Relative Biological Effectiveness Studies Using 3 MeV Proton Beam from Folded Tandem Ion Accelerator: An Experimental and Theoretical Approach

Proton being the easiest light ion to accelerate and achieve desired beam profile, has been pursued as a popular particulate radiation for therapy applications. In the present study, Saccharomyces cerevisiae D7 strain was used to estimate the RBE values of the 3 MeV proton beam, and an attempt was made to derive mathematical formula for calculating RBE value with respect to the dose. Dosimetry studies were carried out using Fricke dosimetry and Semiconductor Surface Barrier detector to calibrate the absorbed doses of Gamma chamber-1200 and Folded Tandem Ion Accelerator respectively. Gold standard cell survival assay and gene conversion assay were used to compare gamma and proton radiation induced cell death and genetic endpoint. Multi target single hit model was used to derive mathematical formula for RBE estimation. The results show a linear survival-dose response after proton radiation and sigmoid survival-dose response after gamma radiation treatment. The calculated RBE value from the survival and gene conversion studies was 1.60 and 3.93, respectively. The derived mathematical formula is very useful in calculating RBE value, which varies from 3.61 to 1.80 with increasing dose. The estimated RBE value from the mathematical formula is comparable with the experimental values. With the help of the present mathematical formulation, RBE value at any dose can be calculated in the exponential and sigmoidal regions of the survival curve without actually extending the experiment in that dose region, which is not possible using conventional methods

Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial

Background: In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy. Methods: UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50–74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032. Findings: 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04–13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4–13·0; p=0·042) at 18 years (21% [95% CI 15·6–26·2] vs 14% [95% CI 10·5–17·4]). Interpretation: To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer. Funding: National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

ACUTE ORAL TOXICITY STUDY OF AQUEOUS AND METHANOLIC EXTRACT OF BLUMEA VIRENS IN SPRAGUE DAWLEY RATS

Blumea virens, belonging to family Asteraceae, is found abundantly in tropical and subtropical zones of Asia, especially in India. The consumption of whole plant has been reported to produce mortality in animals in Kerala. Thus, the present study was undertaken to evaluate the in vivo acute oral toxicity of aqueous and methanolic extract of Blumea virens in Sprague Dawley rats as per OECD guidelines 425. Limit test was conducted at a dose of 2000 mg/Kg. The animals administered with the aqueous and methanolic extract did not produce any related signs of toxicity or mortality during the 14-day observation period. Gross and histopathology was performed at the end of the study. Methanolic extract evinced hepatotoxicity and pulmonary toxicity to the animal whereas no abnormalities were detected with aqueous extract. Phytochemical analysis of the plant methanolic extract revealed presence of steroids, alkaloids, flavonoids, tannins, diterpenes, triterpenes and glycosides whereas aqueous extract revealed presence of steroids, alkaloids, flavonoids, diterpenes and glycosides

Computational methods to locate and reconstruct genes for complexity reduction in comparative genomics

Discovering the functions of proteins in living organisms is an important tool for understanding cellular processes. The source data for such analysis are commonly the peptide sequences. Most common algorithms used to compare a pair of nucleotide sequence are Global alignment algorithm (Needleman-Wunch algorithm) or local alignment algorithm (Smith-Waterman algorithm). Analysis of these algorithms show that time complexity required to the above mentioned algorithms is O(mn) and space complexity required is O(mn), where m is size of one sequence and n is size of the other sequence. This is one of the major bottlenecks as most of the sequences are very large. The proposed Coding Region Sequence Analysis(CRSA) algorithm presents a method to reduce both time and space complexity by meaningfully reducing the size of sequences by removing not so significant exons using wavelet transforms. DSP techniques supply a strong basis for regions identification with three-base periodicity. © Springer-Verlag 2011