Digital business platforms (DBPs) such as eBay, Google, and Uber Technologies have seen enormous growth; this paper explores their salient characteristics, the role of marketing in helping DBPs ...succeed, and important research topics for theory and practice. A new conceptual framework based on insights from transaction cost analysis outlines the role and impact of marketing in DBPs. A key role for marketing is to increase the number and quality of interactions on a DBP while reducing transaction costs for users and production costs for the DPB. The DBPs' interactions and the data thus generated are key enablers of value creation and value appropriation on these platforms. However, there are several challenges to resolve in value creation and value appropriation because DBPs cater to the needs of many different types of users. Therefore, DBPs should carefully coordinate and manage interactions among users on different sides of a platform. For researchers, there are many opportunities to reconceptualize some of the traditional roles of marketing in the context of DBPs.
•Conceptualization of Digital Business Platforms (DBPs) and their characteristics.•Transaction Cost Analysis framework to articulate the roles of of marketing in DBPs.•Marketing in DBPs must reduce transaction and production costs and enhance benefits for users.•How DBPs change the way value is created and appropriated.•Future research to address theoretical, empirical, and managerial issues of DBPs.
Desmosome-anchored keratin intermediate filaments (KFs) are essential for epithelial coherence. Yet, desmosomal KF attachment and network organization are still unexplored in vivo. We, therefore, ...monitored KF network morphogenesis in fluorescent keratin 8 knock-in murine embryos revealing keratin enrichment at newly formed desmosomes followed by KF formation, KF elongation and KF fusion. To examine details of this process and its coupling to desmosome formation, we studied fluorescent keratin and desmosomal protein reporter dynamics in the periphery of expanding HaCaT keratinocyte colonies. Less than 3 min after the start of desmosomal proteins clustering non-filamentous keratin enriched at these sites followed by KF formation and elongation. Subsequently, desmosome-anchored KFs merged into stable bundles generating a rim-and-spokes system consisting of subcortical KFs connecting desmosomes to each other and radial KFs connecting desmosomes to the cytoplasmic KF network. We conclude that desmosomes are organizing centers for the KF cytoskeleton with a hitherto unknown nucleation capacity.
Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2+Ly6Chi monocytes. However, the mechanisms driving tumor cell ...extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2+ endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2−/− mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.
► Tumor-cell derived CCL2 controls vascular permeability, extravasation, and metastasis ► Endothelial CCR2 expression is necessary and sufficient for extravasation/ metastasis ► Activation of JAK2-Stat5 and p38MAPK signaling via CCR2 induce vascular permeability ► CCL2 expression levels correlate with metastatic potential of UICC IV colon carcinoma
Purpose: In carcinomas, invasive tumor growth is accompanied by desmoplastic stroma reaction and facilitated by epithelial-mesenchymal
transition (EMT) of cancer cells. We investigated the prognostic ...significance of the EMT indicator proteins periostin and
vimentin in comparison with versican, a putative indicator of the opposite mechanism mesenchymal-epithelial transition (MET),
and to the desmoplasia proteins collagen and elastin in non-small cell lung cancer (NSCLC).
Experimental Design: Tumor of 533 patients with surgically resected NSCLC was used for analysis of stromal and epithelial protein expression by
immunohistochemistry (EMT-MET proteins) and Elastica van Gieson histochemical staining (collagen and elastin). A semiquantitative
sum scoring system was done on three tissue microarrays.
Results: Of the 533 patients, 48% had squamous cell carcinoma, 47% adenocarcinoma, and 5% adenosquamous carcinoma. High expression
of periostin in either stroma or tumor epithelia, independently scored by two pathologists, correlated with male gender, higher
stage, higher pT category, and larger tumor size, and in only stroma with tumor relapse. High expression of versican in either
stroma or epithelia as well as of stromal collagen had fewer but concordant associations with advanced tumor and periostin,
respectively. High expression of elastin was oppositely associated with less advanced disease. Associations of high vimentin
were inconsistent (all P values <0.05). High stromal periostin was found to be a prognostic factor for decreased progression-free survival on univariate
analysis ( P = 0.007).
