New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes.

Notch signaling is an evolutionary conserved pathway that is mediated by cell-cell contact. It is involved in a variety of developmental processes and has an essential role in vascular development and angiogenesis. Delta-like 4 (Dll4) is a Notch ligand that is up-regulated during angiogenesis. It is expressed in endothelial cells and regulates the differentiation between tip cells and stalk cells of neovasculature. Here, we present evidence that Dll4 is incorporated into endothelial exosomes. It can also be incorporated into the exosomes of tumor cells that overexpress Dll4. These exosomes can transfer the Dll4 protein to other endothelial cells and incorporate it into their cell membrane, which results in an inhibition of Notch signaling and a loss of Notch receptor. Transfer of Dll4 was also shown in vivo from tumor cells to host endothelium. Addition of Dll4 exosomes confers a tip cell phenotype on the endothelial cell, which results in a high Dll4/Notch-receptor ratio, low Notch signaling, and filopodia formation. This was further evidenced by increased branching in a tube-formation assay and in vivo. This reversal in phenotype appears to enhance vessel formation and is a new form of signaling for Notch ligands that expands their signaling potential beyond cell-cell contact

A computational framework for testing hypotheses of the minimal mechanical requirements for cell aggregation using early annual killifish embryogenesis as a model

Introduction: Deciphering the biological and physical requirements for the outset of multicellularity is limited to few experimental models. The early embryonic development of annual killifish represents an almost unique opportunity to investigate de novo cellular aggregation in a vertebrate model. As an adaptation to seasonal drought, annual killifish employs a unique developmental pattern in which embryogenesis occurs only after undifferentiated embryonic cells have completed epiboly and dispersed in low density on the egg surface. Therefore, the first stage of embryogenesis requires the congregation of embryonic cells at one pole of the egg to form a single aggregate that later gives rise to the embryo proper. This unique process presents an opportunity to dissect the self-organizing principles involved in early organization of embryonic stem cells. Indeed, the physical and biological processes required to form the aggregate of embryonic cells are currently unknown.Methods: Here, we developed an in silico, agent-based biophysical model that allows testing how cell-specific and environmental properties could determine the aggregation dynamics of early Killifish embryogenesis. In a forward engineering approach, we then proceeded to test two hypotheses for cell aggregation (cell-autonomous and a simple taxis model) as a proof of concept of modeling feasibility. In a first approach (cell autonomous system), we considered how intrinsic biophysical properties of the cells such as motility, polarity, density, and the interplay between cell adhesion and contact inhibition of locomotion drive cell aggregation into self-organized clusters. Second, we included guidance of cell migration through a simple taxis mechanism to resemble the activity of an organizing center found in several developmental models.Results: Our numerical simulations showed that random migration combined with low cell-cell adhesion is sufficient to maintain cells in dispersion and that aggregation can indeed arise spontaneously under a limited set of conditions, but, without environmental guidance, the dynamics and resulting structures do not recapitulate in vivo observations.Discussion: Thus, an environmental guidance cue seems to be required for correct execution of early aggregation in early killifish development. However, the nature of this cue (e.g., chemical or mechanical) can only be determined experimentally. Our model provides a predictive tool that could be used to better characterize the process and, importantly, to design informed experimental strategies

Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis

Reprogrammed glucose metabolism as a result of increased glycolysis and glucose uptake is a hallmark of cancer. Here we show that cancer cells can suppress glucose uptake by non-tumour cells in the pre-metastatic niche, by secreting vesicles that carry high levels of the miR-122 microRNA. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the pre-metastatic niche. Mechanistically cancer-cell-derived miR-122 suppresses glucose uptake by niche cells in vitro and in vivo by downregulating the glycolytic enzyme pyruvate kinase (PKM). In vivo inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases the incidence of metastasis. These results demonstrate that by modifying glucose utilization by recipient pre-metastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression

Audit quality : how can "high" audit quality be explained according to its various stakeholders perspective?

