bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C15: Neutrophil elastase (NE) induces epithelial-mesenchymal transition (EMT) via upregulation of inhibitor of DNA binding 1 (ID1)
Authors: Kargl Julia , Gregory Alyssa , Yang Hye Youn , Busch Stephanie , Metz Heather , Houghton A. McGarry
Published: October 2016

Neutrophil elastase is a neutrophil-derived serine protease with broad substrate specificity. We have previously shown that NE promotes lung tumor growth in vitro and in vivo and that NE is capable of entering tumor cell endosomes in a clathrin-dependent fashion.

Epithelial-mesenchymal transition (EMT) is a fundamental event for primary tumors to metastasize to distant sites. Altered gene and protein expression causes changes in cell morphology and behavior resulting in the loss of attachment to neighboring cells, intravasation, and migration into distant tissue. However, the entities residing within the tumor microenvironment that drive EMT are poorly understood.

We identified NE, expressed and released by tumor-associated neutrophils, as such an entity. We found that NE induces EMT-like morphology and behavior in several cancer cell lines as well as upregulates genes (Snail and Twist) and proteins (N-cadherin, α-SMA, Fibronectin and Vimentin) associated with EMT. Furthermore, NE provokes tumor cell migration and invasion in vitro and is required for metastasis formation in vivo. Besides known EMT markers we identified significant upregulation of inhibitor of DNA binding 1 (ID1) in tumor cells in the presence of NE. Increased ID1 expression was previously shown to correlate with tumor progression and metastasis. Clathrin-dependent NE internalization is required for both ID1 expression and the EMT-like phenotype. We localized NE in different compartments of tumor cells and found it predominantly in the nuclear fraction; more specifically, NE is located in the chromatin-bound fraction, indicating a potential role in chromatin remodeling and transcriptional regulation. Additionally, the proteolytic activity of NE was measured in the nuclear and chromatin-bound fractions and is required for induction of ID1 expression and EMT-like behavior. Taken together, these data suggest the importance of NE-induced ID1 expression in metastasis formation.

Citation Format: Julia Kargl, Alyssa Gregory, Hye Youn Yang, Stephanie Busch, Heather Metz, A. McGarry Houghton. Neutrophil elastase (NE) induces epithelial-mesenchymal transition (EMT) via upregulation of inhibitor of DNA binding 1 (ID1). [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C15.
Abstract C20: Investigating the role of the tumor microenvironment and its role in radiation therapy in pancreatic cancer
Authors: O'Neill Fiona , Moore Gemma , O'Keeffe Serena , McClean Brendan , McVey Gerard , Moriarty Michael , Breen Laura , Clynes Martin
Published: October 2016

Pancreatic cancer is the 10th most common cancer in Ireland and the 5th most common cause of death. The 5 year survival rate is approximately 6%, due to late diagnosis by which time usually metastasis has occurred. Despite an increase in research on the disease in recent years very little progress has been made and the development of new, more effective therapies is needed.

The role of the tumor microenvironment in the progression of pancreatic cancer is becoming the focus of more and more research. It has been determined that the tumor microenvironment plays a significant role in the progression and invasion of the cancer cells and also plays a role in the resistance of tumor to therapy.

Utilizing established pancreatic cell lines and human derived fibroblasts and stellate cells, an indirect co-culture approach has been utilized to investigate the mechanisms by which the fibroblasts and stellate cells in the tumor influence the behavior of the cancer cells.

Using the same indirect co-culture approach we have sought to evaluate the role in which these stromal components have in the tumor cells response to radiation therapy. We have utilized single and fractionated doses to determine if the different approaches have varying effects on the proliferation, invasion and colony forming ability of the cancer cells.

It is hoped that this in vitro evaluation could be used to inform a better approach to radiation treatment of pancreatic cancer.

Citation Format: Fiona O'Neill, Gemma Moore, Serena O'Keeffe, Brendan McClean, Gerard McVey, Michael Moriarty, Laura Breen, Martin Clynes. Investigating the role of the tumor microenvironment and its role in radiation therapy in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C20.
Abstract C21: IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis
Authors: Pena Maria Marjorette O. , Zhang Yu , Davis Celestia , Ryan James C. , Altomare Diego , Shah Sapana , Hughes Daniel Titus
Published: October 2016

The major cause of death from colorectal cancer (CRC) is liver metastasis and understanding its mechanisms is necessary for early diagnosis and development of new therapies. Interleukin-33 (IL-33) is an IL-1 cytokine that functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or early danger signal. Its role in invoking type 2 immune response is firmly established; however, its role in tumor development and metastasis in only beginning to be elucidated. We identified IL-33 as a potently upregulated cytokine in highly metastatic CRC cells and examined its role in tumor growth and metastasis to the liver. We expressed IL-33 in murine and human CRC cell lines and their growth and spontaneous metastasis to the liver was assessed in orthotopic models of CRC in wild type and IL33 knockout mice. The results suggest that tumor- rather than host- derived IL-33 promoted growth and metastasis by inducing expression of cytokines that stimulated mobilization of CD11b+ GR1+ and CD11b+F4/80+ myeloid cells to remodel the tumor microenvironment, and increase tumor angiogenesis, potentially by activating endothelial cells. Conversely, pro-tumorigenic cytokines derived from the microenvironment induced IL-33 expression in tumor cells to create a sustained pro-tumorigenic loop that promotes tumor growth and metastasis. Our findings underscore the potential of IL-33 as a novel and viable therapeutic target for CRC and liver metastasis.

