Delicate balance: what is it like for an organization consultant to work live?

People know what they do; they frequently know why they do what they do; but what they don't know is what what they do does. (Foucault cited in Shatter, 2011 p. 1) In this thesis I aim to shed light on the practice of working live from within the continuous emergence of transitory moments in order to get into aware contact with what I experience in each moment of now and with what I want to contribute to emerge in the next moment. I do this from the vantage point of what I call the living process perspective, that is, regarding the 'moving but invisible' (Shotter citing Anderson, Ibid., p. 75) phenomena of human living such as self, mind, present moment, intention, change, relationship, group, and organization as complex responsive self-organizing processes happening within and between human bodies in their local situation in the present. I argue that in contrast to this view the conventional change methods treat the phenomena of human living as if they were objects that we possess, can steer and control, thus splitting the experiencer from the experience and not working from within what is subjectively happening within and between people here now and next. I explain that although living and thus changing happens constantly from emerging moment to emerging moment there is a fundamental difference between simply being situated in the present moment (as we all are) and being consciously aware of and engaged with our experiencing in the present moment. I show that for the process of relating to ourselves, each other and the world at large not to develop into repetitive or going-through-the-motions patterns consisting of largely unaware,- habitual and self-identical gestures and responses, but become consciously aware of and actively engaged with our actual experiencing of now and next, working from within the process of experiencing itself - a phenomenological-dialogical practice of engaging with our moment-to-moment experiencing I call working live - is essential for our relational processes to become 'free-flowing and flexible' (Stacey, 2003b p. 364) and thus remain fresh and alive within the ever-changing process of living. In essence, I demonstrate how the practice_ of working live can help organizational consultants to engage with the process of living, this continuous flow of ( ... ) first-time, unique events ( ... ) without "losing the phenomenon", that is, without losing the novelty expressed in first-time occurrence by assimilating it to already existing rules, principles, or conventions. (Shatter, 2011 p. 219, his emphasis) I describe the practice of working live well as a conscious, embodied and improvisational, paradoxical moment-to-moment activity of being choiceful and deliberate while at the same time being spontaneous and intuitive. This is so because the transitory micro and macro outcomes of our individual and collective gestures can neither be controlled nor predicted, but can significantly impact people and the world at large. I then identify and describe the interrelated aspects constituting the essence of the experience of working live well. I go on to show that through paying conscious attention to one's emerging 'transitory understandings and action guiding anticipations' (Shotter, 2011 p. 60} it becomes possible to realize that we have much more latitude in each moment as to what to do next then we often realize. I explain that this is so because the continuous and self-organizing social processes of human living have neither fixed, pre-determined and inevitable steps nor final end-states or ideal outcomes, but are simply constantly arising and disappearing transitory and unique micro manifestations. That means the process of changing from emerging moment to emerging moment is only conditioned to a certain degree by what has gone on before and by what is anticipated in the future - a phenomenological experience I call the five movements of the present moment - and therefore the future 'is partly open' (Griffin, 2007 p. 109) to what we want to contribute to help emerge next. I conclude the thesis by identifying and describing the five working live practice routines of presencing, raising, thinking, reframing, and nexting. I regard this thesis as a useful addition to the still small but steadily growing number of academic publications 4 related to the practice of working live focusing predominantly on abstract, theoretical reasonings and/or accurate this-is-what-is-going-on-now descriptions and therefore see the unique contribution of my from within exploration as taking a small step towards offering 'living pragmatics' (Varela, Thompson and Rosch, 1993 p. 22), that is, being useable by and useful 'for everyday work people who want to inquire into what is involved in having to think 'in the moment', while 'in motion,' both from within the midst of the complexity, and in relation to unique, never before encountered first-time events' (Shotter, 2011 p. 1, his emphasis)

Retinoic Acid Can Enhance Conversion of Naive into Regulatory T Cells Independently of Secreted Cytokines

It has been reported that retinoic acid (RA) enhances regulatory T (T reg) cell conversion by inhibiting the secretion of cytokines that interfere with conversion. This report shows that these conclusions provide a partial explanation at best. First, RA not only interfered with cytokine secretion but also with the ability of these cytokines to inhibit T reg cell conversion of naive T cells. Furthermore, RA enhanced conversion even in the absence of inhibitory cytokines. The latter effect depended on the RA receptor α (RARα) but did not require Smad3, despite the fact that RA enhanced Smad3 expression. The RARα1 isoform was not essential for RA-dependent enhancement of transforming growth factor β–driven conversion, suggesting that conversion can also be mediated by RARα2. Interleukin (IL)-6 strongly reduced RARα expression levels such that a deficiency of the predominant RARα1 isoform leaves too little RARα2 for RA to inhibit the generation of Th17 cells in the presence of IL-6

