Genetic of radiation-induced toxicities in cancer patients

Cancer remains a leading cause of death globally, and radiotherapy has contributed significantly to improvements in the treatment of cancer patients. However, not every cancer responds to radiotherapy in the same way. Despite applying uniform treatment protocols for radiotherapy to minimize damage to the surrounding healthy tissue, a large patient-to-patient variability exists in radiation-induced toxicities. Many cancer patients achieve survivorship at the cost of treatment complications occurring in normal tissues. However, the solution is not to eliminate radiation exposure but to protect individuals who are the most sensitive to radiation and minimize dose and exposure to all individuals.In this thesis, I focused on uncovering the underlying genetic causes of individual variation in sensitivity to radiation in cancer patients. I applied various genetic epidemiological designs, methods, and concepts in a range of studies to identify genetic variants associated with radiation-induced toxicities in cancer patients. Eventually, this thesis identified several genomic regions associated with radiation-induced toxicities. In addition, the thesis showed for the first time, radiation-induced toxicities are mostly heritable and predictable by genetic profiles of cancer patients. The identified predictors aim to contribute to an algorithm to improve the guidelines of therapeutic decisions. Patients at high risk of developing radiation-induced toxicities may be offered an alternative treatment approach, or, for patients who have received radiotherapy, advanced planning corrections can be introduced to better-individualized radiotherapy treatment. In addition to predictive and prognostic testing, the products of the identified genes could become targets for innovative therapies in susceptible individuals

Assessment of flocculation induced by pH increase for harvesting microalgae Cyanothece sp.

One of the most important challenges lies in the microalgae mass production is the high cost of harvesting process which is the separation of a low amount of biomass consisting of small individual cells from a large volume of culture medium. Therefore, finding an efficient and cost-effective technique for harvesting microalgae is important issue. In the current study, pH-induced flocculation method was tested for microalgae Cyanothece sp. harvesting. The halophilic microalgae were cultured and grown in laboratory with hypersaline water in F/2 medium. After reaching the stationary phase, the impact of pH induction (from natural medium culture pH:8.2 to pH:11) on flocculation efficiency, chlorophyll a, chlorophyll b, total carotenoid, β-Carotene and phycocyanin component and the possibility of reuse flocculated medium of microalgae Cyanothece sp. were evaluated. The results indicated that the increasing the medium pH value by adding NaOH from pH natural at 8.2 to 9.4 increased flocculation efficiency significantly from 10 up to 90% (P<0.05), but after that remained stable up to pH: 11. Regarding the pigment content, the increase in pH value from natural pH: 8.2 to pH: 9.1 had a relatively a medium effect on pigment components, including chlorophyll a, chlorophyll b, total carotenoid, β-Carotene and phycocyanin amount of the harvested biomass of Cyanothece sp, but after that from pH: 9.4 to 11 the reduction was severe. The medium culture from pH: 8.5 to pH: 11 was reusable for new culture of microalgae. Thus, the flocculation induced by pH increase up to pH: 9.1 is a suitable method for harvesting microalgae Cyanothece sp. with no serious adverse effect on pigment component

Association of retinopathy and intima media thickness of common carotid artery in type 2 diabetic patients

Background: This study was carried out in order to evaluate the relationship between retinopathy and carotid intima-media thickness (CIMT). Materials and Methods: In a cross-sectional study, 154 diabetic patients who had a history of diabetic disease were evaluated in two equal groups of 77 patients with and without retinopathy, respectively. CIMT was evaluated in all of the patients. Results: Mean age of the patients was 59.65 +/- 9.37 years. Mean CIMT of all patients was 0.84 +/- 0.18. CIMT of patients with retinopathy was significantly greater than patients without retinopathy (P < 0.001). CIMT also correlated with age, duration of diabetes, systolic blood pressure, blood urea nitrogen, and serum creatinine. Conclusion: CIMT may be used as a simple, available and noninvasive method for screening of macro and microvascular complication of diabetic patients

A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer

BACKGROUND: Most head and neck cancer (HNC) patients receive radiotherapy (RT) and develop toxicities. This genome-wide association study (GWAS) was designed to identify single nucleotide polymorphisms (SNPs) associated with common acute radiation-induced toxicities (RITs) in an HNC cohort. METHODS: A two-stage GWAS was performed in 1279 HNC patients treated with RT and prospectively scored for mucositis, xerostomia, sticky saliva, and dysphagia. The area under the curve (AUC) was used to estimate the average load of toxicity during RT. At the discovery study, multivariate linear regression was used in 957 patients, and the top-ranking SNPs were tested in 322 independent replication cohort. Next, the discovery and the replication studies were meta-analyzed. RESULTS: A region on 5q21.3 containing 16 SNPs showed genome-wide (GW) significance association at P-value < 5.0 × 10-8 with patient-rated acute xerostomia in the discovery study. The top signal was rs35542 with an adjusted effect size of 0.17*A (95% CI 0.12 to 0.23; P-value <  = 3.78 × 10-9). The genome wide significant SNPs were located within three genes (EFNA5, FBXL17, and FER). In-silico functional analysis showed these genes may be involved in DNA damage response and co-expressed in minor salivary glands. We found 428 suggestive SNPs (P-value < 1.0 × 10-5) for other toxicities, taken to the replication study. Eleven of them showed a nominal association (P-value < 0.05). CONCLUSIONS: This GWAS suggested novel SNPs for patient-rated acute xerostomia in HNC patients. If validated, these SNPs and their related functional pathways could lead to a predictive assay to identify sensitive patients to radiation, which may eventually allow a more individualized RT treatment