Conclusions: Because up-regulation is frequently observed in the stromal and epithelial tumor compartment, EMT-MET indicator proteins
may be integrated in progression models of NSCLC.
Hepatocellular carcinoma (HCC), the fastest rising cancer in the United States and increasing in Europe, often occurs with nonalcoholic steatohepatitis (NASH). Mechanisms underlying NASH and ...NASH-induced HCC are largely unknown. We developed a mouse model recapitulating key features of human metabolic syndrome, NASH, and HCC by long-term feeding of a choline-deficient high-fat diet. This induced activated intrahepatic CD8+ T cells, NKT cells, and inflammatory cytokines, similar to NASH patients. CD8+ T cells and NKT cells but not myeloid cells promote NASH and HCC through interactions with hepatocytes. NKT cells primarily cause steatosis via secreted LIGHT, while CD8+ and NKT cells cooperatively induce liver damage. Hepatocellular LTβR and canonical NF-κB signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development.
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•CD-HFD recapitulates metabolic syndrome, NASH, and NASH-induced HCC in humans•NKT cells mediate lipid uptake via LTβR activation on hepatocytes•CD8+ and NKT cells promote liver damage, NASH, and HCC development•NASH-to-HCC transition is facilitated by hepatic LTβR and canonical NF-κB signaling
Wolf et al. examine a mouse model of human metabolic syndrome that predispose patients to hepatocellular carcinoma (HCC) and find that activated CD8+ T cells and NKT cells in the liver are important in promoting nonalcoholic steatohepatitis that leads to HCC.
Tumor mutational burden (TMB) is a quantitative assessment of the number of somatic mutations within a tumor genome. Immunotherapy benefit has been associated with TMB assessed by whole-exome ...sequencing (wesTMB) and gene panel sequencing (psTMB). The initiatives of Quality in Pathology (QuIP) and Friends of Cancer Research have jointly addressed the need for harmonization among TMB testing options in tissues. This QuIP study identifies critical sources of variation in psTMB assessment.
A total of 20 samples from three tumor types (lung adenocarcinoma, head and neck squamous cell carcinoma, and colon adenocarcinoma) with available WES data were analyzed for psTMB using six panels across 15 testing centers. Interlaboratory and interplatform variation, including agreement on variant calling and TMB classification, were investigated. Bridging factors to transform psTMB to wesTMB values were empirically derived. The impact of germline filtering was evaluated.
Sixteen samples had low interlaboratory and interpanel psTMB variation, with 87.7% of pairwise comparisons revealing a Spearman’s ρ greater than 0.6. A wesTMB cut point of 199 missense mutations projected to psTMB cut points between 7.8 and 12.6 mutations per megabase pair; the corresponding psTMB and wesTMB classifications agreed in 74.9% of cases. For three-tier classification with cut points of 100 and 300 mutations, agreement was observed in 76.7%, weak misclassification in 21.8%, and strong misclassification in 1.5% of cases. Confounders of psTMB estimation included fixation artifacts, DNA input, sequencing depth, genome coverage, and variant allele frequency cut points.
This study provides real-world evidence that all evaluated panels can be used to estimate TMB in a routine diagnostic setting and identifies important parameters for reliable tissue TMB assessment that require careful control. As complex or composite biomarkers beyond TMB are likely playing an increasing role in therapy prediction, the efforts by QuIP and Friends of Cancer Research also delineate a general framework and blueprint for the evaluation of such assays.
