeamSTEPPS, a widely used quality initiative focused on improving health care quality and patient safety. By focusing on small rural hospitals that undertook this quality improvement activity of their own accord, our findings represent effectiveness research in an understudied segment of the health care delivery system. By identifying context and facilitation as the most important contributors to successful implementation, these analyses provide a focus for efficient and effective sustainment of TeamSTEPPS efforts.

Deregulation of the imprinted DLK1-DIO3 locus at chromosome 14q32.1-14q32.31 has been associated with developmental and respiratory disorders, including cancer. In lung cancer, deregulation of imprinting at DLK1-DIO3 was recently described in smokers. Deregulated expression of a microRNA (miRNA) cluster mapping to this locus was also associated with patient outcome, suggesting the importance of this locus to lung cancer disease phenotypes. The DLK1-DIO3 locus is complex, and encodes several protein-coding genes, in addition to long and short non-coding RNAs. While the role of miRNAs is established, the biological importance of another relevant class of small RNAs, PIWI-interacting RNAs (piRNAs), has not been investigated. When somatically expressed, piRNAs regulate gene transcription through DNA methylation. Interestingly, their expression patterns have been observed to be altered in cancer and correlated with patient outcome. Here, we characterize the somatic expression of piRNAs encoded at DLK1-DIO3 in two independent cohorts of lung adenocarcinoma and lung squamous cell carcinoma and investigate their associations with patient outcome. We find that the expression of piRNAs encoded at DLK1-DIO3 enhances the prognostic potential of small non-coding RNAs specific to this locus in predicting patient outcome, further emphasizing the importance of regulation at this locus in lung cancer.

Research evaluating the effectiveness, function, and implementation of patient-centered medical homes (PCMHs) has found major socioprofessional transformations and contributions of primary care physicians and, to a lesser degree, nurses. Our longitudinal ethnographic research with teams implementing PCMH in Veterans Health Administration (VHA) primary care identifies the important but largely underutilized contributions of clerks to PCMH outcomes. Although the relationship of high-performing clerical staff to patient satisfaction is widely acknowledged, PCMH can be further enhanced by enabling clerks to use administrative tasks as conduits for investing in long-term personalized relationships with patients that foster trust in the PCMH and the broader health care organization. Such relationships are engendered through the care-coordination activities clerks perform, which may be bolstered by organizational investment in clerks as skilled health care team members., (© 2016 Annals of Family Medicine, Inc.)

Small and rural hospitals face special challenges to implement and sustain organization-wide quality improvement (QI) initiatives due to limited resources and infrastructures. We studied the implementation of TeamSTEPPS, a national QI initiative, in 14 critical access hospitals. Drawing on QI and organization development theories, we propose five strategic preparation steps for TeamSTEPPS: assess needs, reflect on the context, set goals, develop a shared understanding, and select change agents. We explore how hospitals' practices correspond to suggested best practices by analyzing qualitative data collected through quarterly interviews with key informants. We find that the level of deliberation was a key factor that differentiated hospitals' practices. Hospitals that were more deliberate in preparing for the five strategic steps were more likely to experience engagement, perceive efficacy, foresee and manage barriers, and achieve progress during implementation. We discuss potential steps that hospitals may take to better prepare for TeamSTEPPS implementation., (© The Author(s) 2015.)

Although interdependence is a central aspect of team design, there has been a lack of clarity regarding the meaning and impact of different forms of interdependence. To provide theoretical clarity and to advance research on team interdependence, we develop an organizing, conceptual framework of interdependence in teams and test it using meta-analysis. We first review and tie together different conceptualizations of interdependence in the literature and illustrate how they converge around 2 major constructs: task interdependence and outcome interdependence. After providing integrative definitions of these forms of interdependence, as well as subdimensions, we then explore the relative effects of task and outcome interdependence on team functioning and performance. Specifically, we propose a pattern of differential effects in which task interdependence is primarily associated with team performance through its effects on task-focused team functioning (i.e., transition/action processes, collective efficacy), whereas outcome interdependence is primarily associated with team performance through its effects on relational team functioning (i.e., interpersonal processes, cohesion). We test these differential effects using a meta-analytic database of 107 independent samples and 7,563 teams. The meta-analytic path model provides strong support for our hypotheses. Implications and future directions for the study of interdependence in work teams are discussed., ((c) 2015 APA, all rights reserved).)

