Additive Manufacturing for Localized Medical Parts Production: A Case Study.

Centralized supply chains (SCs) are prone to disruption, which makes them a risky choice for medical equipment production. Additive manufacturing (AM) allows for production localization and improvements in SC resilience. However, the comparative competitiveness of a localized SC from the time and cost perspective is still unclear. In this study, we investigate the competitiveness of localized medical part AM SCs against centralized ones by analyzing the responsiveness and cost of each SC. We utilize a real-world case study in which an AM service provider supplies medical parts to university medical centers in the Netherlands to construct six scenarios. We also develop a thorough empirical cost formulation for both central and local AM of patient-specific medical parts. The results of scenario analysis show that when utilizing the currently available AM technology, localized SC configurations significantly reduce the delivery time from about 54 to 27h, but at a 4.3-fold higher cost. Hence, we illustrate that the cost difference between the localized and centralized scenarios can be reduced when state-of-the-art AM machines are utilized, demand volumes increase, and the distances between the SC network nodes expand. Moreover, our scenario analysis confirms that the cost of the measures taken to prevent dust dispersion associated with powder-bed fusion AM has a major impact on the total cost of localized AM SCs for medical parts. The results of this study contribute to the understanding of the relevant factors in deciding whether central or localized SC configurations can be used in the AM production of medical parts. Furthermore, this study provides managerial insights for decision-makers at governments and hospitals as well as AM service providers and AM equipment manufacturers.

Targeting the STAT pathway in head and neck cancer: recent advances and future prospects.

Head and neck cancer, the sixth most common type of cancer worldwide, is associated with a dismal prognosis that has minimally improved during the last few decades. Future advances in the treatment and prognosis of this fatal disease largely rely upon a better understanding of the molecular events that underlie tumor development and progression, allowing specific targeting of the involved molecules and pathways. In this context, recent efforts have revolved around a family of transcription factors known as STATs (signal transducers and activators of transcription). STAT proteins comprise a family of latent cytoplasmic transcription factors that become transiently activated in response to extracellular signals, leading to regulation of diverse physiological responses. There is compelling evidence that persistent activation of specific STAT molecules, especially Stat3 and Stat5, possesses oncogenic properties in a number of human cancers, including head and neck cancer. The presence of constitutively activated STAT molecules in cancer cells is mainly attributed to the dysregulation of upstream activating pathways and the aberration of negative regulatory mechanisms. The end result is induction of specific target genes that stimulate cell proliferation, prevent apoptosis, promote angiogenesis and facilitate tumor immune evasion. Therefore, targeting and disruption of oncogenic STAT signaling may theoretically be accomplished through various approaches, involving direct (e.g. interference with the various facets of STAT expression, activation or function) and indirect strategies (e.g. inhibition of upstream signaling events and enhancement or restoration of negative regulatory mechanisms). The availability of multiple potential targets for interruption of aberrant STAT signaling in cancer and the thus-far promising results have generated optimism for the clinical applicability of STAT targeting in head and neck cancer, which is the focus of this review.

Signal transducers and activators of transcription: insights into the molecular basis of oral cancer.

Recent efforts on developing more direct and effective targets for cancer therapy have revolved around a family of transcription factors known as STATs (signal transducers and activators of transcription). STAT proteins are latent cytoplasmic transcription factors that become activated in response to extracellular signaling proteins. STAT proteins have been convincingly reported to possess oncogenic properties in a plethora of human cancers, including oral and oropharyngeal cancer. Signal transduction pathways mediated by these oncogenic transcription factors and their regulation in oral cancer are the focus of this review.

Abrogation of IL-6-mediated JAK signalling by the cyclopentenone prostaglandin 15d-PGJ(2) in oral squamous carcinoma cells.

