Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer

Background Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Patient-derived xenograft (PDX) models in mice have demonstrated high accuracy in predicting therapeutic outcomes, but methods for predicting tumor invasiveness and early stages of vascular/lymphatic dissemination are still lacking. Here we show that a zebrafish tumor xenograft (ZTX) platform based on implantation of PDX tissue fragments recapitulate both treatment outcome and tumor invasiveness/dissemination in patients, within an assay time of only 3 days. Methods Using a panel of 39 non-small cell lung cancer PDX models, we developed a combined mouse-zebrafish PDX platform based on direct implantation of cryopreserved PDX tissue fragments into zebrafish embryos, without the need for pre-culturing or expansion. Clinical proof-of-principle was established by direct implantation of tumor samples from four patients. Results The resulting ZTX models responded to Erlotinib and Paclitaxel, with similar potency as in mouse-PDX models and the patients themselves, and resistant tumors similarly failed to respond to these drugs in the ZTX system. Drug response was coupled to elevated expression of EGFR, Mdm2, Ptch1 and Tsc1 (Erlotinib), or Nras and Ptch1 (Paclitaxel) and reduced expression of Egfr, Erbb2 and Foxa (Paclitaxel). Importantly, ZTX models retained the invasive phenotypes of the tumors and predicted lymph node involvement of the patients with 91% sensitivity and 62% specificity, which was superior to clinically used tests. The biopsies from all four patient tested implanted successfully, and treatment outcome and dissemination were quantified for all patients in only 3 days. Conclusions We conclude that the ZTX platform provide a fast, accurate, and clinically relevant system for evaluation of treatment outcome and invasion/dissemination of PDX models, providing an attractive platform for combined mouse-zebrafish PDX trials and personalized medicine

Genomics and molecular analysis of RPL9 and LIAS in lung cancer : emerging implications in carcinogenesis

Worldwide, lung cancer is a leading cause of cancer-related deaths and is the most commonly diagnosed form of cancer. A major characteristic of lung cancer is its profound clinical, histological and molecular heterogeneity. This heterogeneity is not only spatial but also temporal thus stressing the need for personalized patient-tailored treatment planning. The current optimal treatment planning is currently based on real-time monitoring of the evolving molecular profiling of the tumour throughout the course of the disease and treatment. In the current work, we will investigate the emerging role that that RPL9 and LIAS could have in carcinogenesis. While the aberrant expression of RPL9 has already been shown to occur in colorectal cancer its role in lung cancer is not yet known. In a similar manner, the role of LIAS, as a metabolism-linked gene, in cancer biology and especially in lung cancer is still unknown. Emerging research reveals both RPL9 and LIAS as interacting partners and apoptosis resistance genes. The aim of this study is to determine the differential expression of the rpl9 and lias genes in both normal lung tissue and lung cancer samples. This was achieved by using in situ hybridization (ISH) and quantitative Real-time PCR (qPCR). Further data on the role played by RPL9 in lung cancer was established through the use of in silico bioinformatic analysis. This was done in order to map biological pathways enriched by the expression of these genes. Both the KEGG pathway and Reactome analysis confirmed the role of these genes in RNA metabolic pathways. Furthermore, RPL9 was shown to play a role in signal transduction, autophagy, and cellular response to stress pathways. The function of these two proteins overlapped with regard to protein metabolism. STRING analysis also demonstrated an interaction between RPL9 and LIAS. Here we propose that the aberrant expression of RPL9 and LIAS may contribute to lung carcinogenesis and can be targeted for molecular therapy.Appendix A. Supplementary dataThe South African Medical Research Council (SAMRC) and the National Research Foundation (NRF).https://www.elsevier.com/locate/imuam2022Medical Virolog

Microbiomics in collusion with the nervous system in carcinogenesis : diagnosis, pathogenesis and treatment

The influence of the naturally occurring population of microbes on various human diseases has been a topic of much recent interest. Not surprisingly, continuously growing attention is devoted to the existence of a gut brain axis, where the microbiota present in the gut can affect the nervous system through the release of metabolites, stimulation of the immune system, changing the permeability of the blood–brain barrier or activating the vagus nerves. Many of the methods that stimulate the nervous system can also lead to the development of cancer by manipulating pathways associated with the hallmarks of cancer. Moreover, neurogenesis or the creation of new nervous tissue, is associated with the development and progression of cancer in a similar manner as the blood and lymphatic systems. Finally, microbes can secrete neurotransmitters, which can stimulate cancer growth and development. In this review we discuss the latest evidence that support the importance of microbiota and peripheral nerves in cancer development and dissemination.The South African Medical Research Council (SAMRC).https://www.mdpi.com/journal/microorganismsam2022Surger

Tumour-induced neoneurogenesis and perineural tumour growth:A mathematical approach

It is well-known that tumours induce the formation of a lymphatic and a blood vasculature around themselves. A similar but far less studied process occurs in relation to the nervous system and is referred to as neoneurogenesis. The relationship between tumour progression and the nervous system is still poorly understood and is likely to involve a multitude of factors. It is therefore relevant to study tumour-nerve interactions through mathematical modelling: this may reveal the most significant factors of the plethora of interacting elements regulating neoneurogenesis. The present work is a first attempt to model the neurobiological aspect of cancer development through a system of differential equations. The model confirms the experimental observations that a tumour is able to promote nerve formation/elongation around itself, and that high levels of nerve growth factor and axon guidance molecules are recorded in the presence of a tumour. Our results also reflect the observation that high stress levels (represented by higher norepinephrine release by sympathetic nerves) contribute to tumour development and spread, indicating a mutually beneficial relationship between tumour cells and neurons. The model predictions suggest novel therapeutic strategies, aimed at blocking the stress effects on tumour growth and dissemination

Control of Flame Spray Pyrolysis synthesis of Li4Ti5O12: Experimental and Computational study

Lithium titanate (Li4Ti5O12, LTO) is a promising anode material for the next generation of lithium ion batteries. Its physical properties and morphology (which consequently affect its electrochemical performance) highly depend on its synthesis method. Flame spray pyrolysis (FSP) is an attractive process for the controlled one-step synthesis of functional multicomponent oxides from low cost precursors. The main aim of this study is to control the growth process of LTO by FSP in order to maintain the desired particle properties. LTO nanoparticles of different sizes are synthesized by variation of the FSP processing conditions and characterized accordingly. Numerical simulations based on Population Balance Models are also implemented in order to investigate the evolution of primary and agglomerate particle growth