A Network-based Approach to Organizational Culture and Learning in System Safety

AbstractWhile it is now generally agreed that system safety cannot be adequately addressed using technical analysis alone, an approach to modeling the organizational issues associated with safety is still needed. This paper offers an analytical approach to assessing the complex relationships among organizational culture and safety practices and outcomes. The paper argues that, in principle, organizational culture can be represented as a network of shared mental models (SMMs). While it would be impractical to construct a network that fully captures an organization's culture, the approach can be used to model particular dimensions of culture. Thus, a network of SMMs is a meaningful representation of safety culture to the extent that the data effectively capture shared knowledge about system safety. Similarly, organizational learning can be quantified as the evolution of that network's structure over time. The goal of the research is to develop a quantitative methodology for analyzing the relationship of organizational culture and learning to safety performance. The research is built on a collaborative effort between academia and industry focused on improving process safety in the oil and gas industry, but it can be applied to safety-related problems across organizations. The results are expected to have implications for training, professional development, safety protocols, and methods for measuring and managing safety practices in the development and operation of complex engineered systems

New advances in the study of bone tumors: A lesson from the 3D environment

Bone primary tumors, such as osteosarcoma, are highly aggressive pediatric tumors that in 30% of the cases develop lung metastasis and are characterized by poor prognosis. Bone is also the third most common metastatic site in patients with advanced cancer and once tumor cells become homed to the skeleton, the disease is usually considered incurable, and treatment is only palliative. Bone sarcoma and bone metastasis share the same tissue microenvironment and niches. 3D cultures represent a new promising approach for the study of interactions between tumor cells and other cellular or acellular components of the tumor microenvironment (i.e., fibroblasts, mesenchymal stem cells, bone ECM). Indeed, 3D models can mimic physiological interactions that are crucial to modulate response to soluble paracrine factors, tumor drug resistance and aggressiveness and, in all, these innovative models might be able of bypassing the use of animal-based preclinical cancer models. To date, both static and dynamic 3D cell culture models have been shown to be particularly suited for screening of anticancer agents and might provide accurate information, translating in vitro cell cultures into precision medicine. In this mini-review, we will summarize the current state-of-the-art in the field of bone tumors, both primary and metastatic, illustrating the different methods and techniques employed to realize 3D cell culture systems and new results achieved in a field that paves the way toward personalized medicine

The microfluidic trainer: Design, fabrication and validation of a tool for testing and improving manual skills

Microfluidic principles have been widely applied for more than 30 years to solve biological and micro-electromechanical problems. Despite the numerous advantages, microfluidic devices are difficult to manage as their handling comes with several technical challenges. We developed a new portable tool, the microfluidic trainer (MT), that assesses the operator handling skills and that may be used for maintaining or improving the ability to inject fluid in the inlet of microfluidic devices for in vitro cell culture applications. After several tests, we optimized the MT tester cell to reproduce the real technical challenges of a microfluidic device. In addition to an exercise path, we included an overfilling indicator and a correct infilling indicator at the inlet (control path). We manufactured the MT by engraving a 3 mm-high sheet of methacrylate with 60W CO2 laser plotter to create multiple capillary paths. We validated the device by enrolling 21 volunteers (median age 33) to fill both the MT and a commercial microfluidic device. The success rate obtained with MT significantly correlated with those of a commercial microfluidic culture plate, and its 30 min-continuous use for three times significantly improved the performance. Overall, our data demonstrate that MT is a valid assessment tool of individual performances in using microfluidic devices and may represent a low-cost solution to training, improve or warm up microfluidic handling skills

Perfused Platforms to Mimic Bone Microenvironment at the Macro/Milli/Microscale: Pros and Cons

