There is increasing evidence supporting the role of genetic variants in the development of radiation-induced toxicity. However, previous candidate gene association studies failed to elucidate the ...common genetic variation underlying this phenotype, which could emerge years after the completion of treatment. We performed a genome-wide association study on a Spanish cohort of 741 individuals with prostate cancer treated with external beam radiotherapy (EBRT). The replication cohorts consisted of 633 cases from the UK and 368 cases from North America. One locus comprising TANC1 (lowest unadjusted P value for overall late toxicity=6.85×10(-9), odds ratio (OR)=6.61, 95% confidence interval (CI)=2.23-19.63) was replicated in the second stage (lowest unadjusted P value for overall late toxicity=2.08×10(-4), OR=6.17, 95% CI=2.25-16.95; Pcombined=4.16×10(-10)). The inclusion of the third cohort gave unadjusted Pcombined=4.64×10(-11). These results, together with the role of TANC1 in regenerating damaged muscle, suggest that the TANC1 locus influences the development of late radiation-induced damage.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The reaction of fac-ReX(CH3CN)2(CO)3 (X = Cl, Br) with N-phenyl-4-(dimethylamino)benzaldehyde thiosemicarbazone (HL A ) or N-4-methoxybenzyl-4-(dimethylamino)benzaldehyde thiosemicarbazone (HL B ) ...under controlled synthetic conditions gave 4 mononuclear ReX(HL)(CO)3 (X = Cl, Br) and 16 dinuclear Re2L2(CO)6 compounds. These complexes were obtained as single crystals, and their structures were established by X-ray diffraction. The structural study of these dimers showed the formation of several solvates, the presence of linkage isomerism, and the stabilization of four- and/or five-membered chelate rings. The different ligand coordination modes (a new μ-κ2-S,N2:κ-N3 coordination mode for a thiosemicarbazone ligand was observed), the conformation of the thiosemicarbazone chain in each case, the formal symmetry of the dimers, and the role of the synthetic procedure in the stability of the different chelate rings were analyzed and are discussed. Theoretical calculations in the gas phase were performed for the dimers with the HL A ligand in order to identify the thermodynamically most stable species. The behavior and structural stability of dimers in dimethyl sulfoxide and acetone solutions was investigated by 1H NMR spectroscopy. The strength of the ReI–L bond in solution was evidenced by the formation of Re2(LNO2 )2(CO)6 and Re(LA)(py)(CO)3 upon reaction of the corresponding dimer with concentrated nitric acid and pyridine, respectively.
Radiation therapy is fundamental in the treatment of cancer. Imaging has always played a central role in radiation oncology. Integrating imaging technology into irradiation devices has increased the ...precision and accuracy of dose delivery and decreased the toxic effects of the treatment. Although CT has become the standard imaging modality in radiation therapy, the development of recently introduced next-generation imaging techniques has improved diagnostic and therapeutic decision making in radiation oncology. Functional and molecular imaging techniques, as well as other advanced imaging modalities such as SPECT, yield information about the anatomic and biologic characteristics of tumors for the radiation therapy workflow. In clinical practice, they can be useful for characterizing tumor phenotypes, delineating volumes, planning treatment, determining patients' prognoses, predicting toxic effects, assessing responses to therapy, and detecting tumor relapse. Next-generation imaging can enable personalization of radiation therapy based on a greater understanding of tumor biologic factors. It can be used to map tumor characteristics, such as metabolic pathways, vascularity, cellular proliferation, and hypoxia, that are known to define tumor phenotype. It can also be used to consider tumor heterogeneity by highlighting areas at risk for radiation resistance for focused biologic dose escalation, which can impact the radiation planning process and patient outcomes. The authors review the possible contributions of next-generation imaging to the treatment of patients undergoing radiation therapy. In addition, the possible roles of radio(geno)mics in radiation therapy, the limitations of these techniques, and hurdles in introducing them into clinical practice are discussed.
RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.
Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to ...the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio OR 3.12, 95% confidence interval CI 2.08–4.69, p-value 4.16×10−8) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value=3.21×10−8). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.
•SNPs rs17599026 and rs7720298 increase risk of urinary toxicity following radiotherapy in prostate cancer patients.•Data from heterogeneous radiotherapy cohorts can be meta-analyzed to identify genetic variants associated with toxicity.•A SNP-based predictive assay could improve the therapeutic index of radiotherapy and aid in individualization of cancer treatment.