Citation Format: Maria Marjorette O. Pena, Yu Zhang, Celestia Davis, James C. Ryan, Diego Altomare, Sapana Shah, Daniel Titus Hughes. IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C21.
Abstract C26: Melanoma brain metastasis is facilitated by instigation of reactive astrogliosis
Authors: Schwartz Hila , Blacher Eran , Amer Malak , Livneh Nir , Klein Anat , Ben-Shushan Dikla , Soffer Shelly , Stein Reuven , Satchi-Fainaro Ronit , Umansky Viktor , Pukrop Tobias , Erez Neta
Published: October 2016

Melanoma frequently metastasizes to the brain, resulting in dismal survival. A major obstacle for characterizing mechanisms of brain metastasis is the lack of tractable pre-clinical models that mimic the multi-stage process of brain metastasis. We established a novel model of spontaneous melanoma brain metastasis in immunocompetent mice. Aggressive local tumors are formed following orthotopic injection, and 3-4 months after surgical excision of the primary tumor, 50% of the mice develop brain macrometastases. By utilizing a unique ex-vivo modeling system, we detected brain micrometastases in 50-60% of the mice and quantified the metastatic load. Moreover, we show that the detection of melanoma transcripts in cerebrospinal fluid (CSF) is correlated with brain metastases. Interestingly, preliminary findings suggest that the melanoma-derived transcripts are found in exosomes. Astrocytes are glial cells that maintain brain homeostasis, and constitute a central part of the brain microenvironment. Reactive astrogliosis is the primary response of astrocytes to brain insult. While much data have accumulated on the contribution of astrogliosis to neurodegenerative diseases, the functional role of astrogliosis in promoting melanoma brain metastases is unknown. Utilizing our model we demonstrate early changes in the microenvironment and show that micrometastases are associated with activation of astrocytes and with hyperpermeability of the blood-brain-barrier. In-vitro, paracrine signaling by melanoma cells activated astrocytes to up-regulate a ‘wound healing program’ including Cxcl10 and Serpins. Reciprocally, astrocytes facilitated the invasion of melanoma cells and were necessary for primary outgrowth in 3D co-cultures. Finally, we show that intracranial co-injection of astrocytes with melanoma cells resulted in a 9 fold increase of tumor volume, and that the same gene-signature was up-regulated in astrocytes in-vivo. Studying spontaneous melanoma brain metastasis in a clinically relevant setting enables in-depth understating of the metastatic microenviromet which is the key to developing therapeutic approaches that may prevent brain metastatic relapse.

Citation Format: Hila Schwartz, Eran Blacher, Malak Amer, Nir Livneh, Anat Klein, Dikla Ben-Shushan, Shelly Soffer, Reuven Stein, Ronit Satchi-Fainaro, Viktor Umansky, Tobias Pukrop, Neta Erez. Melanoma brain metastasis is facilitated by instigation of reactive astrogliosis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C26.
Abstract IA04: Stromal regulation of pancreatic cancer epigenome and metabolome
Authors: Sherman Mara H. , Evans Ronald
Published: October 2016

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the dramatic accumulation of stromal components implicated in tumor growth, metastasis, and resistance to therapy. This creates a living chimera in which stroma-derived growth factors, matrix proteins and inflammatory cytokines are thought to nurture the nascent tumor. This study reveals that the stromal secretome exerts rapid epigenomic changes in the cancer cells that effectively marshals up metabolic and genomic networks needed to power cell growth.

To tackle the complexity of the tumor microenvironment (TME), we devised a three-dimensional culture system to dissect the adaptive impact of the stromal secretome on the cancer cell. This integrative approach identified the rapid mobilization of more than a dozen gene networks (cell cycle, steroid biosynthesis, metabolic pathways, DNA replication, etc.), as well as a commensurate adaptive metabolome. A major unanswered question relates to the sequence of events that result in the formation and ultimate function of these networks, in part generated by rapid changes in acetylation of histone H3 at lysines 9 and 27 (H3K9ac and H3K27ac).

Our work suggests the existence of a molecular and-gate such that tumor activation is the consequence of mutant Ras and the tumor micro-environment. To mediate this molecular hand-shake, we find that BRD2 acts in the epithelial compartment to transduce stromal cues at the genomic level. Based on the above, and consistent with recent Mazur PK et al Nat Med (2015), we show the BET bromodomain inhibitor JQ1 targets a key synergy point and reduces pancreatic tumor growth in vivo. Collectively, this work describes a novel connection between the stromal response and a driver oncogene and may offer new insights into the role of the TME in the treatment of ras-driven tumor.