Hepatocellular carcinomas (HCCs) and bile duct carcinomas (BDCs) have a poor prognosis. Therefore, surveillance strategies including sensitive and specific serum markers for early detection are ...needed. Recently, Golgi Phosphoprotein 2 (GOLPH2) has been proposed as a serum marker for HCC, but GOLPH2 expression data in liver tissues was not available. Using tissue microarrays and immunohistochemistry, we semiquantitatively analyzed GOLPH2 protein expression in patients with HCC (n = 170), benign liver tumors (n = 22), BDC (n = 114) and normal liver tissue (n = 105). A newly designed sandwich enzyme‐linked immunoassay (ELISA) was used to analyze GOLPH2 levels in the sera of patients with HCC (n = 62), hepatitis C virus (HCV) (n = 29), BDC (n = 10), and healthy control persons (n = 12). By immunohistochemistry 121/170 (71%) of HCC showed strong GOLPH2 expression, which was significantly associated with a higher tumor grade (P = 0.01). A total of 97/114 (85%) BDCs showed a strong GOLPH2 expression which proved to be an independent prognostic factor for overall survival (P < 0.05). Serum levels of GOLPH2 measured by ELISA were significantly elevated in patients with HCC with underlying HCV infection (median 18 mg/L, P < 0.05) and patients with BDC (median = 14.5 mg/L, P < 0.01) in comparison to healthy controls (median 4 mg/L). Conclusion: GOLPH2 protein is highly expressed in tissues of HCC and BDC. GOLPH2 protein levels are detectable and quantifiable in sera by ELISA. In patients with hepatitis C, serial ELISA measurements in the course of the disease appear to be a promising complementary serum marker in the surveillance of HCC. GOLPH2 should be further evaluated as a serum tumor marker in BDC on a larger scale. (HEPATOLOGY 2009.)
Proteins of the lysyl oxidase (LOX) family are important modulators of the extracellular matrix. However, they have an important role in the tumour development as well as in tumour progression. To ...evaluate the diagnostic and prognostic value of the LOX protein in oral and oropharyngeal squamous cell carcinoma (OSCC) we performed QRT‐PCR and immunohistochemical analysis on two tissue microarrays (622 tissue samples in total). Significantly higher LOX expression was detected in high grade dysplastic oral mucosa as well as in OSCC when compared to normal oral mucosa (P < 0.001). High LOX expression was correlated with clinical TNM stage (P = 0.020), lymph node metastases for the entire cohort (P < 0.001), as well as in the subgroup of small primary tumours (T1/T2, P < 0.001). Moreover, high LOX expression was correlated with poor overall survival (P = 0.004) and disease specific survival (P = 0.037). In a multivariate analysis, high LOX expression was an independent prognostic factor, predicting unfavourable overall survival. In summary, LOX expression is an independent prognostic biomarker and a predictor of lymph node metastasis in OSCC. Moreover, LOX overexpression may be an early phenomenon in the pathogenesis of OSCC and thus an attractive novel target for chemopreventive and therapeutic strategies.
Prognostic factors in predicting occult lymph node metastasis in patients with head and neck squamous-cell carcinoma (HNSCC) are necessary to improve the results of the sentinel lymph node procedure ...in this tumour type. The E-Cadherin glycoprotein is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections.
To determine the value of the molecular marker E-Cadherin in predicting regional metastatic disease.
E-Cadherin expression in tumour tissue of 120 patients with HNSCC of the oral cavity and oropharynx were evaluated using the tissue microarray technique. 110 tumours were located in the oral cavity (91.7%; mostly tongue), 10 tumours in the oropharynx (8.3%). Intensity of E-Cadherin expression was quantified by the Intensity Reactivity Score (IRS). These results were correlated with the lymph node status of biopsied sentinel lymph nodes. Univariate and multivariate analysis was used to determine statistical significance.
pT-stage, gender, tumour side and location did not correlate with lymph node metastasis. Differentiation grade (p = 0.018) and down regulation of E-Cadherin expression significantly correlate with positive lymph node status (p = 0.005) in univariate and multivariate analysis.
These data suggest that loss of E-cadherin expression is associated with increased lymhogeneous metastasis of HNSCC. E-cadherin immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity and oropharynx.
2b.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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