Every year, millions of people around the world benefit from radiation therapy to treat cancers localized in the pelvic area. Damage to healthy tissue in the radiation field can cause undesirable toxic effects leading to gastrointestinal complications called pelvic radiation disease. A change in the composition and/or function of the microbiota could contribute to radiation-induced gastrointestinal toxicity. In this study, we tested the prophylactic effect of a new generation of probiotic like Faecalibacterium prausnitzii (F. prausnitzii) on acute radiation-induced colonic lesions. Experiments were carried out in a preclinical model of pelvic radiation disease. Rats were locally irradiated at 29 Gray in the colon resulting in colonic epithelial barrier rupture. Three days before the irradiation and up to 3 d after the irradiation, the F. prausnitzii A2-165 strain was administered daily (intragastrically) to test its putative protective effects. Results showed that prophylactic F. prausnitzii treatment limits radiation-induced para-cellular hyperpermeability, as well as the infiltration of neutrophils (MPO+ cells) in the colonic mucosa. Moreover, F. prausnitzii treatment reduced the severity of the morphological change of crypts, but also preserved the pool of Sox-9+ stem/progenitor cells, the proliferating epithelial PCNA+ crypt cells and the Dclk1+/IL-25+ differentiated epithelial tuft cells. The benefit of F. prausnitzii was associated with increased production of IL-18 by colonic crypt epithelial cells. Thus, F. prausnitzii treatment protected the epithelial colonic barrier from colorectal irradiation. Newgeneration probiotics may be promising prophylactic treatments to reduce acute side effects in patients treated with radiation therapy and may improve their quality of life.
SummaryA factor recently described and for which the designation Stuart-Prower Factor is proposed, was investigated. It is detected by the usual Factor VII assay but differs from this factor (Matching experiments with plasma and serum of Owren’s Factor VII deficient patient). Stuart-Prower factor is necessary for the conversion prothrombin-thrombin with tissue thromboplastin as well as for the formation of blood thromboplastin. Therefore lack of Stuart-Prower factor produces abnormal Quick’s prothrombin time (not normalized with Russell’s viper venom [Stypven]), and also abnormal prothrombin consumption, abnormal recalcification time and abnormal thromboplastin generation with serum. Matching experiments with plasma and serum of the patients of Graham and Hougie, Telfer Denson and Wright, and Beaumont and Bernard show that we are dealing with the same defect. Physiological and physico-chemical properties are indicated. The possible relationship between Stuart-Prower factor and Factor X is discussed. A critical review with 59 cases of the so-called Factor VII deficiency is given. Investigation of the family of our patient Delia B. indicates that the mode of inheritance is an intermediate autosomal one.
Background The estimated increase in prevalence of radiation enteropathy associated with a current scarcity of effective treatment options underline the need for the development of new therapies. Extracellular vesicles (EV), which are membrane-bound particles secreted by cells containing proteins, lipids and nucleic acids, have yielded promising preclinical results in various applications in regenerative medicine. Here, we aimed to investigate whether EV from adipose-derived stromal cells (ADSC) may present a therapeutic potential in the context of radiation colitis. Methods EV were produced from primary rat ADSC by exposure to a turbulent flow. Radiation colitis was induced by fractionated irradiation at a dose of 3x10Gy on a colorectal window (3x2cm) in male Sprague-Dawley rats (311-386g) at days 0, 2 and 4; following a pre-established protocol. Treatment was administered at days 11 and 15 through submucosal endoscopic injections of rat ADSC (n=9 rats, 2x106cells per dose), EV (n=9 rats, 1.06x1011 particles per dose), or an equivalent volume of saline (n=10 rats). The rats were sacrificed at day 17. Our primary endpoint was the extent of colonic epithelial injury at histological analysis (Table 1). Secondary endpoints included an endoscopic assessment of the severity of lesions at day 15 (Table 2) and an evaluation of macrophage infiltration in the colonic mucosa by CD68 immunohistochemistry. Comparisons of proportions were performed by the Chi-squared test followed by Fisher’s exact test. Results In the ADSC group, 1 rat died from anaesthesia complications. No other adverse effects were observed. No differences in total body weight evolution were observed between the groups. At day 15, a statistically significant decrease of the proportion of animals with moderate to severe lesions was evidenced by endoscopy in the EV group compared to the saline group (p=0.0031; Figure 1). No differences were observed between the other groups. Histological analysis of the colonic epithelial injury score evidenced a non-significant tendency towards a decreased length of high-grade lesions in the EV group (mean±standard deviation: 9180±3684µm; Figure 2) compared with the saline (11536±2711µm) and ADSC (11636±2815) groups. Similarly, CD68+ macrophage infiltration at the site of colonic mucosal lesions tended to be lower in the EV and ADSC groups compared to the saline group. Conclusion This proof-of-concept study seemed to demonstrate a beneficial effect of locally administered extracellular vesicles for the treatment of radiation colitis in the acute setting. A confirmation study in a larger animal cohort is underway, and further investigations focusing on dose effects or long-term effects on fibrosis are required to complete these preliminary results.
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