Risk of radiotherapy side-effects in a minority limits doses given to the majority. A test is needed to predict risks so treatments are personalized. Recent whole-genome studies in a few hundred patients found none or one genetic variant increasing side-effect risk. Larger studies are needed, but difficult because treatments differ between centers. Our study of >1500 prostate cancer patients from four centers found two variants. The research shows combining heterogeneous radiotherapy datasets works and larger collaborative efforts identifying enough variants for a future test are worthwhile. As nearly 50% of cancer patients have radiotherapy, our work could benefit many people.
Large amounts of sewage sludge are generated in wastewater treatment plants during the water purification process. In small populations – defined as urban settlements with less than 2000 population ...equivalent – sewage sludge is normally produced in anaerobic systems (e.g. septic tanks, Imhoff tanks or anaerobic ponds) or in extended aeration systems. According to the European Directives 86/278/EEC and 2006/12/EC, sewage sludge must be treated before its final fate. Although there are various alternatives, land application of sewage sludge after its composting has been widely promoted because of its high nutrient content. However, the employment of composted sludge as a soil amendment has some limitations, including social rejection. In this paper, a hydrolytic process for obtaining an agricultural biofertiliser from sewage sludge has been assessed. The enzymatic hydrolysis of sludge produced two by-products: an insoluble paste and a nutrient-enriched liquid that constituted the fertilising product. This biofertiliser had higher contents of organic matter, proteins, potassium (K) and sulphur (S) compared to the fresh sludge. Protein content was characterised by a low molecular size, thus increasing the bioavailability of nitrogen (N). Further, high levels of enzymatic activity were detected in soil after the addition of the obtained biofertiliser.
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•An oral high-dose CoQ10 oleogel was assessed in its genotoxicity and acute toxicity.•There was no genotoxic risk associated with the use of CoQ10 oleogel in volunteers.•Biochemical ...parameters remained within reference values after oleogel treatment.•No signs of toxicity or mortality were observed in the rats exposed to the oleogel.•The novel high-dose CoQ10 oleogel formulation designed is safe for oral consumption.
Coenzyme Q10 (CoQ10) supplementation has demonstrated to be safe and effective in primary and secondary CoQ10 deficiencies. Previously, we have designed a high-dose CoQ10 oleogel (1 g/disk) with excipients used in quantities that do not represent any toxic risk. However, it was necessary to demonstrate their safety in the final formulation. Following this purpose, an acute toxicity study of the oleogel in rats was performed. Furthermore, the genotoxic risk was evaluated in human volunteers after CoQ10 supplementation with oleogel and compared to the solid form (1 g/three 00-size-capsules). In addition, the general health status and possible biochemical changes of the participants were determined using serum parameters. Results suggested the absence of adverse effects caused by the interaction of the components in the oleogel formulation. Therefore, we conclude that the designed novel high-dose CoQ10 oleogel was safe for oral consumption.
Abstract
Background
A total of 10%–20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to ...radiotoxicity might improve risk prediction and inform functional mechanistic studies.
Methods
We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10−8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided.
Results
Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10−10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10−10), and rs11122573 with hematuria (Pmeta = 1.8 × 10−8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10−6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts.
Conclusions
This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.
Condom use is the best available strategy to prevent HIV infection during sexual intercourse. However, since many people choose not to use condoms in circumstances in which HIV risk exists, ...alternatives to condom use for HIV prevention are needed. Currently there are several alternative bio-medical HIV-prevention products in different stages of development: microbicides, vaccines, post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP). Seventy-two men who have sex with men (MSM) who took part in a study on Internet use and intentional condomless anal intercourse were asked about these four products during a semi-structured interview. The questions explored knowledge and acceptability of all the products and willingness to participate in microbicide and vaccine trials. Qualitative analysis of the data suggests that these men had virtually no knowledge of PrEP, very limited knowledge of microbicides, some information about PEP and considerably more knowledge about vaccines. Reactions towards the products were generally positive except for PrEP, for which reactions were polarized as either enthusiastic or negative. With the exception of PrEP, many men expressed willingness to use the products in the future. Most men would be willing to participate in trials for microbicides and vaccines if given basic reassurances. Concerns over negative side effects and preoccupation with possible infection were some of the motives given for non-willingness to participate in a vaccine trial. These results should inform the development of future trials of biomedical prevention products.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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