As life expectancy increases, the population experiences progressive ageing. Ageing, in turn, is connected to an increase in bone-related diseases (i.e., osteoporosis and increased risk of fractures). Hence, the search for new approaches to study the occurrence of bone-related diseases and to develop new drugs for their prevention and treatment becomes more pressing. However, to date, a reliable in vitro model that can fully recapitulate the characteristics of bone tissue, either in physiological or altered conditions, is not available. Indeed, current methods for modelling normal and pathological bone are poor predictors of treatment outcomes in humans, as they fail to mimic the in vivo cellular microenvironment and tissue complexity. Bone, in fact, is a dynamic network including differently specialized cells and the extracellular matrix, constantly subjected to external and internal stimuli. To this regard, perfused vascularized models are a novel field of investigation that can offer a new technological approach to overcome the limitations of traditional cell culture methods. It allows the combination of perfusion, mechanical and biochemical stimuli, biological cues, biomaterials (mimicking the extracellular matrix of bone), and multiple cell types. This review will discuss macro, milli, and microscale perfused devices designed to model bone structure and microenvironment, focusing on the role of perfusion and encompassing different degrees of complexity. These devices are a very first, though promising, step for the development of 3D in vitro platforms for preclinical screening of novel anabolic or anti-catabolic therapeutic approaches to improve bone health

Impairment of lysosomal activity as a therapeutic modality targeting cancer stem cells of embryonal rhabdomyosarcoma cell line RD.

Rhabdomyosarcoma is the most frequent soft tissue sarcoma in children and adolescents, with a high rate of relapse that dramatically affects the clinical outcome. Multiagent chemotherapy, in combination with surgery and/or radiation therapy, is the treatment of choice. However, the relapse rate is disappointingly high and identification of new therapeutic tools is urgently needed. Under this respect, the selective block of key features of cancer stem cells (CSC) appears particularly promising. In this study, we isolated rhabdomyosarcoma CSC with stem-like features (high expression of NANOG and OCT3/ 4, self-renewal ability, multipotency). Rhabdomyosarcoma CSC showed higher invasive ability and a reduced cytotoxicity to doxorubicin in comparison to native cells, through a mechanism unrelated to the classical multidrug resistance process. This was dependent on a high level of lysosome acidity mediated by a high expression of vacuolar ATPase (V-ATPase). Since it was not associated with other paediatric cancers, like Ewing\u2019s sarcoma and neuroblastoma, V-ATPase higher expression in CSC was rhabdomyosarcoma specific. Inhibition of lysosomal acidification by the V-ATPase inhibitor omeprazole, or by specific siRNA silencing, significantly enhanced doxorubicin cytoxicity. Unexpectedly, lysosomal targeting also blocked cell growth and reduced the invasive potential of rhabdomyosarcoma CSC, even at very low doses of omeprazole (10 and 50 mM, respectively). Based on these observations, we propose lysosome acidity as a valuable target to enhance chemosensitivity of rhabdomyosarcoma CSC, and suggest the use of anti-V-ATPase agents in combination with standard regimens as a promising tool for the eradication of minimal residual disease or the prevention of metastatic disease

Pre-clinical Models for Studying the Interaction between Mesenchymal Stromal Cells and Cancer Cells and the Induction of Stemness

Mesenchymal stromal cells (MSC) have essential functions in building and supporting the tumour microenvironment, providing metastatic niches, and maintaining cancer hallmarks, and it is increasingly evident that the study of the role of MSC in cancer is crucial for paving the way to clinical opportunities for novel anti-cancer therapies. To date, the vast majority of preclinical models that have been used for studying the effect of reactive MSC on cancer growth, metastasis, and response to therapy has been mainly based on in vitro flat biology, including the co-culturing with cell compartmentalization or with cell-to-cell contact, and on in vivo cancer models with different routes of MSC inoculation. More complex in vitro 3D models based on spheroid structures that are formed by intermingled MSC and tumour cells are also capturing the interest in cancer research. These are innovative culture systems tailored on the specific tumour type and that can be combined with a synthetic extracellular matrix, or included in in silico technologies, to more properly mimic the in vivo biological, spatial, biochemical, and biophysical features of tumour tissues. In this review, we summarized the most popular and currently available preclinical models for evaluating the role of MSC in cancer and their specific suitability, for example, in assaying the MSC-driven induction of epithelial-to-mesenchymal transition or of stem-like traits in cancer cells. Finally, we enlightened the need to carefully consider those parameters that might unintentionally strongly affect the secretome in MSC-cancer interplay and introduce confounding variables for the interpretation of results

Annual Meeting of the International Society of Cancer Metabolism (ISCaM): Metabolic Adaptations and Targets in Cancer

