Radiobiologically derived biphasic fractionation schemes to overcome the effects of tumour hypoxia

OBJECTIVE: As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3–4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation. METHODS: The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity. 40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration) 30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution) The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions. RESULTS: Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5–8 Gy when delivered in 2 Gy fractions. CONCLUSION: In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation. ADVANCES IN KNOWLEDGE: We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC

Evaluation of Chinese Saccharomyces cerevisiae wine strains from different geographical origins

Interdelta sequence typing was used to investigate the genetic diversity of 54 Chinese indigenous wine strains of Saccharomyces cerevisiae selected on the basis of preliminary sequence analysis from 349 strains that were isolated previously from 15 spontaneous fermentations in Shanshan, Xinjiang, and Qing Tongxia, Ningxia, China. Of the 54 strains tested, 78% (42/54) were confirmed as genetically distinct. Dendrograms based on strain similarity revealed differences in the genetic relationships of Xinjiang yeast populations between table and wine grape varieties, in addition to differences between red and white grape varieties in Ningxia (Dice coefficients of 0.448 and 0.674, respectively). When data from Saccharomyces strains collected from California, France, Italy, northern Europe, and Spain were included in the analysis, the dendrogram revealed five groups containing 51, 4, 48, 3, and 1 strain, respectively. Ningxia and Xinjiang provinces displayed local specific S. cerevisiae biotas that show a clear separation from other strains. Cluster XJ19 isolated from Xinjiang displayed a high level of similar­ity with UCD587, UCD2515, and UCD2516 from California. Clusters XJ2, XJ7, XJ20, and XJ3, also isolated from Xinjiang, had a lower degree of similarity with other Chinese indigenous genotypes and strains from other regions. This study compares, for the first time, the genetic diversity and relationships between indigenous S. cerevisiae wine strains collected from Xinjiang and Ningxia provinces in China with wine strains from different geographic regions

Nesting biology of the leafcutting bee Megachile (Pseudocentron) gomphrenoides (Hymenoptera: Megachilidae) in an agro-ecosystem

The nesting biology of the leafcutting bee Megachile (Pseudocentron) gomphrenoides Vachal (Hymenoptera: Megachilidae) was studied in an agro-ecosystem in the Province of Buenos Aires, Argentina. Data were obtained from trap-nests placed in the field margin during two agricultural years (2008/2009 and 2009/2010). Females made an average of 7.55 cells per nest, and used leaves of at least three plant species to build their nests. Provisions of cells were principally of Asteraceae pollen. Adult emergence showed a bimodal pattern suggesting a facultative bivoltinism life cycle. Approximately, 30 % of all offspring failed to complete development to the adult stage and an additional 10 % were killed by natural enemies. These included parasitic wasps (Eulophidae: Melittobia and Horismenus), a cleptoparasite bee (Megachilidae: Coelioxys), and a bristle beetle (Meloidae: Tetraonyx). The host/cleptoparasite association between M. gomphrenoides and Coelioxys remissa constitutes the first such record for both species, and the Megachile–Tetraonyx interaction was previously unknown. M. gomphrenoides possesses some characteristics that make it an interesting potential opportunity to use this species for pollination of commercial sunflowers in the Pampean region.Fil: Torretta, Juan Pablo. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Recursos Naturales y Ambiente. Cátedra de Botánica Agrícola; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Durante, Silvana Patricia. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División Entomología; ArgentinaFil: Colombo, María Guadalupe. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División Entomología; ArgentinaFil: Basilio, Alicia Mabel. Universidad de Buenos Aires. Facultad de Agronomia. Departamento de Producción Animal. Cátedra de Avicultura, Cunicultura y Apicultura; Argentin