HIF2 Regulates Intestinal Wnt5a Expression

Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including Wnt5a. Non-canonical Wnt5a signaling has been shown by other groups to improve intestinal crypt regeneration in response to injury. Here we show that HIF2 drives Wnt5a expression in multiple duodenal organoid models. Luciferase reporter assays performed in human cells showed that HIF2 directly activates the WNT5A promoter via a hypoxia response element. We then evaluated crypt regeneration using spheroid formation assays. Duodenal organoids that were pre-treated with recombinant Wnt5a had a higher cryptogenic capacity after irradiation, compared to vehicle-treated organoids. Conversely, we found that Wnt5a knockout decreased the cryptogenic potential of intestinal stem cells following irradiation. Treatment with recombinant Wnt5a prior to irradiation rescued the cryptogenic capacity of Wnt5a knockout organoids, indicating that Wnt5a is necessary and sufficient for duodenal radioprotection. Taken together, our results suggest that HIF2 radioprotects the GI tract by inducing Wnt5a expression.

Prognostic value of tumour volume in patients with a poor Karnofsky performance status scale – a bicentric retrospective study

Backround Median overall survival (OS) after diagnosis of glioblastoma (GBM) remains 15 months amongst patients receiving aggressive surgical resection, chemotherapy and irradiation. Treatment of patients with a poor preoperative Karnofsky Performance Status Scale (KPSS) is still controversial. Therefore, we retrospectively assessed the outcome after surgical treatment in patients with a KPSS of ≤60%. Methods We retrospectively included patients with a de-novo glioblastoma WHO °IV and preoperative KPSS ≤60%, who underwent surgery at two neurosurgical centres between September 2006 and March 2016. We recorded pre- and postoperative tumour volume, pre- and postoperative KPSS, OS, age and MGMT promoter status. Results One hundred twenty-three patients (58 females/65 males, mean age 67.4 ± 13.4 years) met the inclusion criteria. Seventy-five of the 123 patients (61%) underwent surgical resection. 48/123 patients (39%) received a biopsy. The median preoperative and postoperative tumour volume of all patients was 33.0 ± 31.3 cm3 (IR 15.0–56.5cm3) and 3.1 ± 23.8 cm3 (IR 0.2–15.0 cm3), respectively. The median KPSS was 60% (range 20–60%) preoperatively and 50% (range 0–80%) postoperatively. Patients who received a biopsy showed a median OS for patients who received a biopsy only was 3.0 months (95% CI 2.0–4.0 months), compared to patients who had a resection and had a median OS of 8 months (95% CI 3.1–12.9 months). Age (p < 0.001, HR: 1.045 [95% CI 1.022–1.068]), postoperative tumour volume (p = 0.02, HR: 1.016 [95% CI 1.002–1.029]) and MGMT promotor status (p = 0.016, HR: 0.473 [95% CI 0.257–0.871]) were statistically significant in multivariate analysis. In subgroup analyses only age was shown as a significant prognostic factor in multivariate analyses for patients receiving surgery (p < 0.001, HR: 1.046 [95% CI 1.022–1.072]). In the biopsy group no significant prognostic factors were shown in multivariate analysis. Conclusion GBM patients with a preoperative KPSS of ≤60% might profit from surgical reduction of tumour burden.

Case Study of Bacterial Decontamination of an Aromatic and Medicinal Plant: Decontamination of Thymus Satureioides by Gamma Radiation at Low Doses and Impact on Hygienic and Physicochemical Quality

The purpose of our study is to verify the usefulness of gamma irradiation treatment at low doses (0.25, 0.5 and 1 kGy) combined to vacuum packaging on commercial teas of Thymus satureioides deliberately contaminated with Escherichia coli. The efficiency and the influence of the process on contamination level and the shelf life of the product were studied. The phenolic composition and concentration were identified in the unirradiated and irradiated thyme. The total phenolic content (TPC) was assayed by the Folin-Ciocalteu method, the individual phenolic compounds were determined by high liquid chromatography (HPLC) and the essential oil was characterized by gas chromatography coupled to mass spectroscopy (GC-MS). The plant was observed by scanning electrons microscopy and the radioactivity effect was analyzed. The results show a complete decontamination of thyme depending to the dose and the storage time. Privileged hygienic quality was found in the irradiated thyme with the highest concentrations of polyphenols. The process showed the conservation of thyme quality without any alteration of its characteristics or radioactivity effect.