Citation Format: Mara H. Sherman, Ronald Evans. Stromal regulation of pancreatic cancer epigenome and metabolome. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA04.
Abstract IA06: Influence of macrophage metabolism on vessel shape: Implications for cancer
Authors: Mazzone Massimiliano
Published: October 2016

Cancer typically has an inflammatory nature. Of all immune cells invading the tumor, the role of macrophages remains controversial because of their functionally distinct differentiation states. Classically activated (M1-like) macrophages and alternatively activated (M2-like) macrophages represent the two extremities of a continuum, in which the former are proinflammatory and tumoricidal, whereas the latter display pro-angiogenic and protumoral activities. This heterogeneity reflects the plasticity and versatility of these cells in response to microenvironmental signals. The tumor environment is constituted of cancer cells and stromal cells that coexist under different oxygen tensions and the influence of soluble factors. A plethora of (hypoxia-induced) cytokines and chemokines can define the macrophage phenotype and their positioning within the tumor. We have elucidated an elegant mechanism by which macrophages are recruited and retained in avascular hypoxic niches of the tumor, where they exert their immunosuppressive and pro-angiogenic activity. Hypoxia by itself indeed strongly affects macrophage function, as the cells are forced to adapt and alter their metabolism, which is accompanied by a drastic change in their transcriptome and proteome. We have found that the resultant metabolic changes drive macrophages towards a pro-angiogenic phenotype in an attempt to restore oxygenation. Soluble factors derived from the tumor exacerbate this macrophage shift by further enforcing this metabolic adaptation. As a consequence, tumor blood vessels are abnormal and dysfunctional, thus perpetuating hypoxia, which in turn fosters metastasis. By using genetic tools in mice, we show that inhibiting macrophage recruitment in hypoxic niches, or altering their metabolic and energetic state can break this feed-forward loop, resulting in normalized blood vessels and thus, strongly reducing metastatic dissemination.

Citation Format: Massimiliano Mazzone. Influence of macrophage metabolism on vessel shape: Implications for cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA06.
Abstract IA08: p62/SQSTM1 accumulation links chronic tissue damage to malignant progression in liver and pancreas
Authors: Karin Michael
Published: October 2016

Despite extensive genomic exploration, the mechanisms that initiate malignancy remain obscure. We addressed this issue by studying how chronic liver diseases progress to hepatocellular carcinoma (HCC). We focused our studies on the role of p62/SQSTM1, whose accumulation is a hallmark of premalignant liver disease. Using mice, we found that hepatocyte-specific p62 ablation inhibits HCC development in four distinct models, with strongest effect exerted in etiologies involving mTORC1 activation. Forced p62 expression in autophagy-competent livers suffices for HCC induction. Amongst p62 activities including aggregate formation, binding ubiquitinated proteins, mTORC1 stimulation and transcription factor activation, most critical is the NRF2 pathway, which is mutationally activated in 14% of human HCCs. We propose that environmentally-induced p62-dependent NRF2 signaling is a key early event inHCC pathogenesis that together with mTORC1 promotes survival and expansion of superoxide-accumulating HCC-initiating cells. Indeed, high p62 expression in preneoplastic human liver predicts rapid HCC recurrence after curative ablation.

Citation Format: Michael Karin. p62/SQSTM1 accumulation links chronic tissue damage to malignant progression in liver and pancreas. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA08.
Abstract IA20: Hypoxic influences on the tumor microenvironment
Authors: Simon M. Celeste
Published: October 2016

Solid tumors typically develop hostile microenvironments characterized by irregular vascularization and poor oxygen (O2) and nutrient supply. Whereas normal cells modulate anabolic and catabolic pathways in response to changes in nutrient availability, cancer cells exhibit unregulated growth even under nutrient scarcity. Recent studies have demonstrated that constitutive activation of growth-promoting pathways results in dependence on unsaturated fatty acids for survival under O2 deprivation. In cancer cells, this dependence represents a critical metabolic vulnerability that could be exploited therapeutically. Here I will review how this dependence on unsaturated lipids is affected by the microenvironmental conditions faced by cancer cells, particularly in the setting of sarcomas.

Citation Format: M. Celeste Simon. Hypoxic influences on the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA20.
Abstract IA23: Deconvolution of the triple-negative breast cancer microenvironment
Authors: Saleh Sadiq , Gruosso Tina , Gigoux Mathieu , Bertos Nicholas , Omeroglu Atilla , Zuo Dongmei , Meterissian Sarkis , Hallett Michael , Park Morag
Published: October 2016

Breast cancer heterogeneity is one of the principal obstacles both to predicting outcome and to determining an effective course of treatment for this disease. Although genomic technologies have been used to gain a better understanding, by identifying gene expression signatures associated with clinical outcome and breast cancer subtypes, relatively little is known about heterogeneity in the tumor microenvironment. It is now accepted that changes in the normal cells that constitute the tumor microenvironment (TME) play important roles in determining cancer progression and ultimate outcome. We and others have established that an immune gene expression signature correlates with good outcome in triple negative breast cancer (TNBC), yet fails to accurately predict outcome in all patients. Examining stromal heterogeneity in TNBC has identified four distinct stromal clusters, three of which are prognostic, contain distinct immune signatures and a signature of fibrosis. Lymphocytic infiltration and access to tumor parenchyma is not well understood due to high levels of spatial heterogeneity within tumors. We show that location of CD8+T cells is strongly influenced by TME subtypes and identify gene expression signatures predictive of distinct CD8+T cell localization and patient outcome. Since mounting evidence suggests that immune-checkpoint inhibitor immunotherapies may be promising for only a subset of TNBC patients, highlights the importance of understanding how the TME influences CD8+T cell location.