De senaste åren har vikten av en trovärdig finansiell rapportering av hög revisionskvalité lyfts fram. En högre kvalité säkerställs genom att besluta om gemensamma regler och principer för revisionsbyråer. Intresset av revisionen är olika och således finns olika syn på syftet med revisionen och vad den bör innehålla. Tolkningsskillnaderna gör att hög revisionskvalité upplevs olika.   Syftet med vår undersökning är att förklara ”hög” revisionskvalité utifrån revisorers och revisionens olika intressenters perspektiv samt att identifiera eventuella skillnader mellan revisorernas och dessa intressenters syn.   En kvantitativ ansats har använts och utifrån teorin har sex hypoteser skapats. Hypoteserna undersöker om det finns skillnader mellan revisorer och revisionens intressenter om vad hög revisionskvalité är. Genom en webbenkät fick respondenterna bedöma i vilken utsträckning 28 variabler leder till högre revisionskvalité.    Med undersökningen har vi funnit bevis för att det finns skillnader i uppfattningen om hur hög revisionskvalité uppnås mellan revisorer och intressenterna. Skillnader uppmättes för följande kategorier; revisorns oberoende, revisorns egenskaper, en god kommunikation och extern kontroll. Vi har också kunnat urskilja enskilt viktiga kvalitetsvariabler.   Eftersom författarna av denna uppsats inte har funnit någon tidigare studie som tittat på skillnader mellan revisorerna och studiens tre utvalda intressentgrupper i vad som leder till hög revisionskvalité, kan resultatet hjälpa till att sprida ljus över detta område. Resultatet kan också vara användbart för att se hur revisorerna och intressenterna ska närma sig varandra för att uppnå en trovärdigare revision. In recent years, the importance of a credible financial report of high quality, have been highlighted. A high audit quality is ensured by the adoption of common rules and principles for accounting firms. The interest of the audit is different and therefore are there different views on the purpose and what the audit should contain. Interpreting differences allows high quality to be perceived different.   The aim of our study is to explain the “high” audit quality by auditors and audit stakeholders’ perspectives and to identify any differences between the auditors and those stakeholders’ views.   A quantitative approach has been used and based on the theory has six hypotheses been created. The hypotheses investigate whether there are differences between auditors and audit stakeholders on what the high level of audit quality is. Through a web survey, respondents were assessing the extent to which 28 variables leads to higher audit quality.   In our study we found evidence that there are differences in perceptions of the high level of audit quality is achieved between the auditors and stakeholders. Differences were measured for the following categories: auditor independence, auditor characteristics, good communication and external control. We have also been able to distinguish individual key quality variables.   Since the authors of this paper haven’t found any previous study that looked at the differences between the auditors and this study’s three selected stakeholder groups in what leads to high audit quality, the result may help to give light on this area. The results can also be useful to see how auditors and stakeholders should approach each over to achieve a credible audit.

Hur kommersiella är vi? : en studie om hur identitet påverkar revisorernas uppfattning av kommersialisering i revisionsbyråerna.

Aim: The aim of this study is to explain how professional and organisational identity influence auditors’ perception of commercialisation in audit firms. The purpose is to see if there are possible differences between these identities and how they influence auditors’ perception of commercialisation in audit firms and if this perception is positive or negative. Theoretical approach: Theory that focuses on commercialisation in especially marketing literature and theory regarding professional identify in foremost organisational research, have been used. Empirical Methodology: A quantitative approach was used to be able to analyse auditors’ response from a questionnaire. When analysing the data, Pearson correlation matrix and multiple linear regression have been used. 374 answers from participating auditors in Sweden have been analysed. Conclusions: The empirical result of this study suggests that both professional and organisational identity influence auditors’ perception of commercialisation in audit firms positively. Syfte: Syftet med denna studie är att förklara hur professionell och organisatorisk identitet påverkar revisorernas uppfattning av kommersialisering i revisionsbyråer. Vidare vill vi se om det finns eventuella skillnader mellan nämnda identiteter och hur de påverkar revisorernas uppfattning av kommersialisering i revisionsbyråer och om uppfattningen är positiv eller negativ. Teoretiskt perspektiv: Studien utgår ifrån marknadsföringslitteratur med fokus på kommersialisering samt teori om professionell identitet från främst organisatorisk forskning. Empirisk metod: En kvantitativ metod har använts för att kunna analysera revisorernas svar från en enkät. Vid analys av data har Pearson korrelationsmatris och multipel linjär analys använts. Totalt har 374 svar från revisorer i Sverige analyserats.   Resultat: Det empiriska resultatet av studien tyder på att både professionell och organisatorisk identitet har en positiv påverkan på revisorernas uppfattning av kommersialiseringen i revisionsbyråerna

