Building a competitive infrastructure to support clinical research in healthcare institution.

BACKGROUND: Clinical research is becoming increasingly popular in Europe at a growth rate much higher than expected, especially in Benelux. Although traditionally thought to be the purview of academic health centres, clinical research to evaluate new drugs, devices and medical practices is being done more and more in healthcare organizations with little or no academic affiliation. METHODS: By managing a new infrastructure and centralizing resources and demands, clinical research unit (CRU) has become an effective mechanism for hospital research. The 'infrastructure' or CRU refers to the necessary resources and how the CRU is organized and communicates operationally to conduct clinical research within the institution. The creation of a new CRU within the Robert Schuman Hospital in Luxembourg is described in this article. RESULTS: This article discusses the concrete steps and basic elements such as patient-centric and hospital approaches needed to create and structure a CRU to provide academic or industry-sponsored research support in clinical research. CONCLUSIONS: Some infrastructure challenges (insufficient engagement, regulatory and administrative barriers) and possible courses of action (standardized procedures, training and centralization) will be discussed.

Towards lipidomics of low-abundant species for exploring tumor heterogeneity guided by high-resolution mass spectrometry imaging.

Many studies have evidenced the main role of lipids in physiological and also pathological processes such as cancer, diabetes or neurodegenerative diseases. The identification and the in situ localization of specific low-abundant lipid species involved in cancer biology are still challenging for both fundamental studies and lipid marker discovery. In this paper, we report the identification and the localization of specific isobaric minor phospholipids in human breast cancer xenografts by FTICR MALDI imaging supported by histochemistry. These potential candidates can be further confirmed by liquid chromatography coupled with electrospray mass spectrometry (LC-ESI-MS) after extraction from the region of interest defined by MALDI imaging. Finally, this study highlights the importance of characterizing the heterogeneous distribution of low-abundant lipid species, relevant in complex histological samples for biological purposes.

Design a Clinical Research Protocol: Influence of Real-World Setting.

The design of a clinical research protocol to evaluate new therapies, devices, patient quality of life, and medical practices from scratch is probably one of the greatest challenges for the majority of novice researchers. This is especially true since a high-quality methodology is required to achieve success and effectiveness in academic and hospital research centers. This review discusses the concrete steps and necessary guidelines needed to create and structure a research protocol. Along with the methodology, some administrative challenges (ethics, regulatory and people-management barriers) and possible time-saving recommendations (standardized procedures, collaborative training, and centralization) are discussed.

Clinical Research in Prehospital Care: Current and Future Challenges.

Prehospital care plays a critical role in improving patient outcomes, particularly in cases of time-sensitive emergencies such as trauma, cardiac failure, stroke, bleeding, breathing difficulties, systemic infections, etc. In recent years, there has been a growing interest in clinical research in prehospital care, and several challenges and opportunities have emerged. There is an urgent need to adapt clinical research methodology to a context of prehospital care. At the same time, there are many barriers in prehospital research due to the complex context, posing unique challenges for research, development, and evaluation. Among these, this review allows the highlighting of limited resources and infrastructure, ethical and regulatory considerations, time constraints, privacy, safety concerns, data collection and analysis, selection of a homogeneous study group, etc. The analysis of the literature also highlights solutions such as strong collaboration between emergency medical services (EMS) and hospital care, use of (mobile) health technologies and artificial intelligence, use of standardized protocols and guidelines, etc. Overall, the purpose of this narrative review is to examine the current state of clinical research in prehospital care and identify gaps in knowledge, including the challenges and opportunities for future research.

Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence.

PROBLEM: Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and progress under a continuous shift between hypoxia-reoxygenation after neoadjuvent-therapy are unknown. In this study, we investigated the role of lipid metabolism and tumor redox balance in tumor recurrence. METHODS: Lipidomics, proteomics and mass spectrometry imaging approaches where applied to mouse tumor models of recurrence. Genetic and pharmacological inhibitions of lipid mediators in tumors were used in vivo and in functional assays in vitro. RESULTS: We found that stearoyl-CoA desaturase-1 (SCD1) expressed by cancer cells and fatty acid binding protein-4 (FABP4) produced by tumor endothelial cells (TECs) and adipocytes in the tumor microenvironment (TME) are essential for tumor relapse in response to tyrosine kinase inhibitors (TKI) and chemotherapy. SCD1 and FABP4 were also found upregulated in recurrent human breast cancer samples and correlated with worse prognosis of cancer patients with different types of tumors. Mechanistically, SCD1 leads to fatty acid (FA) desaturation and FABP4 derived from TEM enhances lipid droplet (LD) in cancer cells, which cooperatively protect from oxidative stress-induced ferroptosis. We revealed that lipid mobilization and desaturation elicit tumor intrinsic antioxidant and anti-ferroptotic resources for survival and regrowth in a harsh TME. Inhibition of lipid transport from TME by FABP4 inhibitor reduced tumor regrowth and by genetic - or by pharmacological - targeting SCD1 in vivo, tumor regrowth was abolished completely. CONCLUSION: This finding unveils that it is worth taking advantage of tumor lipid addiction, as a tumor vulnerability to design novel treatment strategy to prevent cancer recurrence.

Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal.

The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets.

EGFR activation and signaling in cancer cells are enhanced by the membrane-bound metalloprotease MT4-MMP.

MT4-MMP (MMP-17) is a glycosylphosphatidyl inositol-anchored matrix metalloprotease expressed on the surface of cancer cells that promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein inactivation. We also determine a functional link between MT4-MMP and the growth factor receptor EGFR. Mechanistic experiments revealed direct association of MT4-MMP and its positive effects on EGFR phosphorylation in response to TGFα and EGF in cancer cells. Notably, the effects of MT4-MMP on proliferation and EGFR activation did not rely on metalloprotease activity. Clinically, MT4-MMP and EGFR expressions were correlated in human triple-negative breast cancer specimens. Altogether, our results identify MT4-MMP as a positive modifier of EGFR outside-in signaling that acts to cooperatively drive cancer cell proliferation.