A genome-wide association study of radiotherapy induced toxicity in head and neck cancer patients identifies a susceptibility locus associated with mucositis

PURPOSE: A two-stage genome-wide association study was carried out in head and neck cancer (HNC) patients aiming to identify genetic variants associated with either specific radiotherapy-induced (RT) toxicity endpoints or a general proneness to develop toxicity after RT.MATERIALS AND METHODS: The analysis included 1780 HNC patients treated with primary RT for laryngeal or oro/hypopharyngeal cancers. In a non-hypothesis-driven explorative discovery study, associations were tested in 1183 patients treated within The Danish Head and Neck Cancer Group. Significant associations were later tested in an independent Dutch cohort of 597 HNC patients and if replicated, summary data obtained from discovery and replication studies were meta-analysed. Further validation of significantly replicated findings was pursued in an Asian cohort of 235 HNC patients with nasopharynx as the primary tumour site.RESULTS: We found and replicated a significant association between a locus on chromosome 5 and mucositis with a pooled OR for rs1131769*C in meta-analysis = 1.95 (95% CI 1.48-2.41; ppooled = 4.34 × 10-16).CONCLUSION: This first exploratory GWAS in European cohorts of HNC patients identified and replicated a risk locus for mucositis. A larger Meta-GWAS to identify further risk variants for RT-induced toxicity in HNC patients is warranted.</p

Early Sasanian landscape modification: New geoarchaeological evidence from the Ardashir Pond in southwest Iran (Palace of Ardashir, third century CE)

The Sasanian period (224–651 CE) marked an era of large‐scale urban projects insouthwest Asia, including Iran's semi‐arid highlands, with particular efforts to ma-nipulate water bodies. This study presents a recent interdisciplinary investigation ofa spring‐fed pond at the entrance of the Palace of Ardashir (Firuzabad plain,southwest Iran), part of a recently registered World Heritage site. Historical ac-counts suggest that the entire water system of the plain, including the pond, un-derwent a hydraulic re‐organization at the beginning of the Sasanian period, a factthat has never been investigated geoarchaeologically. A series of sediment coreswere retrieved from the pond to probe its evolution and examine the extent of itslandscape modification. The cores were sedimentologically described andradiocarbon‐dated with age–depth models established based on 57 AMS (accel-erator mass spectrometry)14C dates to understand the basin's depositional history.The results indicate that (i) Ardashir Pond has existed as part of a larger wetlandcomplex since at least 4500 years ago, (ii) it was substantially enlarged at the be-ginning of the Sasanian era, and (iii) it was abandoned at the end of the Sasanianperiod. The Ardashir Pond is one of the first geoarchaeologically investigated casestudies to demonstrate the Sasanian landscape in the framework of the“Iranshahr”sociopolitical concept

Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers

BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity (RIT) across four cancer types (prostate, head and neck, breast, and lung).METHODS: A GWAS meta-analysis was performed using 19 cohorts including 12,042 patients. Acute standardized total average toxicity (rSTATacute) was modelled using a generalized linear regression model for additive effect of genetic variants adjusted for demographic and clinical covariates. LD score regression estimated shared SNP-based heritability of rSTATacute in all patients and for each cancer type.RESULTS: Shared SNP-based heritability of STATacute among all cancer types was estimated at 10% (se = 0.02), and was higher for prostate (17%, se = 0.07), head and neck (27%, se = 0.09), and breast (16%, se = 0.09) cancers. We identified 130 suggestive associated SNPs with rSTATacute (5.0x10-8&lt;P-value&lt;1.0x10-5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size -0.17; P-value=1.7x10-7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 x10-6, Pcorrected =0.079) as the top gene set associated with rSTATacute among all patients. In-silico gene expression analysis showed the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed Pcorrected=0.004; sun exposed Pcorrected=0.026).CONCLUSIONS: There is shared SNP-based heritability for acute RIT across and within individual cancer sites. Future meta-GWAS among large radiotherapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.</p

Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (ndiscovery=52654 and nreplication=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined=1.8x10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined=1.5x10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined=1.2x10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.</p