Cyclopentenone 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) exerts antineoplastic effects on various types of human cancer. We recently showed that treatment with 15d-PGJ(2) induces apoptosis accompanied by downregulation of the oncogenic signal transducer and activator of transcription 3 (Stat3) signalling in human oral squamous cell carcinoma (SCC) cells. The current study examines the effects of 15d-PGJ(2) on the epidermal growth factor receptor (EGFR) and Janus Kinase (JAK)-mediated signalling pathways. Inhibition of Stat3 by 15d-PGJ(2) was abolished by exogenous stimulation with transforming growth factor alpha (TGF-alpha), but not interleukin 6 (IL-6), supporting a selective effect of 15d-PGJ(2) on IL-6-mediated signalling. Importantly, 15d-PGJ(2) selectively abrogated constitutive and IL-6-mediated JAK phosphorylation without affecting EGFR-activated levels. Moreover, the inhibitory effect of 15d-PGJ(2) on JAK signalling required the reactive alpha,beta-unsaturated carbon within the cyclopentenone ring. Targeting of JAK signalling using a specific JAK inhibitor also abolished Stat3 phosphorylation and resulted in apoptosis in oral SCC cells. Our findings provide the first evidence for 15d-PGJ(2)-mediated downregulation of constitutive and IL-6-induced JAK signalling in cancer and support that JAK inhibition and suppression of EGFR-independent Stat3 activation by 15d-PGJ(2) represent a promising approach for induction of apoptosis in oral SCC cells.

Phenotypic switching of VEGF and collagen XVIII during hypoxia in head and neck squamous carcinoma cells.

The present study sought to determine the potential role of stress activated MAPK and phosphatidylinositol 3-kinase (PI3K) signaling pathways in mediating phenotypic switching between angiogenic and angiostatic elements among squamous cell carcinoma (SCC) cell lines. In particular, we investigated the effects of hypoxia and those of cobalt chloride (CoCl(2)), which mimics the hypoxic response including the production of reactive oxygen species, on such phenotypic shifts. The expression and production of collagen XVIII, and CBP2/Hsp47 provided a measure of an angiostatic phenotype, while vascular endothelial growth factor (VEGF) expression was used to assess potential angiogenic states. These studies revealed that hypoxia produced a slight up-regulation of collagen XVIII and CBP2/Hsp47 that was inhibited by the stress kinase inhibitor SB203580 but was unaffected by N-acetylcysteine (NAC). In addition, VEGF expression was increased following hypoxia and this effect was reversed with inhibition of by SB203580. Conversely, CoCl(2) significantly diminished the expression of both collagen XVIII and CBP2/Hsp47 and enhanced VEGF expression. These changes were reversed by the PI3K inhibitor wortmannin and by treating cells with NAC. These studies show that phenotypic switching between collagen XVIII and VEGF is controlled by stress activated kinases under hypoxia, and PI3K signaling pathways as well as reactive oxygen species (ROS) following CoCl(2) treatment. Furthermore, modulation of the angiogenic switch is most profound during Akt activation than during activation of stress activated kinases.

15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells.

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been linked to induction of differentiation, cell growth inhibition and apoptosis in several types of human cancer. However, the possible effects of PPARgamma agonists on human oral squamous cell carcinoma have not yet been reported. In this study, treatment with 15-deoxy-Delta(12,14)-PGJ(2) (15-PGJ(2)), a natural PPARgamma ligand, induced a significant reduction of oral squamous cell carcinoma cell growth, which was mainly attributed to upregulation of apoptosis. Interestingly, rosiglitazone and ciglitazone, two members of the thiazolidinedione family of PPARgamma activators, did not exert a growth inhibitory effect. Given the critical role that the oncogene signal transducer and activator of transcription 3 (Stat3) plays in head and neck carcinogenesis, its potential regulation by PPARgamma ligands was also examined. Treatment of oral squamous cell carcinoma cells with 15-PGJ(2) induced an initial reduction and eventual elimination of both phosphorylated and unphosphorylated Stat3 protein levels. In contrast, other PPARgamma did not induce similar effects. Our results provide the first evidence of significant antineoplastic effects of 15-PGJ(2) on human oral squamous cell carcinoma cells, which may be related to downmodulation of Stat3 and are at least partly mediated through PPARgamma-independent events.