Auditors’ professional and organisational identities and perceived commercialisation in audit firms

Purpose: The purpose of this paper is to explain how professional and organisational identities influence auditors’ perception of commercialisation in audit firms. Design/methodology/approach: The paper is based on a survey distributed to 3588 members of FAR, the professional institute for authorized public accountants, approved public accountants and other highly qualified professionals in the accountancy sector in Sweden, and answered by 374 of the professionals surveyed. Findings: Findings of the study indicate that commercialisation in audit firms is a three- dimensional construct consisting of market-, customer- and firm process orientations. The results of the study show that the stronger the auditors’ organisational identity, the more influence it has on auditors’ perception of all three dimensions of the increasing commercialisation of their firm. The increasing strength of that professional identity is shown to be reflected in the perception of their firm to be firm process oriented, while no effect is shown on the other two dimensions of commercialisation (market and customer orientations orientations). Originality/value: The paper presents a new conceptualisation and set of measures of audit firms’ commercialisation and shows how professional and organisational identities influence perception

Auditors professional and organizational identities and commercialization in audit firms

Purpose The purpose of this paper is to explain how auditors professional and organizational identities are associated with commercialization in audit firms. Unlike previous studies exploring the consequences of commercialization in the firms, the study directs its attention toward the potential driver of commercialization, which the authors argue to be the identities of the auditors. Design/methodology/approach The paper is based on 374 responses to a survey distributed to 3,588 members of FAR, the professional association of accountants, auditors and advisors in Sweden. The study used established measures of organizational and professional identity and introduced market, customer and firm process orientation as aspects of commercialization. The study explored the data through descriptive statistics, principle component analysis and correlation analysis and tested the hypotheses with multiple linear regression analysis. Findings The findings indicated that the organizational identity of auditors has a positive association with three aspects of commercialization: market orientation, customer orientation and firm process orientation. Contrary to the arguments based on prior literature, the study has found that the professional identity of auditors is also a positively associated with commercialization. This indicates a change of the role of professional identity vis-a-vis commercialization of audit firms. The positive association between professional identity and commercial orientation could indicate the development of organizational professionalism. The study also found differences between the association between professional identity and commercialization in Big 4 and non-Big 4 firms. While in Big 4 firms, professional identity is positively associated only with the firms process orientation, in non-Big 4 firms, professional identity has a positive association with all three aspects of commercialization. Originality/value The paper provides insight into how auditors identities have influenced commercialization of audit firms and into the normalizing of commercialization within auditing. The study also developed a new instrument for measuring commercialization, one based on market, customer and firm process orientation concepts. This paper suggests that this instrument is an alternative to the observation through proxies

Do both heterocyclic amines and omega-6 polyunsaturated fatty acids contribute to the incidence of breast cancer in postmenopausal women of the Malmö diet and cancer cohort?

