A joint modeling and exploratory framework for intra-firm collaboration within construction and mining equipment industry

PurposeIn this research, collaboration attributes related to the firm's intrinsic and extrinsic facets at pertinent levels (i.e. enterprise, strategic, operational, and tactical levels) for construction equipment OEMs (original equipment manufacturers) operating in India have been quantified and modeled.Design/methodology/approachFor modeling the intra-firm collaboration at respective organizational levels, relevant attributes have been populated employing literature review followed by subsequent validation from pertinent focus groups. The focus groups comprising professionals working in the construction and mining equipment industry in India aided us in estimating the extent of interdependencies and influences within/amongst collaboration attributes. The collaboration attributes and respective interdependencies/influences are modeled employing the concept of graph theory wherein the individual attributes are represented using vertices and influences/interdependencies are represented using edges. The collaboration indices resulting from the variable permanent matrix have been derived as well.FindingsScenario and subsequent sensitivity analysis are performed. This research discusses the significance and aspects related to various collaborative attributes and the interrelations amongst them. Further, the research also evolves quantitative measures of collaboration indices at enterprise, strategic, tactical and operational levels by employing a graph-theoretic approach (GTA). The authors have also extricated and discussed a number of meaningful implications from both the perspectives of interorganizational relationships (IORs) and the normative theory of organizations using a cross-case analysis of five firms having operations in India.Originality/valueThe research would aid organizations (particularly those belonging to the construction equipment sector) measure the efficacy of collaboration in respective value-chains at strategic, tactical and operational levels. From the theoretical perspective, the integration of the IORs and normative theory of organizations enables looking at the intra-firm collaboration problem from a multi-dimensional standpoint involving activities, performance measures, action initiation, communication, shades of top management, level of activity, etc

Role of the growth hormone–IGF-1 axis in cancer

A substantial body of evidence supports a role for the growth hormone (GH)–IGF-1 axis in cancer incidence and progression. This includes epidemiological evidence relating elevated plasma IGF-1 to cancer incidence as well as a lack of cancers in GH/IGF-1 deficiency. Rodent models lacking GH or its receptor are strikingly resistant to the induction of a wide range of cancers, and treatment with the GH antagonist pegvisomant slows tumor progression. While GH receptor expression is elevated in many cancers, autocrine GH is present in several types, and overexpression of autocrine GH can induce cell ransformation. While the mechanism of autocrine action is not clear, it does involve both STAT5 and STAT3 activation, and probably nuclear translocation of the GH receptor. Development of a more potent GH receptor antagonist or secretion inhibitor is warranted for cancer therapy

BRN2, a POUerful driver of melanoma phenotype switching and metastasis

The POU domain family of transcription factors play a central role in embryogenesis and are highly expressed in neural crest cells and the developing brain. BRN2 is a class III POU domain protein that is a key mediator of neuroendocrine and melanocytic development and differentiation. While BRN2 is a central regulator in numerous developmental programs, it has also emerged as a major player in the biology of tumourigenesis. In melanoma, BRN2 has been implicated as one of the master regulators of the acquisition of invasive behaviour within the phenotype switching model of progression. As a mediator of melanoma cell phenotype switching, it coordinates the transition to a dedifferentiated, slow cycling and highly motile cell type. Its inverse expression relationship with MITF is believed to mediate tumour progression and metastasis within this model. Recent evidence has now outlined a potential epigenetic switching mechanism in melanoma cells driven by BRN2 expression that induces melanoma cell invasion. We summarize the role of BRN2 in tumour cell dissemination and metastasis in melanoma, while also examining it as a potential metastatic regulator in other tumour models.</p

Reciprocal regulation of BRN2 and NOTCH1/2 signaling synergistically drives melanoma cell migration and invasion

Phenotypic plasticity drives cancer progression, impacts on treatment response and is a major driver of therapeutic resistance. In melanoma, a regulatory axis between the MITF and BRN2 transcription factors has been reported to promote tumor heterogeneity by mediating switching between proliferative and invasive phenotypes respectively. Despite strong evidence that subpopulations of cells that exhibit a BRN2high/MITFlow expression profile switch to a predominantly invasive phenotype, the mechanisms by which this switch is propagated and promotes invasion remain poorly defined. We have found that a reciprocal relationship between BRN2 and NOTCH1/2 signaling exists in melanoma cells in vitro, within patient datasets and in vivo primary and metastatic human tumors that bolsters acquisition of invasiveness. Working through the epigenetic modulator EZH2, the BRN2- NOTCH1/2 axis is potentially a key mechanism by which the invasive phenotype is maintained. Given the emergence of agents targeting both EZH2 and NOTCH, understanding the mechanism through which BRN2 promotes heterogeneity may provide crucial biomarkers to predict treatment response to prevent metastasis

NR4A2 promotes DNA double-strand break repair upon exposure to UVR

Exposure of melanocytes to ultraviolet radiation (UVR) induces the formation of UV-lesions that can produce deleterious effects in genomic DNA. Encounters of replication forks with unrepaired UV-lesions can lead to several complex phenomena, such as the formation of DNA double strand breaks (DSBs). The NR4A family of nuclear receptors are transcription factors that have been associated with mediating DNA repair functions downstream of the MC1R signalling pathway in melanocytes. In particular, emerging evidence shows that upon DNA damage, the NR4A2 receptor can translocate to sites of UV-lesion by mechanisms requiring post-translational modifications within the N-terminal domain and at a serine residue in the DNA biding domain at position 337. Following this, NR4A2 aids in DNA repair by facilitating chromatin relaxation, allowing accessibility for DNA repair machinery. Using A2058 and HT144 melanoma cells engineered to stably express wild-type or mutant forms of the NR4A2 proteins, we reveal that the expression of functional NR4A2 is associated with elevated cytoprotection against UVR. Conversely, knock-down of NR4A2 expression by siRNA results in a significant loss of cell viability after UV insult. By analysing the kinetics of the ensuing 53BP1 and RAD51 foci following UV-irradiation, we also reveal that the expression of mutant NR4A2 isoforms, lacking the ability to translocate, trans-activate or undergo phosphorylation, display compromised repair capacity. Implications: These data expand the understanding of the mechanism by which the NR4A2 nuclear receptor can facilitate DNA DSB repair