Detection of Cellular Senescence Reveals the Existence of Senescent Tumor Cells within Invasive Breast Carcinomas and Related Metastases

Oncogene-induced senescence is thought to constitute a barrier to carcinogenesis by arresting cells at risk of malignant transformation. However, numerous findings suggest that senescent cells may conversely promote tumor growth and metastatic progression, for example, through the senescence-associated secretory phenotype (SASP) they produce. Here, we investigated the degree to which senescent tumor cells exist within untreated human primary breast carcinomas and whether the presence of senescent cancer cells in primary tumors is recapitulated in their matched lymph node metastases. For the detection of senescence, we used SA-β-galactosidase (SA-β-gal) staining and other senescence markers such as Ki67, p21, p53, and p16. In patients with invasive luminal A and B breast carcinomas, we found broad similarities in the appearance of cancer cells between primary tumors and their corresponding metastases. Analysis of lymph nodes from patients with other breast cancer subtypes also revealed senescent tumor cells within metastatic lesions. Collectively, our findings show that senescent tumor cells exist within primary breast carcinomas and metastatic lesions. These results suggest a potential role for senescent breast tumor cells during metastatic progression and raise the question as to whether the targeting of senescent tumor cells with anti-senescent drugs might represent a novel avenue for improved treatment of breast and other cancers

Proteasome inhibitors prevent bi-directional HER2/estrogen-receptor cross-talk leading to cell death in endocrine and lapatinib-resistant HER2+/ER+ breast cancer cells

Amplification and/or overexpression of the human epidermal growth factor 2 (HER2) oncogene occurs in about 13–15% of invasive breast cancer and triggers breast cancer cell proliferation, survival and metastatic progression. Around half of all breast cancers with HER2 overexpression co-express hormone receptors (HR) such as those for estrogen and progesterone. Aberrant signaling through HER2 and other members of the HER-family mediates endocrine-resistance in estrogen receptor alpha (ERα) positive breast cancer. On the other hand, ERα co-expression has been shown to attenuate the efficiency of anti-HER2 therapies. These findings indicate that HER2 and ERα synergize to escape from both anti-ERα and anti-HER2-targeted therapies. Rationally designed clinical trials that combine endocrine therapy with anti-HER2 agents to interfere with HER2/ERα cross-talk have been conducted. However, the outcome of these trials suggests that novel therapeutic approaches are needed to further improve inhibition of HER2 and other HER-family members in conjunction with a more efficient ERα blockade. Here, we demonstrate that carfilzomib and bortezomib stabilize the HER2-specific protein tyrosine phosphatase BDP1 leading to decreased HER2 autophosphorylation, reduced HER2 activity and subsequently attenuated activation of the PI3K/Akt-pathway, together with blockade of ERα expression. We further observed that proteasome inhibitors (PIs) reverse autophosphorylation and thereby inhibit the activity of constitutively active mutant HER2. We also demonstrate that PIs cause cell death in lapatinib and endocrine-resistant HER2+/ER+ breast cancer cells. These findings suggest that PIs might have the potential to improve the management of HER2+/ER+ breast cancer patients by efficiently disrupting the bi-directional HER2/ERα cross-talk

Diverging and Converging: Integrative Insights on a Paradox Meta-perspective

Paradox theory stands at an exciting moment in organization and management theory. Scholars increasingly seek out insights about the nature and management of contradictory demands to explain a wide array of organizational phenomena across multiple levels of analysis. Our two reviews in the 2016 Academy of Management Annals attest to this growing breadth and depth, each integrating and expanding related, yet different bodies of research. Schad, Lewis, Raisch, and Smith (2016) emphasize the depth of scholarship by analyzing an increasing number of paradox studies within management science. Putnam, Fairhurst, and Banghart (2016) highlight the breadth of scholarship by comparing paradoxes that emerge from multiple theories and paradigms that embrace an interdisciplinary orientation. By drawing on distinct literatures, these two manuscripts reveal diverse insights and reflections about paradoxical demands in organizations. In this integrative reflection, we juxtapose our two review articles, surface distinct assumptions and emphases, highlight complementarities, and raise questions for future scholarship. In doing so, we hope to fuel insights toward a meta-perspective on paradox

Strongyloides stercoralis age-1: A Potential Regulator of Infective Larval Development in a Parasitic Nematode