Citation Format: Sadiq Saleh, Tina Gruosso, Mathieu Gigoux, Nicholas Bertos, Atilla Omeroglu, Dongmei Zuo, Sarkis Meterissian, Michael Hallett, Morag Park. Deconvolution of the triple-negative breast cancer microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA23.
Abstract IA26: Regulation of epithelial versus mesenchymal polarity and malignant progression
Authors: Pattabiraman Diwakar , Pattabiraman Diwakar , Shibue Tsukasa , Shibue Tsukasa , Ye Xin , Ye Xin , Weinberg Robert A. , Weinberg Robert A. , Weinberg Robert A.
Published: October 2016

The ability of carcinoma cells to acquire cell-biological phenotypes associated with advanced malignancies is increasingly associated with activation of the EMT (epithelial-mesenchymal transition) program. Among the acquired phenotypes are those of motility, invasiveness, the ability to disseminate, and the ability to form increased numbers of tumor-initiating cells/cancer stem cells (CSCs). We have investigated the regulation of the EMT program and found that a key intracellular determinant is the levels of the cAMP second messenger molecule. When elevated, it causes exit of more mesenchymal carcinoma cells into an epithelial state. The formation of the CSCs within tumors has long been posited to arise following the conversion of normal tissue SCs into CSCs. However, in our hands, in a transgenic model of breast carcinoma formation, the SCs reside in one cell layer of the mammary ducts while the CSCs arise in another, making the direct derivation of CSCs from normal SCs unlikely, at least in this experimental model of mammary carcinogenesis. Once the EMT program is activated, carcinoma cells are able to acquire attributes that not only enable their dissemination from the primary tumor but also affect their subsequent post-extravasation proliferation in the lung parenchyma. The basis of this proliferation derives from the EMT-induced ability of extravasated carcinoma cells to form mature focal adhesions and activate the mitogenic signaling pathway via focal adhesion kinase (FAK). Additional consequences of EMT action will be discussed.

Citation Format: Diwakar Pattabiraman, Diwakar Pattabiraman, Tsukasa Shibue, Tsukasa Shibue, Xin Ye, Xin Ye, Robert A. Weinberg, Robert A. Weinberg, Robert A. Weinberg. Regulation of epithelial versus mesenchymal polarity and malignant progression. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA26.
Abstract PR06: Reciprocal prostate cancer signaling with its microenvironment mediates castrate-resistant disease progression
Authors: Tripathi Manisha , Nandana Srinivas , Huang Jen-Ming , Kato Manabu , Chung Leland W. K. , Mishra Rajeev , Xin Li , Bhowmick Neil
Published: October 2016

Our lab has previously reported that the mouse model knocked out for TGF-beta receptor type II in fibroblasts results in castrate resistance of prostate tissues, mediated by paracrine Wnt signaling. We found that antagonizing androgen signaling leads to Wnt ligand expression by prostatic fibroblasts, interestingly dependent on cell-cell contact. This led us to hypothesize that a juxtacrine action within the stromal compartment was important to the development of castrate resistance. Building upon this observation, we found that Notch signaling was upregulated in prostate cancer associated fibroblasts (CAFs) compared with normal tissue associated fibroblasts (NAFs). Further, inhibition of Notch signaling in CAFs, using DAPT, resulted in decrease in Wnt2b and decreased expression of Notch target genes. Similarly, castration or androgen receptor antagonism (i.e. bicalutamide or enzalutamide) resulted in increased Notch signaling and downstream Wnts 2 and 2b up regulation. The further generation of chimeric tissue recombinant xenografts with human RV1 prostate cancer epithelia with mouse prostate stromal cells with activated Notch signaling, derived from NICD transgenic mice resulted in increased tumor size compared with wild type control stromal recombinants. Conversely, recombinants derived from prostatic fibroblasts having a loss of Notch signaling, from RBPJ-knockout mice, had diminished tumorigenesis, compared to xenografts with the wild type fibroblasts counterpart. In trying to determine the mediator of Wnt-associated paracrine prostate epithelial expansion, we found downstream YAP activation in the RV1 cells. In a reciprocal epithelial-to-fibroblast communication we found that the RV1 cells treated with conditioned media from NICD fibroblasts showed increased IL-6 expression. Conversely, conditioned media from prostate cancer cells increased Notch target gene expression in CAFs, which was blocked upon addition of IL-6 neutralizing antibody. Taken together there is a stromal-derived signaling cascade involving Notch and Wnt ligands, that activates YAP in the epithelia for paracrine IL-6-dependent Notch activity back in the stromal fibroblasts. Critically, disruption of this cross-talk in the fibroblasts can limit the gain of stem features and castrate resistance of the adjacent epithelia in halting lethal progression of prostate cancer.