Transient Tumor-Fibroblast Interactions Increase Tumor Cell Malignancy by a TGF-β Mediated Mechanism in a Mouse Xenograft Model of Breast Cancer

Carcinoma are complex societies of mutually interacting cells in which there is a progressive failure of normal homeostatic mechanisms, causing the parenchymal component to expand inappropriately and ultimately to disseminate to distant sites. When a cancer cell metastasizes, it first will be exposed to cancer associated fibroblasts in the immediate tumor microenvironment and then to normal fibroblasts as it traverses the underlying connective tissue towards the bloodstream. The interaction of tumor cells with stromal fibroblasts influences tumor biology by mechanisms that are not yet fully understood. Here, we report a role for normal stroma fibroblasts in the progression of invasive tumors to metastatic tumors. Using a coculture system of human metastatic breast cancer cells (MCF10CA1a) and normal murine dermal fibroblasts, we found that medium conditioned by cocultures of the two cell types (CoCM) increased migration and scattering of MCF10CA1a cells in vitro, whereas medium conditioned by homotypic cultures had little effect. Transient treatment of MCF10CA1a cells with CoCM in vitro accelerated tumor growth at orthotopic sites in vivo, and resulted in an expanded pattern of metastatic engraftment. The effects of CoCM on MCF10CA1a cells were dependent on small amounts of active TGF-β1 secreted by fibroblasts under the influence of the tumor cells, and required intact ALK5-, p38-, and JNK signaling in the tumor cells. In conclusion, these results demonstrate that transient interactions between tumor cells and normal fibroblasts can modify the acellular component of the local microenvironment such that it induces long-lasting increases in tumorigenicity and alters the metastatic pattern of the cancer cells in vivo. TGF-β appears to be a key player in this process, providing further rationale for the development of anti-cancer therapeutics that target the TGF-β pathway

Characterisation of the Cell Line HC-AFW1 Derived from a Pediatric Hepatocellular Carcinoma

Current treatment of paediatric hepatocellular carcinoma (HCC) is often inefficient due to advanced disease at diagnosis and resistance to common drugs. The aim of this study was to generate a cell line derived from a paediatric HCC in order to expand research in this field. We established the HC-AFW1 cell line from a liver neoplasm of a 4-year-old boy through culturing of primary tumor specimens. The cell line has been stable for over one year of culturing and has a doubling time of 40 h. The tumour cells have an epithelial histology and express HCC-associated proteins such as Alpha-fetoprotein (AFP), Glypican 3, E-cadherin, CD10, CD326, HepPar1 and Vimentin. Forty-nine amino acids in exon 3 of β-Catenin that involve the phosphorylation sites of GSK3 were absent and β-Catenin is detectable in the cell nuclei. Cytogenetic analysis revealed large anomalies in the chromosomal map. Several alterations of gene copy numbers were detected by genome-wide SNP array. Among the different drugs tested, cisplatin and irinotecan showed effective inhibition of tumour cell growth in a proliferation assay at concentrations below 5 µg/ml. Subcutaneous xenotransplantation of HC-AFW1 cells into NOD/SCID mice resulted in fast growing dedifferentiated tumours with high levels of serum AFP. Histological analyses of the primary tumour and xenografts included national and international expert pathological review. Consensus reading characterised the primary tumour and the HC-AFW1-derived tumours as HCC. HC-AFW1 is the first cell line derived from a paediatric HCC without a background of viral hepatitis or cirrhosis and represents a valuable tool for investigating the biology of and therapeutic strategies for childhood HCC

Engineered Breast Cancer Cell Spheroids Reproduce Biologic Properties of Solid Tumors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135116/1/adhm201600644-sup-0001-S1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135116/2/adhm201600644.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135116/3/adhm201600644_am.pd

