Methyl donor deficiency impairs fatty acid oxidation through PGC-1α hypomethylation and decreased ER-α, ERR-α, and HNF-4α in the rat liver.

BACKGROUND & AIMS: Folate and cobalamin are methyl donors needed for the synthesis of methionine, which is the precursor of S-adenosylmethionine, the substrate of methylation in epigenetic, and epigenomic pathways. Methyl donor deficiency produces liver steatosis and predisposes to metabolic syndrome. Whether impaired fatty acid oxidation contributes to this steatosis remains unknown. METHODS: We evaluated the consequences of methyl donor deficient diet in liver of pups from dams subjected to deficiency during gestation and lactation. RESULTS: The deprived rats had microvesicular steatosis, with increased triglycerides, decreased methionine synthase activity, S-adenosylmethionine, and S-adenosylmethionine/S-adenosylhomocysteine ratio. We observed no change in apoptosis markers, oxidant and reticulum stresses, and carnityl-palmitoyl transferase 1 activity, and a decreased expression of SREBP-1c. Impaired beta-oxidation of fatty acids and carnitine deficit were the predominant changes, with decreased free and total carnitines, increased C14:1/C16 acylcarnitine ratio, decrease of oxidation rate of palmitoyl-CoA and palmitoyl-L-carnitine and decrease of expression of novel organic cation transporter 1, acylCoA-dehydrogenase and trifunctional enzyme subunit alpha and decreased activity of complexes I and II. These changes were related to lower protein expression of ER-α, ERR-α and HNF-4α, and hypomethylation of PGC-1α co-activator that reduced its binding with PPAR-α, ERR-α, and HNF-4α. CONCLUSIONS: The liver steatosis resulted predominantly from hypomethylation of PGC1-α, decreased binding with its partners and subsequent impaired mitochondrial fatty acid oxidation. This link between methyl donor deficiency and epigenomic deregulations of energy metabolism opens new insights into the pathogenesis of fatty liver disease, in particular, in relation to the fetal programming hypothesis.

Performance of an integrated multimodality image guidance and dose-planning system supporting tumor-targeted HDR brachytherapy for prostate cancer.

BACKGROUND AND PURPOSE: Advances in high-dose-rate brachytherapy to treat prostate cancer hinge on improved accuracy in navigation and targeting while optimizing a streamlined workflow. Multimodal image registration and electromagnetic (EM) tracking are two technologies integrated into a prototype system in the early phase of clinical evaluation. We aim to report on the system's accuracy and workflow performance in support of tumor-targeted procedures. MATERIALS AND METHODS: In a prospective study, we evaluated the system in 43 consecutive procedures after clinical deployment. We measured workflow efficiency and EM catheter reconstruction accuracy. We also evaluated the system's MRI-TRUS registration accuracy with/without deformation, and with/without y-axis rotation for urethral alignment at initialization. RESULTS: The cohort included 32 focal brachytherapy and 11 integrated boost whole-gland implants. Mean procedure time excluding dose delivery was 38 min (range: 21-83) for focal, and 56 min (range: 38-89) for whole-gland implants; stable over time. EM catheter reconstructions achieved a mean difference between computed and measured free-length of 0.8 mm (SD 0.8, no corrections performed), and mean axial manual corrections 1.3 mm (SD 0.7). EM also enabled the clinical use of a non or partially visible catheter in 21% of procedures. Registration accuracy improved with y-axis rotation for urethral alignment at initialization and with the elastic registration (mTRE 3.42 mm, SD 1.49). CONCLUSION: The system supported tumor-targeting and was implemented with no demonstrable learning curve. EM reconstruction errors were small, correctable, and improved with calibration and control of external distortion sources; increasing confidence in the use of partially visible catheters. Image registration errors remained despite rotational alignment and deformation, and should be carefully considered.

Corrigendum: MRI-guided focal or integrated boost high dose rate brachytherapy for recurrent prostate cancer.

[This corrects the article DOI: 10.3389/fonc.2022.971344.].

MRI-guided focal or integrated boost high dose rate brachytherapy for recurrent prostate cancer.

Background and purpose: Locally recurrent prostate cancer after radiotherapy merits an effective salvage strategy that mitigates the risk of adverse events. We report outcomes of a cohort enrolled across two institutions investigating MRI-guided tumor-targeted salvage high dose rate brachytherapy (HDR-BT). Materials and methods: Analysis of a prospective cohort of 88 patients treated across two institutions with MRI-guided salvage HDR-BT to visible local recurrence after radiotherapy (RT). Tumor target dose ranged from 22-26 Gy, using either an integrated boost (ibBT) or focal technique (fBT), delivered in two implants over a median of 7 days. Outcome metrics included cancer control and toxicity (CTCAE). Quality of life (QoL-EPIC) was analyzed in a subset. Results: At a median follow-up of 35 months (6 -134), 3 and 5-year failure-free survival (FFS) outcomes were 67% and 49%, respectively. At 5 years, fBT was associated with a 17% cumulative incidence of local failure (LF) outside the GTV (vs. 7.8% ibBT, p=0.14), while LF within the GTV occurred in 13% (vs. 16% ibBT, p=0.81). Predictors of LF outside fBT volumes included pre-salvage PSA>7 ng/mL (p=0.03) and interval since RT less than 5 years (p=0.04). No attributable grade 3 events occurred, and ibBT was associated with a higher rate of grade 2 toxicity (p<0.001), and trend towards a larger reduction in QoL sexual domain score (p=0.07), compared to fBT. Conclusion: A tumor-targeted HDR-BT salvage approach achieved favorable cancer control outcomes. While a fBT was associated with less toxicity, it may be best suited to a subgroup with lower PSA at later recurrence. Tumor targeted dose escalation may be warranted.

Ricinodendron heutelotii (Bail.) or Tetracarpidium conophorum Müll. oils fed to male rats lower blood lipids.

Ricinodendron heudelotii and Tetracarpidium conophorum (Euphorbiaceae family) are 2 oil-bearing wild plants whose fruits are generally consumed in Cameroon. T conophorum kernels are eaten as nibbles after cooking. Kernels of R heudelotii are used as spice in many dishes in Cameroon. Oil from T conophorum contains a high level of alpha-linolenic acid (72.24%), and oil from R heudelotii kernels is a good source of alpha-eleostearic acid (9c, 11t, 13t; 52.61%), which is a conjugated linolenic acid. Polyunsaturated fatty acids have received considerable interest because their consumption has been associated with beneficial health effects. We hypothesized that the consumption of R heudelotii and T conophorum oils would alter the in vivo lipid profiles and some antioxidants parameters. Therefore, male Sprague-Dawley rats (age, 1 month, n = 18) were fed with a standard, commercial diet (control group), or a diet containing T conophorum oil (TCO group) or R heudelotii oil (RHO group). After 60 days of feeding the respective diets, blood samples were collected and used to determine biochemical parameters. High-protein lipoprotein cholesterol, creatinine, alanine aminotransferase, alkaline phosphatase, total bilirubin, malondialdehyde, and selenium levels were not significantly different (P > .05) between the RHO and TCO groups. The atherogenicity index was higher for the group of rats fed a standard, commercial diet compared with the RHO and TCO groups. The oils examined in this study reduced cholesterol and triglyceride levels in rats compared with the control group fed the standard diet.