Raghavan, K. | bioRxiv Science

bioRxiv2024

Pulsed low-dose-rate radiation (PLDR) reduces the tumor-promoting responses induced by conventional chemoradiation in pancreatic cancer-associated fibroblasts

Pancreatic cancer is becoming increasingly deadly, with treatment options limited due to, among others, the complex tumor microenvironment (TME). This short communications study investigates pulsed low-dose-rate radiation (PLDR) as a potential alternative to conventional radiotherapy for pancreatic cancer neoadjuvant treatment. Our ex vivo research demonstrates that PLDR, in combination with chemotherapy, promotes a shift from tumor-promoting to tumor-suppressing properties in a key component of the pancreatic cancer microenvironment we called CAFu (cancer-associated fibroblasts and selfgenerated extracellular matrix functional units). This beneficial effect translates to reduced desmoplasia (fibrous tumor expansion) and suggests PLDRs potential to improve total neoadjuvant therapy effectiveness. To comprehensively assess this functional shift, we developed the HOST-Factor, a single score integrating multiple biomarkers. This tool provides a more accurate picture of CAFu function compared to individual biomarkers and could be valuable for guiding and monitoring future therapeutic strategies. Our findings support the ongoing NCT04452357 clinical trial testing PLDR safety and TME normalization potential in pancreatic cancer patients. The HOST-Factor will be used in samples collected from this trial to validate its potential as a key tool for personalized medicine in this aggressive disease.

cancer biology↗

bioRxiv2022

Two unique biological response-modifier glucans beneficially regulating gut microbiota and faecal metabolome in a non-alcoholic steatohepatitis animal model, with potential for applications in human health and disease

ObjectiveThe gut microbiome and its metabolites, influenced by age and stress, reflect the metabolism and immune systems health. We assessed the gut microbiota and faecal metabolome in a Stelic Animal Model of non-alcoholic steatohepatitis (NASH). DesignThis model was subjected to the following treatments: reverse osmosis water, AFO-202, N-163, AFO-202+N-163, and telmisartan. Faecal samples were collected at 6 weeks and 9 weeks of age. The gut microbiome was analysed using 16S ribosomal RNA sequence acquired by next-generation sequencing and the faecal metabolome using gas chromatography-mass spectrometry. ResultsThe gut microbial diversity increased greatly in the AFO-202+N-163 group. Post-intervention, the abundance of Firmicutes decreased, while that of Bacteroides increased and was the highest in the AFO-202+N-163 group. The decrease in the Enterobacteria and other Firmicutes abundance and in the Turicibacter and Bilophila abundance was the highest in the AFO-202 and N-163 groups, respectively. The Lactobacillus abundance increased the most in the AFO-202+N-163 group. The faecal metabolites spermidine and tryptophan, beneficial against inflammation and NASH, respectively, were greatly increased in the N-163 group. Succinic acid, beneficial in neurodevelopmental and neurodegenerative diseases, increased in the AFO-202 group. Decrease in fructose was the highest in the AFO-202 group. Leucine and phenylalanine decreased, whereas ornithine, which is beneficial against chronic immune-metabolic-inflammatory pathologies, increased in the AFO-202+N-163 group. ConclusionAFO-202 treatment in mice is beneficial against neurodevelopmental and neurodegenerative diseases and has prophylactic potential against metabolic conditions. N-163 treatment has anti-inflammatory effects against organ fibrosis and neuroinflammatory conditions. In combination, they present anticancer activity. Key messagesO_LIThe influence of gut microbiome on fecal metabolome and their association to several diseases is already known. C_LIO_LIThis study proves the efficacy of 1,3-1,6 beta glucans with pre-biotic potentials, beneficially influencing both gut microbiome and metabolome. C_LIO_LIThese results recommends for an in-depth exploration of relationship among pre-biotics, gut microbiome and gut-multi-organ axes on the fundamentals of disease onset. C_LIO_LIHidden prophylactic and therapeutic solutions to non-contagious diseases with Aureobasidium pullulans produced 1,3-1,6 beta glucans may be unveiled. C_LI

microbiology↗