This abstract is also presented as Poster A44.

Citation Format: Manisha Tripathi, Srinivas Nandana, Jen-Ming Huang, Manabu Kato, Leland W. K. Chung, Rajeev Mishra, Li Xin, Neil Bhowmick. Reciprocal prostate cancer signaling with its microenvironment mediates castrate-resistant disease progression. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR06.
Abstract PR13: Understanding the systemic interactions between primary tumors and disseminated tumor initiating cells
Authors: Castano Zafira , Chaffer Christine L. , Spiegel Asaf , Pant Ayush , Richardson Andrea L. , Reinhardt Ferenc , Marsh Timothy , Janssen Susanne , Gifford Ann M. , Weinberg Robert A. , McAllister Sandra S.
Published: October 2016

The causes for breast cancer recurrence in the form of metastatic disease and the reasons why less than 1% of disseminated tumor cells form metastases are unknown. A number of studies have demonstrated that the aggressive cancer cell population capable of driving metastasis feature properties of the epithelial-mesenchymal transition (EMT) and tumor initiation (TI). We previously reported novel mechanisms by which systemic and microenvironmental factors enrich tumors for EMT and TI genes and demonstrated that recurrence rates are not strictly due to tumor cell intrinsic properties (Castano et al., Cancer Discovery 2013). Using a preclinical model of breast cancer during the early phases of metastatic disease, when patients harbor disseminated tumor initiating cells (TICs) in the periphery at the time of their primary diagnosis (McAllister SS et al., Cell 2008), we recently made a surprising, and seemingly contrasting discovery. Specifically, we found that certain primary tumors can inhibit progression of disseminated TICs into overt tumors, maintaining them in the TI state and slowing their proliferation and differentiation to form tumor tissue mass. We established that the primary tumor induce mobilization of IL1beta-expressing monocytes that are recruited to sites where TICs reside. At those sites, signaling via the IL1 receptor maintains the EMT/TI state of the disseminated cells, thus promoting disease indolence. Importantly, surgical removal of the primary tumor enables TICs at the secondary sites to exit the EMT/TI state and to produce robustly growing tumors. Confirming our xenograft results, we established that stromal expression of IL1β in patient tumors is associated with poor outcome. Collectively, these data highlight the profound impact a primary tumor can exert on metastasizing cells - in this case, by altering the systemic environment to the detriment of secondary tumor growth. Moreover, our data highlight a central role for IL1β in modulating tumor cell plasticity and suggest it may provide a novel avenue for targeting recurrent disease.

Citation Format: Zafira Castano, Christine L. Chaffer, Asaf Spiegel, Ayush Pant, Andrea L. Richardson, Ferenc Reinhardt, Timothy Marsh, Susanne Janssen, Ann M. Gifford, Robert A. Weinberg, Sandra S. McAllister. Understanding the systemic interactions between primary tumors and disseminated tumor initiating cells. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR13.
Assessment of Palliative Care in Lung Cancer in Turkey
Authors: Bülbül Y. , Ozlu T. , Arinc S. , Ozyurek B.A. , Gunbatar H. , Senturk A. , Bahadir A. , Ozcelik M. , Yilmaz U. , Akbay M.O. , Saglam L. , Kilic T. , Kirkil G. , Ozcelik N. , Tatar D. , Baris S.A. , Yavsan D.M. , Sen H.S. , Berk S. , Acat M. , Cakmak G. , Yumuk P.F. , Intepe Y.S. , Toru U. , Ayik S.O. , Basyigit I. , Ozkurt S. , Mutlu L.C. , Yasar Z.A. , Esme H. , Erol M.M. , Oruc O. , Erdoğan Y. , Asker S. , Ulas A. , Erol S. , Kerget B. , Erbaycu A.E. , Teke T. , Beşiroğlu M. , Can H. , Dalli A. , Talay F.
Published: October 2016

Objective: To investigate the symptoms of lung cancer in Turkey and to evaluate approaches to alleviate these symptoms. Subjects and Methods: This study included 1,245 lung cancer patients from 26 centers in Turkey. Demographic characteristics as well as information regarding the disease and treatments were obtained from medical records and patient interviews. Symptoms were evaluated using the Edmonton Symptom Assessment Scale (ESAS) and were graded on a scale between 0 and 10 points. Data were compared using the χ2, Student t, and Mann-Whitney U tests. Potential predictors of symptoms were analyzed using logistic regression analysis. Results: The most common symptom was tiredness (n = 1,002; 82.1%), followed by dyspnea (n = 845; 69.3%), appetite loss (n = 801; 65.7%), pain (n = 798; 65.4%), drowsiness (n = 742; 60.8%), anxiety (n = 704; 57.7%), depression (n = 623; 51.1%), and nausea (n = 557; 45.5%). Of the 1,245 patients, 590 (48.4%) had difficulty in initiating or maintaining sleep. The symptoms were more severe in stages III and IV. Logistic regression analysis indicated a clear association between demographic characteristics and symptom distress, as well as between symptom distress (except nausea) and well-being. Overall, 804 (65.4%) patients used analgesics, 630 (51.5%) received treatment for dyspnea, 242 (19.8%) used enteral/parenteral nutrition, 132 (10.8%) used appetite stimulants, and 129 (10.6%) used anxiolytics/antidepressants. Of the 799 patients who received analgesics, 173 (21.7%) reported that their symptoms were under control, and also those on other various treatment modalities (dyspnea: 78/627 [12.4%], appetite stimulant: 25/132 [18.9%], and anxiolytics/antidepressants: 25/129 [19.4%]) reported that their symptoms were controlled. Conclusion: In this study, the symptoms progressed and became more severe in the advanced stages of lung cancer, and palliative treatment was insufficient in most of the patients in Turkey.
Harun Farocki: operador de mídias
Authors: Genaro Ednei De
Published: October 2016