The metabolism of cancer cells differs from that of their normal counterparts in a spectrum of attributes, including imbalances in diverse metabolic arms and pathways, metabolic plasticity and extent of adaptive responses, levels, and activities of metabolic enzymes and their upstream regulators and abnormal fluxes of metabolic intermediates and products. These attributes endow cancer cells with the ability to survive stressors of the tumor microenvironment and enable them to landscape and exploit the host terrain, thereby facilitating cancer progression and therapy resistance. Understanding the molecular and physiological principles of cancer metabolism is one of the key prerequisites for the development of better anticancer treatments. Therefore, various aspects of cancer metabolism were addressed at the 5th annual meeting of the International Society of Cancer Metabolism (ISCaM) in Bratislava, Slovakia, on October 17\u201320, 2018. The meeting presentations and discussions were traditionally focused on mechanistic, translational, and clinical characteristics of metabolism and pH control in cancer, at the level of molecular pathways, cells, tissues, and organisms. In order to reflect major healthcare challenges of the current era, ISCaM has extended its scope to metabolic disorders contributing to cancer, as well as to opportunities for their prevention, intervention, and therapeutic targeting

Photodynamic Surgery for Feline Injection-Site Sarcoma

Musculoskeletal sarcomas are rare and aggressive human malignancies affecting bones and soft tissues with severe consequences, in terms of both morbidity and mortality. An innovative technique that combines photodynamic surgery (PDS) and therapy (PDT) with acridine orange has been recently suggested, showing promising results. However, due to the low incidence of sarcoma in humans, this procedure has been attempted only in pilot studies and stronger evidence is needed. Naturally occurring tumors in cats are well-established and advantageous models for human cancers. Feline injection-site sarcoma (FISS) shares with human musculoskeletal sarcomas a mesenchymal origin and an aggressive behavior with a high relapse rate. Furthermore, wide surgical excision is not always possible due to the size and site of development. We assessed the feasibility and the effectiveness of PDS and PDT with acridine orange to prevent FISS recurrence by treating a short case series of cats. For PDS, the surgical field was irrigated with an acridine orange solution and exposed to UV light to enlighten the residual tumor tissue, and the resultant fluorescent areas were trimmed. For PDT, before wound closure, the field was again irrigated with acridine orange solution and exposed to visible light to get the antitumoral cytocidal effect. The procedure was easy to perform and well tolerated, we did not observe any major complications, and all the surgical resection margins were free of disease. Finally, at follow-up, all treated patients did not show evidence of tumor recurrence and had a significantly higher event-free survival rate in respect to a control group treated only by surgery. In conclusion, by this study we demonstrated that, in FISS, PDS and PDT with acridine orange may improve local tumor control, granting a better outcome, and we laid the foundation to validate its effectiveness for the treatment of human musculoskeletal sarcomas

Contribution of mitochondrial activity to doxorubicin-resistance in osteosarcoma cells

: Osteosarcoma is considered the most common bone tumor affecting children and young adults. The standard of care is chemotherapy; however, the onset of drug resistance still jeopardizes osteosarcoma patients, thus making it necessary to conduct a thorough investigation of the possible mechanisms behind this phenomenon. In the last decades, metabolic rewiring of cancer cells has been proposed as a cause of chemotherapy resistance. Our aim was to compare the mitochondrial phenotype of sensitive osteosarcoma cells (HOS and MG-63) versus their clones when continuously exposed to doxorubicin (resistant cells) and identify alterations exploitable for pharmacological approaches to overcome chemotherapy resistance. Compared with sensitive cells, doxorubicin-resistant clones showed sustained viability with less oxygen-dependent metabolisms, and significantly reduced mitochondrial membrane potential, mitochondrial mass, and ROS production. In addition, we found reduced expression of TFAM gene generally associated with mitochondrial biogenesis. Finally, combined treatment of resistant osteosarcoma cells with doxorubicin and quercetin, a known inducer of mitochondrial biogenesis, re-sensitizes the doxorubicin effect in resistant cells. Despite further investigations being needed, these results pave the way for the use of mitochondrial inducers as a promising strategy to re-sensitize doxorubicin cytotoxicity in patients who do not respond to therapy or reduce doxorubicin side effects