Heterocyclic amines (HAs), formed when meat and fish are cooked at high temperatures, have been linked to mammary gland cancer in rats, and some epidemiological studies indicate increased breast cancer risk by consumption of well-done meat. The epidemiological evidence linking HAs per se to breast cancer is however sparse, especially from prospective studies. Moreover, high-fat diets rich in omega-6 polyunsaturated fatty acids (PUFAs) have produced higher frequencies of HA-induced mammary gland tumors in rats compared to those fed low-fat diets. The aim was to evaluate prospectively if intake of HAs is associated with breast cancer incidence, and if the association is independent of omega-6 PUFA intakes. Among women 50 years or older at baseline from the population-based prospective Malmö Diet and Cancer cohort (n = 11,699), 430 women were diagnosed with incident invasive breast cancer during a mean follow-up of 10.4 years. Information on dietary habits was collected by a modified diet history method. Cox proportional hazards regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with energy-adjusted intakes of HAs and omega-6 PUFA. Intakes of HAs were not associated with breast cancer incidence (HR, 0.94; 95% CI, 0.69-1.28, for highest compared to lowest quintile). In individuals with low HA intakes, a significant increased risk was observed among those with high intakes of omega-6 PUFAs. In conclusion, intakes of HAs are not associated with breast cancer incidence in this Swedish cohort, but dietary patterns very high in omega-6 PUFA may promote breast cancer development. (c) 2008 Wiley-Liss, Inc

Abstract 3386: Development of next generation extracellular vesicle based urine tests for prostate cancer

Abstract Introduction and Objective: Non-invasive urine and blood biomarkers are commercially available to assess the risk of clinically significant prostate cancer (csPCa) and the need for a biopsy. However, these tests are limited in their specificity resulting in a significant number of men still undergoing biopsy to avoid missing a csPCa. Exosomes and other extracellular vesicles (EVs) provide a platform for blood and urine biomarkers since they are released by all types of cells and preserve molecular constituents from their cells of origin within lipid membranes. The EPI urine test from Exosome Diagnostics (ExoDx) is currently the only commercially available EV based cancer diagnostic test; it uses three well established EV RNA markers to estimate the risk of csPCa. Studies by us and others have shown that an expanded urine EV PCa marker panel would improve disease stratification if these markers could be incorporated into a clinical grade assay. Our objective in this current study is to identify and characterize the EV RNA transcripts that are enriched by using antibodies for prostate specific membrane antigen (PSMA) to capture urinary EVs that originated from PCa cells. This is the first step in the development of a next generation urinary EV test with increased specificity for csPCa within a rigorous and reproducible assay format. Methods: Urine EVs from patients with csPCa and from healthy controls were prepared using the ExoDx clinical platform. These total EV samples were then compared with EVs enriched by immunocapture either with a PSMA specific antibody or with an isotype IgG control reagent. RNA was prepared from each of these three types of urinary EV samples and analyzed using RNAseq. Results: RNAseq analysis of urinary total EVs, PSMA-antibody captured EVs and isotype IgG control captured EVs showed excellent mapping to transcriptome regions. We detected over 600 genes differentially enriched by PSMA antibody vs. isotype IgG EV capture and identified 18 genes from a candidate list of prostate biomarkers that have been assembled based on previous studies. A principal component analysis of 196 differentially expressed transcripts obtained from EVs enriched by PSMA immunocapture vs IgG controls showed excellent discrimination between prostate cancer patients and healthy controls. By using a feature selection approach to optimize for discrimination between prostate cancer patients and healthy controls we identified a novel 6-gene signature that, when derived from a PSMA capture EV dataset, shows a superior AUC for the accuracy of cancer detection (greater than 0.95) than that obtained from applying the same 6-gene signature on total EVs or on isotype IgG controls. Conclusions: EV PSMA immuno-capture provides a robust approach to expanding the panel of PCa biomarkers that can be incorporated into clinical grade PCa urine EV assays, supporting the translation of pre-clinical discovery into clinical practice. Citation Format: Sandra M. Gaston, Douglas Roberts, Sudipto Chakrabortty, Emily Mitsock, Kailey Babcock, Rikky Xing, Benjamin Spieler, Radka Stoyanova, Mark L. Gonzalgo, Chad Ryan Ritch, Bruno Nahar, Alan Pollack, Dipen J. Parekh, Seth Yu, Johan Skog, Sanoj Punnen. Development of next generation extracellular vesicle based urine tests for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3386