The work of Harun Farocki (1944-2014) gives us a respectable contribution to the method of working with images and words. This paper intended to apprehend and systematize the coherence of his contribution, suggesting three fundamental approaches of this method/style: the horizontal (image/word), the transverse (images of the world) and the transindividual (operation), thus catching sight of the larger perspective of Farocki: operating media as a pharmakon inflection point.
O corpo fragmentado do cinema contemporâneo
Authors: Dantas Elenildes
Published: October 2016

In The cinematic body, Steven Shaviro explores the relationship between the cinematic apparatus and the life of the body, suggesting that both are not alien or extrinsic to each other, since their symbolic and parasitic interpretation is part of the postmodern culture of social and technological relations of capitalist society. Understanding the cinema as a living medium that causes bodily reactions of desire and fear, pleasure and disgust, fascination and shame, the author seeks relations with postmodernity, the politics of human bodies, the construction of masculinity and the masochistic aesthetic, present in films.
A outra caixa de Pandora
Authors: Ferrara Lucrécia D' Alessio
Published: October 2016

As a result of previous studies, this research aims to study the cultural consequences of digital technology and their interference on communication by developing a necessary and urgent distinction between mediation and interaction. Therefore, the subject of this study is to investigate to what extent communication can overcome the linear dimension of simple transmission and be sensitive to contemporary social transformations that allude to political roots of communication and redefine it as a scientific area.
Pim-1L Protects Cell Surface–Resident ABCA1 From Lysosomal Degradation in Hepatocytes and Thereby Regulates Plasma High-Density Lipoprotein Level
Authors: Katsube Akira , Hayashi Hisamitsu , Kusuhara Hiroyuki
Published: October 2016

Objective—

ATP-binding cassette transporter A1 (ABCA1) exerts an atheroprotective action through the biogenesis of high-density lipoprotein in hepatocytes and prevents the formation of foam cells from macrophages. Controlling ABCA1 is a rational approach to improving atherosclerotic cardiovascular disease. Although much is known about the regulatory mechanism of ABCA1 synthesis, the molecular mechanism underpinning its degradation remains to be clearly described.

Approach and Results—

ABCA1 possesses potential sites of phosphorylation by serine/threonine-protein kinase Pim-1 (Pim-1). Pim-1 depletion decreased the expression of cell surface–resident ABCA1 (csABCA1) and apolipoprotein A-I–mediated [
3
H]cholesterol efflux in the human hepatoma cell line HepG2, but not in peritoneal macrophages from mice. In vitro kinase assay, immunoprecipitation, and immunocytochemistry suggested phosphorylation of csABCA1 by the long form of Pim-1 (Pim-1L). Cell surface biotinylation indicated that Pim-1L inhibited lysosomal degradation of csABCA1 involving the liver X receptor β, which interacts with csABCA1 and thereby protects it from ubiquitination and subsequent lysosomal degradation. Cell surface coimmunoprecipitation with COS-1 cells expressing extracellularly hemagglutinin-tagged ABCA1 showed that Pim-1L–mediated phosphorylation of csABCA1 facilitated the interaction between csABCA1 and liver X receptor β and thereby stabilized the csABCA1–Pim-1L complex. Mice deficient in Pim-1 kinase activity showed lower expression of ABCA1 in liver plasma membranes and lower plasma high-density lipoprotein levels than control mice.

Conclusions—

Pim-1L protects hepatic csABCA1 from lysosomal degradation by facilitating the physical interaction between csABCA1 and liver X receptor β and subsequent stabilization of the csABCA1–Pim-1L complex and thereby regulates the circulating level of high-density lipoprotein. Our findings may aid the development of high-density lipoprotein–targeted therapy.
Nationalism, Justice and Taxation in an Ottoman Urban Context during the Tanzimat: The Gazino-Club in Manastır
Authors: Vakali Anna
Published: October 2016