Objective: The experiences of RNs and licensed practical nurses (LPNs) implementing a patient-centered medical home (PCMH) in the Department of Veterans Affairs (VA) primary care clinics were examined to understand model implications for nursing practice and professional identity., Background: National implementation of the PCMH model, called patient-aligned care teams (PACTs) in VA, emphasizes areas of nursing expertise, yet little is known about the effect of medical homes on the day-to-day work of nurses., Methods: As part of a formative evaluation to identify barriers and facilitators to PACT implementation, we interviewed 18 nurses implementing PACT., Results: Challenges to nurse's organizational and professional roles were experienced differently by RNs and LPNs in the following areas: (1) diversified modes of care and expanded clinical duties, (2) division of labor among PACT nurses, and (3) interprofessional status in the team., Conclusions: Healthcare managers implementing PCMH should consider its inherent cultural and practice transformations.

Implementation of TeamSTEPPS for improving patient safety is examined via descriptive qualitative analysis of semistructured interviews with 21 informants at 12 hospitals. Implementation approaches fit 3 strategies: top-down, bottom-up, and combination. The top-down approach failed to develop enough commitment to spread implementation. The bottom-up approach was unable to marshal the resources necessary to spread implementation. Combining top-down and bottom-up processes best facilitated the implementation and spread of the TeamSTEPPS safety initiative.

Purpose: Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) is being widely promoted in healthcare settings to train staff in evidence-based approaches that promote patient safety. It involves a comprehensive curriculum that spells out key principles and actionable tools for a culture change toward patient-safety-focussed teamwork. Activities begin with selected personnel attending TeamSTEPPS Master Trainer Training (MTT) and then organizing and providing TeamSTEPPS training for staff in their organization. The authors conducted interviews with respondents at community hospitals conducting TeamSTEPPS staff training. To structure the interviews, the authors used 11 key questions identified by Weaver et al. in their in-depth team training literature review. The purpose of this paper is to examine approaches taken by community hospital personnel and compare those to the best practices recommended by Weaver et al., Design/methodology/approach: The authors interviewed 57 staff and administrators at 22 community hospitals sending teams to TeamSTEPPS MTT., Findings: The authors find that training implementation in community hospitals differs significantly from the established, research-based principles for effective team training described in the research literature, which is largely based in academic medical centers., Originality/value: The current findings suggest that several TeamSTEPPS training features could be enhanced in community hospitals including: choosing staff who have the skills to be effective trainers in this train-the-trainer model; emphasizing active learning; and sustaining lessons through on-the-job application, practice and feedback. These principles apply to many training approaches employed in small healthcare organizations.

In this paper we present results of a mixed methods study conducted to identify barriers to team function among staff implementing patient aligned care teams - the Department of Veterans Affairs' patient centered medical home (PCMH) model. Using a convergent mixed methods design, we administered a standardized survey measure (Team and Individual Role Perception Survey) to assess work role challenge and engagement; and conducted discussion groups to gather context pertaining to role change. We found that the role of primary care providers is highly challenging and did not become less difficult over the initial year of implementation. Unexpectedly over the course of the first year nurse care managers reported a decrease in their perceptions of empowerment and clerical associates reported less skill variety. Qualitative data suggest that more skilled team members fail to delegate and share tasks within their teams. We characterize this interprofessional knowledge factor as an empowerment paradox where team members find it difficult to share tasks in ways that are counter to traditionally structured hierarchical roles. Health care systems seeking to implement PCMH should dedicate resources to facilitating within-team role knowledge and negotiation.

Implementation of a patient centered medical home challenges primary care providers to change their scheduling practices to enhance patient access to care as well as to learn how to use performance metrics as part of a self-reflective practice redesign culture. As medical homes become more commonplace, health care administrators and primary care providers alike are eager to identify barriers to implementation. The objective of this study was to identify non-technological barriers to medical home implementation from the perspective of primary care providers. We conducted qualitative interviews with providers implementing the medical home model in Department of Veterans Affairs clinics-the most comprehensive rollout to date. Primary care providers reported favorable attitudes towards the model but discussed the importance of data infrastructure for practice redesign and panel management. Respondents emphasized the need for administrative leadership to support practice redesign by facilitating time for panel management and recognizing providers who utilize non-face-to-face ways of delivering clinical care. Health care systems considering adoption of the medical home model should ensure that they support both technological capacities and vertically aligned expectations for provider performance., (Published by Elsevier Inc.)