Smad4-expression is decreased in breast cancer tissues: a retrospective study

BACKGROUND: Although transforming growth factor β (TGF-β) typically inhibits proliferation of epithelial cells, consistent with a tumor suppressor activity, it paradoxically also exhibits pro-metastatic activity in the later stages of carcinogenesis. Since tumors often display altered TGF-β signaling, particularly involving the Smad-pathway, we investigated the role of Smad4-expression in breast cancer. METHODS: Smad4 expression was investigated by immunohistochemistry in formalin-fixed, paraffin-embedded tissue from 197 samples of primary breast cancer obtained between 1986 and 1998. The prognostic value of Smad4-expression was analyzed. RESULTS: Smad4 expression was found to be reduced in lobular and ductal breast carcinoma as compared to surrounding uninvolved lobular and ductal breast epithelia (p < 0.001, n = 50). Smad4-expression correlated positively with expression of TGF-β-receptor I (p < 0.001, n = 197) and TGF-β-receptor II (p < 0.001, n = 197), but showed no significant correlation with tumor size, metastases, nodal status, histological grade, histological type, or estrogen receptor expression. While not achieving statistical significance, there was a trend towards longer survival times in patients with Smad4 negative tumors. CONCLUSION: According to the suggested role of Smad4 as a tumor suppressor we observed that expression of Smad4 is lower in human breast cancer than in surrounding breast epithelium. However, we also observed a trend towards longer survival times in Smad4-negative patients, indicating the complex role of TGF-β signaling in tumor progression

Influence of the interaction between nodal fibroblast and breast cancer cells on gene expression

Our aim was to evaluate the interaction between breast cancer cells and nodal fibroblasts, by means of their gene expression profile. Fibroblast primary cultures were established from negative and positive lymph nodes from breast cancer patients and a similar gene expression pattern was identified, following cell culture. Fibroblasts and breast cancer cells (MDA-MB231, MDA-MB435, and MCF7) were cultured alone or co-cultured separated by a porous membrane (which allows passage of soluble factors) for comparison. Each breast cancer lineage exerted a particular effect on fibroblasts viability and transcriptional profile. However, fibroblasts from positive and negative nodes had a parallel transcriptional behavior when co-cultured with a specific breast cancer cell line. The effects of nodal fibroblasts on breast cancer cells were also investigated. MDA MB-231 cells viability and migration were enhanced by the presence of fibroblasts and accordingly, MDA-MB435 and MCF7 cells viability followed a similar pattern. MDA-MB231 gene expression profile, as evaluated by cDNA microarray, was influenced by the fibroblasts presence, and HNMT, COMT, FN3K, and SOD2 were confirmed downregulated in MDA-MB231 co-cultured cells with fibroblasts from both negative and positive nodes, in a new series of RT-PCR assays. In summary, transcriptional changes induced in breast cancer cells by fibroblasts from positive as well as negative nodes are very much alike in a specific lineage. However, fibroblasts effects are distinct in each one of the breast cancer lineages, suggesting that the inter-relationships between stromal and malignant cells are dependent on the intrinsic subtype of the tumor

Identification of germline alterations of the mad homology 2 domain of SMAD3 and SMAD4 from the Ontario site of the breast cancer family registry (CFR)

Abstract Introduction A common feature of neoplastic cells is that mutations in SMADs can contribute to the loss of sensitivity to the anti-tumor effects of transforming growth factor-β (TGF-β). However, germline mutation analysis of SMAD3 and SMAD4, the principle substrates of the TGF-β signaling pathway, has not yet been conducted in breast cancer. Thus, it is currently unknown whether germline SMAD3 and SMAD4 mutations are involved in breast cancer predisposition. Methods We performed mutation analysis of the highly conserved mad-homology 2 (MH2) domains for both genes in genomic DNA from 408 non-BRCA1/BRCA2 breast cancer cases and 710 population controls recruited by the Ontario site of the breast cancer family registry (CFR) using denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing. The results were interpreted in several ways. First, we adapted nucleotide diversity analysis to quantitatively assess whether the frequency of alterations differ between the two genes. Next, in silico tools were used to predict variants' effect on domain function and mRNA splicing. Finally, 37 cases or controls harboring alterations were tested for aberrant splicing using reverse-transcription polymerase chain reaction (PCR) and real-time PCR statistical comparison of germline expressions by non-parametric Mann-Whitney test of independent samples. Results We identified 27 variants including 2 novel SMAD4 coding variants c.1350G > A (p.Gln450Gln), and c.1701A > G (p.Ile525Val). There were no inactivating mutations even though c.1350G > A was predicted to affect exonic splicing enhancers. However, several additional findings were of note: 1) nucleotide diversity estimate for SMAD3 but not SMAD4 indicated that coding variants of the MH2 domain were more infrequent than expected; 2) in breast cancer cases SMAD3 was significantly over-expressed relative to controls (P A was associated with elevated germline expression (> 5-fold); 3) separate analysis using tissue expression data showed statistically significant over-expression of SMAD3 and SMAD4 in breast carcinomas. Conclusions This study shows that inactivating germline alterations in SMAD3 and SMAD4 are rare, suggesting a limited role in driving tumorigenesis. Nevertheless, aberrant germline expressions of SMAD3 and SMAD4 may be more common in breast cancer than previously suspected and offer novel insight into their roles in predisposition and/or progression of breast cancer