This article elaborates on the history of a Greek club, the gazino, founded in Manastır during the 1850s. It dwells upon the gazino’s interaction with the city’s Christian population regarding the Tanzimat reforms and the expectations these raised among ordinary people for social justice. Such expectations contributed to the emergence of new forms of political negotiation with the Ottoman authorities, in which the gazinists played a decisive role. Furthermore, this article follows the trial of the gazinists in the Tanzimat courts, after being charged with fesat (sedition) and inciting their coreligionists. Based on the trial’s interrogation protocols (istintakname), it is argued that before the Ottoman authorities the gazinists also negotiated and even camouflaged their ideas – pertaining to nationalism, but also to education and morality – by wrapping them up in discourses of progress and modernization favoured by the Tanzimat bureaucracy.
Revision of Afrotropical Dyscritobaeus Perkins, 1910 (Hymenoptera: Scelionidae)
Authors: TORTORICI FRANCESCO , CALECA VIRGILIO , NOORT SIMON VAN , MASNER LUBOMIR
Published: October 2016

A revision of Afrotropical species of Dyscritobaeus Perkins is presented with re-description of the four known species (D. bicolor O’Connor et Ashe, D. comitans Perkins, D. parvipennis (Dodd) and D. sulawensis Mineo, O’Connor et Ashe) and description of six new species (D. antananarivensis Tortorici et Caleca sp. nov., D. flavus Tortorici et Caleca sp. nov., D. kilimanjarensis Tortorici et Caleca sp. nov., D. madagascarensis Tortorici et Caleca sp. nov., D. ndokii Tortorici et Caleca sp. nov. and D. tanzaniensis Tortorici et Caleca sp. nov.). Dyscritobaeus cerosus is considered to be a junior synonym of D. comitans, D. hannibal is considered to be a junior synonym of D. sulawensis and D. maputanus is a junior synonym of D. parvipennis; so far these species are the only three Dyscritobaeus species that are widely distributed across four zoogeographical regions: Afrotropical, Australian, Oriental and Palearctic. Dyscritobaeus comitans and D. ndokii Tortorici et Caleca sp. nov. belong to the comitans-group, the other eight species belong to the orientalis-group. Dyscritobaeus antananarivensis Tortorici et Caleca sp. nov., D. madagascarensis Tortorici et Caleca sp. nov. and D. sulawensis are morphologically similar to D. orientalis bearing the specillum on T2; D. bicolor, D. flavus Tortorici et Caleca sp. nov., D. kilimanjarensis Tortorici et Caleca sp. nov., are morphologically similar to D. parvipennis; D. tanzaniensis Tortorici et Caleca sp. nov. shares the lack of a protruding metascutellum together with D. aspinosus Mineo, O’Connor et Ashe.Dyscritobaeus species are sexually dimorphic, particularly in the following features: the anterior and posterior fringes of the fore wing are longer in the female than in the male; the odontoid process, when present in females, is less developed or absent in the corresponding males; the specillum, when present in females, is less defined and smaller or absent in the corresponding males; the sculpture of the head is more evident in males than in females; and the first and second tergites are frequently lighter in males than in females.
Modeling of the Denebulization of Warm Fogs by Hygroscopic Seeding: Effect of Various Operating Conditions and of the Turbulence Intensity
Authors: Reuge N. , Fede P. , Berthoumieu J.-F. , Foucoin F. , Simonin O.
Published: October 2016

This study addresses the modeling of the denebulization (i.e., the removal of droplets) of warm fogs (T ≥ 0°C) by hygroscopic salt microparticles from the initial seeding at the top of the fog layer to the fall of the rain droplets on the ground. Two main phenomena can occur: condensation of water vapor on salted droplets and the concomitant evaporation of fog droplets, and coalescence between the salted droplets and the fog droplets. Three salts have been investigated: NaCl, CaCl2, and KCl. Based on the conservation equations, the modeling approach (1D) considers the hygroscopicity of the salts through the water activity in the aqueous solution and the coalescence induced by gravity and turbulence. From this study, NaCl is the most efficient salt in the tested operating conditions. Actually, this result can be explained by the strong hygroscopicity of this salt in very dilute solutions. From the calculations, 15 kg of NaCl particles of 6.7-μm diameter can dissipate a typical fog layer of 40 m in height within less than 17 min over 0.25 km2. According to the calculations, a fog layer of 100 m in height can be denebulized within 45 min. The contribution of the coalescence induced by gravity and by turbulence seems to have a negligible effect on the final horizontal visibility, the condensation/evaporation phenomena being preponderant for these operating conditions.
A Numerical Study of Outer Rainband Formation in a Sheared Tropical Cyclone
Authors: Li Qingqing , Wang Yuqing , Duan Yihong
Published: October 2016

The dynamical process of outer rainband formation in a sheared tropical cyclone (TC) is examined in this study using the fully compressible, nonhydrostatic TC model. After the easterly vertical wind shear of 10 m s−1 was imposed upon an intensifying strong TC, an outer rainband characterized by a wavenumber-1 structure formed as a typical principal rainband downshear. Further analysis indicates that the outer rainband formation was closely connected to the activity of the inner rainband previously formed downshear. Moving radially outward, the inner rainband tended to be filamented owing to the strong radial gradient of angular velocity. As the inner rainband approached the outer boundary of the inner core, convection in its middle and upwind segments reinvigorated and nascent convective cells formed upwind of the rainband, caused mainly by the decreased filamentation and stabilization. Subsequently, the rainband reorganized into a typical outer rainband. Three different scenarios are found to be responsible for the outer rainband formation from downshear inner rainbands. The first is the outer rainband forming from an inner rainband downshear as a sheared vortex Rossby wave. The second is the outer rainband forming directly from a single deformation-induced inner rainband. The third is the outer rainband developing from an inner rainband downshear organized from a blend–merger of inner rainbands that were initiated from locally deformed convection upshear right.
Offshore Transport of Shelf Water by Deep-Ocean Eddies
Authors: Cherian Deepak A. , Brink K. H.
Published: October 2016