Background: The patient-centered medical home (PCMH) relies on a team approach to patient care. For organizations engaged in transitioning to a PCMH model, identifying and providing the resources needed to promote team functioning is essential., Objective: To describe team-level resources required to support PCMH team functioning within the Veterans Health Administration (VHA), and provide insight into how the presence or absence of these resources facilitates or impedes within-team delegation., Design: Semi-structured interviews with members of pilot teams engaged in PCMH implementation in 77 primary care clinics serving over 300,000 patients across two VHA regions covering the Mid-Atlantic and Midwest United States., Participants: A purposive sample of 101 core members of pilot teams, including 32 primary care providers, 42 registered nurse care managers, 15 clinical associates, and 12 clerical associates., Approach: Investigators from two evaluation sites interviewed frontline primary care staff separately, and then collaborated on joint analysis of parallel data to develop a broad, comprehensive understanding of global themes impacting team functioning and within-team delegation., Key Results: We describe four themes key to understanding how resources at the team level supported ability of primary care staff to work as effective, engaged teams. Team-based task delegation was facilitated by demarcated boundaries and collective identity; shared goals and sense of purpose; mature and open communication characterized by psychological safety; and ongoing, intentional role negotiation., Conclusions: Our findings provide a framework for organizations to identify assets already in place to support team functioning, as well as areas in need of improvement. For teams struggling to make practice changes, our results indicate key areas where they may benefit from future support. In addition, this research sheds light on how variation in medical home implementation and outcomes may be associated with variation in team-based task delegation.

Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation.

Identification of novel proteins that can potentially contribute to carcinogenesis is a requisite venture. Herein, we report the first biochemical characterization of the novel F-box and WD40 containing protein, FBXW4. We have identified interacting protein partners and demonstrated that FBXW4 is part of a ubiquitin ligase complex. Furthermore, the Fbxw4 locus is a common site of proviral insertion in a variety of retroviral insertional mutagenesis murine cancer models and Fbxw4 mRNA is highly expressed in the involuting murine mammary gland. To begin to characterize the biochemical function of Fbxw4, we used proteomic analysis to demonstrate that Fbxw4 interacts with Skp1 (SKP1), Cullin1 (CUL1), Ring-box1 (RBX1) and all components of the COP9 signalosome. All of these interactions are dependent on an intact F-box domain of Fbxw4. Furthermore, Fbxw4 is capable of interacting with ubiquitinated proteins within cells in an F-box dependent manner. Finally, we demonstrate that FBXW4 is mutated, lost and under-expressed in a variety of human cancer cell lines and clinical patient samples. Importantly, expression of FBXW4 correlates with survival of patients with non-small cell lung cancer. Taken together, we suggest that FBXW4 may be a novel tumor suppressor that regulates important cellular processes.

Background: The Veterans Health Administration (VHA) is changing its primary care delivery by implementing the patient-centered medical home (PCMH)., Objectives: To evaluate PCMH implementation among 22 newly formed teams working in the VHA., Study Design: Longitudinal formative evaluation of team members' role transformation during the first 18 months of implementation., Methods: We used 3 sequential, semistructured focus groups to gather data from 4 different groups representing the principal team member roles: primary care providers, registered nurse care managers, licensed practical nurses, and clerical associates., Results: Team members identified within-team role and interpersonal conflict, as well as discordant administrative leadership styles, as key implementation challenges., Conclusions: Our results suggest that, in addition to technological and fiscal infrastructure, healthcare leaders implementing the PCMH model must take into account interprofessional issues associated with changes in leadership and the adoption of team-based structures.

The authors use a multilevel framework to introduce peer-based control as a motivational state that emerges in self-managing teams. The authors specifically describe how peer-based rational control, which is defined as team members perceiving the distribution of economic rewards as dependent on input from teammates, extends and interacts with the more commonly studied normative control force of group cohesion to explain both individual and collective performance in teams. On the basis of data from 587 factory workers in 45 self-managing teams at 3 organizations, peer-based rational control corresponded with higher performance for both individuals and collective teams. Results further demonstrated that the rational and normative mechanism of peer-based control interacted to explain performance at both the individual and team levels. Increased peer-based rational control corresponded with higher individual and collective performance in teams with low cohesion, but the positive effects on performance were attenuated in cohesive teams.

Oral epithelial dysplasias are believed to progress through a series of histopathological stages; from mild to severe dysplasia, to carcinoma in situ, and finally to invasive OSCC. Underlying this change in histopathological grade are gross chromosome alterations and changes in gene expression of both protein-coding genes and non-coding RNAs. Recent papers have described associations of aberrant expression of microRNAs, one class of non-coding RNAs, with oral cancer. However, expression profiling of long non-coding RNAs (lncRNAs) has not been reported. Long non-coding RNAs are a novel class of mRNA-like transcripts with no protein coding capacity, but with a variety of functions including roles in epigenetics and gene regulation. In recent reports, the aberrant expression of lncRNAs has been associated with human cancers, suggesting a critical role in tumorigenesis. Here, we present the first long non-coding RNA expression map for the human oral mucosa. We describe the expression of 325 long non-coding RNAs, suggesting lncRNA expression contributes significantly to the oral transcriptome. Intriguingly, ∼60% of the detected lncRNAs show aberrant expression in oral premalignant lesions. A number of these lncRNAs have been previously associated with other human cancers., (Copyright © 2011 Elsevier Ltd. All rights reserved.)