Low dose irradiation of plum peel anthocyanins: Impact on stability and antioxidant activity

Consumer demand for both natural food colorants and non-thermal methods of preservation has increased overwhelmingly during the last few decades. Preventing loss of appeal and color through non-thermal methods without compromising on quality will provide an alternative to conventional thermal methods. In the present study, irradiation of plum peel anthocyanins after extraction and purification was done in a range of 0.1-1.0 kGy. Results revealed that degradation was significantly (p ≤ 0.05) dependent on both time and dose of irradiation. The percentage degradation observed in the first 3 h of treatment was 9.0-21.0±1.2%. The maximum anthocyanin degradation recorded during 8 h of irradiation was 45.3%. Anthocyanin degradation was apparently less at 0.1-0.5 kGy compared to 0.6-1.0 kGy. The retention of anthocyanins was up to the extent of 88.8-62.3% in samples irradiated at 0.1-0.5 kGy. Comparison of the individual anthocyanin indicated that diglucoside anthocyanins were stable towards irradiation than monoglucoside anthocyanins. For monoglucoside anthocyanins, a 50% decrease was observed as the irradiation treatment exceeded 0.6 kGy. A close comparison of the data revealed that at irradiation dose of 1.0 kGy, the decrease in L* and a* values was almost four and three times higher than that observed in samples irradiated at 0.5 kGy and below; while an increase in b* value was almost double. In spite of marginal degradation in color, low dose irradiation (up to 0.5 kGy) significantly (p≤0.05) increased the antioxidant activity of the plum peel anthocyanins.

Analysis of flavor compounds in marinated chicken wings after irradiation and natural antioxidant (phytic acid and tea polyphenols) treatment

Marinated chicken wings is one of the popular marinated meat products in China. Here, electronic nose (e-nose) and solid phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) were used to detect volatile components of four different treatment marinated chicken wings (neither irradiated nor added phytic acid and tea polyphenols, A1; added phytic acid and tea polyphenols but no irradiated, A2; irradiated with 4 kGy irradiation but not added phytic acid and tea polyphenols, A3; irradiated with 4 kGy irradiation and added phytic acid and tea polyphenols, A4). Then odor activity value (OAV) and principal component analysis (PCA) were utilized to analyze their key flavor compounds. E-nose analysis found that antioxidant has a great impact on the odor of the marinated chicken wings, while the irradiation treatment has little effect on it. Besides, the irradiation treatment can reduce the unpleasant odor caused by antioxidants in certain. Through SPME-GC-MS, 101 volatile compounds were identified in four groups. After analysis, the antioxidants can inhibit the production of some volatile compounds, while irradiation treatment will relieve this phenomenon. This result is consistent with the e-nose. Following OAV, PCA analysis and sensory evaluation further verified the above conclusions.

Comparison of Performance Properties and Prediction of Regular and Gamma-Irradiated Granular Waste Polyethylene Terephthalate Modified Asphalt Mixtures

The utilization of waste polyethylene terephthalate (WPET) as aggregate substitutes in pavement has been extensively promoted because of its environmental advantages. However, previous studies have shown that a high percentage of WPET reduces the performance of the pavement. To increase the durability of pavement and mitigate the environmental issues caused by WPET, WPET is treated with gamma-irradiation as a component in asphalt mixtures. The study objectives were to investigate the feasibility of using WPET granules as a sustainable aggregate on asphalt mixture stiffness and rutting and predict the asphalt mixture performance containing irradiated WPET via an RSM-ANN-framework. To achieve the objectives, stiffness and rutting tests were conducted to evaluate the WPET modified mixtures’ performance. The result indicated that samples containing 40% irradiated WPET provided a better performance compared to mixtures containing 20% non-irradiated WPET, increasing the stiffness by 27% and 21% at 25 °C and 40 °C, respectively, and rutting resistance by 11% at 45 °C. Furthermore, both predictive models developed demonstrated excellent reliability. The ANN exhibited superior performance than the RSM. The utilization of WPET as aggregate in asphalt mixtures represents a way to addressing related recycling issues while also improving performance. With gamma-irradiation treatment, the utilization of WPET can be increased with improved asphalt mixture performance.