At continental margins, energetic deep-ocean eddies can transport shelf water offshore in filaments that wrap around the eddy. One example is that of Gulf Stream warm-core rings interacting with the Mid-Atlantic Bight shelf. The rate at which shelf water is exported in these filaments is a major unknown in regional budgets of volume, heat, and salt. This unknown transport is constrained using a series of idealized primitive equation numerical experiments wherein a surface-intensified anticyclonic eddy interacts with idealized shelf–slope topography. There is no shelfbreak front in these experiments, and shelf water is tracked using a passive tracer. When anticyclones interact with shelf–slope topography, they suffer apparent intrusions of shelf–slope water, resulting in a subsurface maximum in offshore transport. The simulations help construct an approximate model for the filament of exported water that originates inshore of any given isobath. This model is then used to derive an expression for the total volume of shelf–slope water transported by the eddy across that isobath. The transport scales with water depth, radius, and azimuthal velocity scale of the eddy. The resulting expression can be used with satellite-derived eddy properties to estimate approximate real-world transports ignoring the presence of a shelfbreak front. The expression assumes that the eddy’s edge is at the shelf break, a condition not always satisfied by real eddies.
European CVE Strategies from a Practitioner’s Perspective
Authors: Korn Judy
Published: October 2016

Countering violent extremism (CVE) is a widely used and defined term. From a practitioner’s perspective, it works on three levels: prevention of radicalization, intervention with individuals in danger of radicalization, and de-radicalization. The European Union pursues a holistic approach, which includes transnational collaboration and eliminating possible root causes of radicalization. The focus is not exclusively on national security concerns but also on prevention, de-radicalization, and rehabilitation. European states have developed a variety of CVE strategies, some of which are perceived as centrally controlled, while others are characterized by participative and cooperative structures. At both the European and national levels, collaborative approaches that encompass incorporation of civil society organizations and governmental programs are seen as the most effective in CVE.
Region in Transition
Authors: Salem Paul
Published: October 2016

This article serves as an introduction to the first section of this volume, a section that focuses on the drivers of instability and radicalization in the Middle East and ways to counter them. This introduction provides a brief sketch of some of the key issues that are dealt with in more detail in this section and a brief précis of what each author addresses in his or her individual article.
Counter-Radicalization via the Internet
Authors: Greenberg Karen J.
Published: October 2016

ISIS and other international terrorist organizations rely on the Internet to disseminate their extremist rhetoric and to recruit people to their cause, particularly through popular online social media applications. Any meaningful counterterrorism strategy must, therefore, account for the ways in which terrorist organizations use the Internet to prey on young, manipulable minds who are drawn to radical ideas and propaganda and to the desire to serve a cause larger than themselves. This article outlines the ways in which extremist organizations use the Internet to ensnare new recruits, analyzes the implications of cyber-recruitment on existing counterterrorism techniques, and suggests ways in which the U.S. government can work with Internet service providers and other major cyber corporations to better address this growing threat.
Radicalization to Extremism and Mobilization to Violence
Authors: Stern Jessica
Published: October 2016

This article discusses individual mobilization to extremist violence from the perspective of a researcher and analyst, exploring what we know about the psychological and social factors motivating young people to join extremist groups and how that knowledge relates to the recruitment of individuals into ISIS. The biggest threat to the West, at least for now, is not core ISIS (or any jihadi group operating in the Middle East and North Africa region), but Westerners who self-mobilize for attacks at home or who return, trained to fight, from the “jihad” abroad. Finally, the article suggests specific ways for governments to respond to this threat, noting the limits of what government can do, and arguing that they join forces with the private sector. Mobilization to extremism must be addressed with broad, multi-institutional social strategies.
Not always a quick fix: The impact of employing temporary agency workers on retention in the Australian aged care workforce
Authors: King Debra , Svensson Sven , Wei Zhang
Published: October 2016

The use of external labour such as temporary agency workers in the general workforce has increased in recent decades, but comparatively little is known about their impact within the aged care workforce. This article analyses quantitative data from a census of aged care facilities and a large-scale survey of their workforce regarding the use and impact of temporary agency workers on internal workers. It demonstrates that employing temporary agency workers helps address labour shortages generally and skill shortages in particular. However, it has a negative impact on the job satisfaction of internal personal care workers – a predictor of an increase in intention to leave. In contrast, there was little impact on internal nurse satisfaction. The use of temporary agency workers could therefore create a paradox: increasing personal care worker numbers in the short term, but negatively impacting on their retention in the long term. Given the need for an expanded and sustainable aged care workforce, this finding has important implications for organisations, policy and unions.