Infective third-stage larvae (L3i) of the human parasite Strongyloides stercoralis share many morphological, developmental, and behavioral attributes with Caenorhabditis elegans dauer larvae. The ‘dauer hypothesis’ predicts that the same molecular genetic mechanisms control both dauer larval development in C. elegans and L3i morphogenesis in S. stercoralis. In C. elegans, the phosphatidylinositol-3 (PI3) kinase catalytic subunit AGE-1 functions in the insulin/IGF-1 signaling (IIS) pathway to regulate formation of dauer larvae. Here we identify and characterize Ss-age-1, the S. stercoralis homolog of the gene encoding C. elegans AGE-1. Our analysis of the Ss-age-1 genomic region revealed three exons encoding a predicted protein of 1,209 amino acids, which clustered with C. elegans AGE-1 in phylogenetic analysis. We examined temporal patterns of expression in the S. stercoralis life cycle by reverse transcription quantitative PCR and observed low levels of Ss-age-1 transcripts in all stages. To compare anatomical patterns of expression between the two species, we used Ss-age-1 or Ce-age-1 promoter::enhanced green fluorescent protein reporter constructs expressed in transgenic animals for each species. We observed conservation of expression in amphidial neurons, which play a critical role in developmental regulation of both dauer larvae and L3i. Application of the PI3 kinase inhibitor LY294002 suppressed L3i in vitro activation in a dose-dependent fashion, with 100 µM resulting in a 90% decrease (odds ratio: 0.10, 95% confidence interval: 0.08–0.13) in the odds of resumption of feeding for treated L3i in comparison to the control. Together, these data support the hypothesis that Ss-age-1 regulates the development of S. stercoralis L3i via an IIS pathway in a manner similar to that observed in C. elegans dauer larvae. Understanding the mechanisms by which infective larvae are formed and activated may lead to novel control measures and treatments for strongyloidiasis and other soil-transmitted helminthiases

Paradox Research in Management Science: Looking Back to Move Forward

Paradox studies offer vital and timely insights into an array of organizational tensions. Yet this field stands at a critical juncture. Over the past 25 years, management scholars have drawn foundational insights from philosophy and psychology to apply a paradox lens to organizational phenomena. Yet extant studies selectively leverage ancient wisdom, adopting some key insights while abandoning others. Using a structured content analysis to review the burgeoning management literature, we surface six key themes, which represent the building blocks of a meta-theory of paradox. These six themes received varying attention in extant studies: paradox scholars emphasize types of paradoxes, collective approaches, and outcomes, but pay less attention to relationships within paradoxes, individual approaches, and dynamics. As this analysis suggests, management scholars have increasingly simplified the intricate, often messy phenomena of paradox. Greater simplicity renders phenomena understandable and testable, however, oversimplifying complex realities can foster reductionist and incomplete theories. We therefore propose a future research agenda targeted at enriching a meta-theory of paradox by reengaging these less developed themes. Doing so can sharpen the focus of this field, while revisiting its rich conceptual roots to capture the intricacies of paradox. This future research agenda leverages the potential of paradox across diverse streams of management science

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Competing demands in organizations: understanding and managing tensions

With unprecedented technological progress, constantly changing markets, and different stakeholder demands, our world is becoming increasingly complex. These developments create contradictions and force organizations to constantly deal with competing demands. In this context, understanding tensions becomes crucial, since managing them effectively is vital for an organization's success and survival. This dissertation examines two literature streams to shed light on the understanding and the management of competing demands: First, the paradox perspective seeks to capture tensions' complexity and provides insights into coping mechanisms. While competing demands traditionally implied trade-off decisions, paradox researchers explore the complementary nature of tensions. Second, the stakeholder literature provides a more specific theoretical lens for studying firm stakeholders' competing demands. This perspective has not only received increasing research attention, but also offers the potential to better understand the fundamental purpose of the corporation

Ad fontes: philosophical foundations of paradox research

With paradox moving toward a meta-theory, research is increasingly drawing on its rich philosophical foundation. These include diverse fields such as dialectics, existentialism, and logic, each of which emphasizes different aspects of paradoxes. However, discussions have mostly focused on single philosophical aspects, potentially leading to an incomplete and polarized view of paradox and hindering cross-fertilization. At worst, this development turns into reproducing “paradigm wars.” To avoid this, I introduce the main philosophical foundations dealing with different aspects of paradox, and interpret them as lenses. As such, I link them to paradox research in management, provide a systematic overview, and highlight avenues for future research

Seeing the Forest and the Trees: How a Systems Perspective Informs Paradox Research

Paradox theory has fundamentally changed how researchers think about organizational tensions by emphasizing their oppositions and their interdependencies. Yet, most paradox studies focus on salient, perceived tensions, ignoring latent, nested tensions and their complex interconnections. This partial view is rooted in the paradox literature focusing on the epistemological realm (actors' perception of tensions) while disregarding the ontological realm (tensions' underlying reality). The focus on the epistemological aspects of the tensions impedes researchers from moving to more intricate insights into paradox, which could help address the realities of complex issues, such as wicked problems. We propose a systems perspective on paradox that discrimi-nates the epistemological understandings from the ontological realities of tensions. By revealing the ontology of tensions, the underlying complexity becomes empirically interpretable. We illustrate the power of this perspective by offering two research strategies that can help researchers and organizations apprehend paradoxes grounded in systems

Who gets attention? firms’ shifting stakeholder orientation at times of ownership volatility

Research on firms’ stakeholder orientation has described two perspectives: An ex ante narrow orientation towards their shareholders and an ex ante broad orientation towards all their stakeholders. Both streams rely on the assumption of long-term owners, who create spillovers to other stakeholders or enable synergies between stakeholders and shareholders. However, stock-holding periods have become much shorter over the past decades, causing unprecedented ownership volatility. In this paper, we clarify the impact of ownership volatility on stakeholder orientation