Irinotecan and topotecan are derivatives of the naturally occurring cytotoxic compound camptothecin that are used in the treatment of patients with colorectal cancer, either as single agents or in ...combination with radiotherapy and/or other chemotherapy drugs. They are inhibitors of DNA topoisomerase I (Top I) and exert their cytotoxic effects in replicating cells by inducing DNA strand breaks. A wide range of DNA repair proteins is involved in the recognition and repair of these breaks, and depletion or inhibition of some of these proteins increases the cytotoxic effects of Top I inhibitors. Building on these laboratory observations, ongoing translational research is aiming to establish whether this mechanistic information can be used to improve the treatment of patients with certain types of cancer. Two potential strategies are under investigation: (1) individualising treatment by evaluating levels and/or patterns of expression of DNA repair proteins that predict clinical response to Top I inhibitors, and (2) developing small molecule inhibitors of these repair enzymes to overcome tumour resistance and improve outcomes. This review summarises the current status of these research endeavours, focusing on the key roles of tyrosyl DNA phosphodiesterase 1 (Tdp1) and poly(ADP-ribose) polymerase (PARP), and examines the pre-clinical and clinical data that support the potential value of these and other DNA repair proteins as predictive markers and therapeutic targets. Since irinotecan is increasingly being combined with radiotherapy, the potential for these proteins to act as predictive biomarkers for both Top I inhibitors and radiation is proposed, and the possibility of synergistic potentiation of chemoradiation regimes by Tdp1 and/or PARP inhibitors is considered.
We present a constraint on the tensor-to-scalar ratio, r, derived from measurements of cosmic microwave background (CMB) polarization B-modes with "delensing," whereby the uncertainty on r ...contributed by the sample variance of the gravitational lensing B-modes is reduced by cross-correlating against a lensing B-mode template. This template is constructed by combining an estimate of the polarized CMB with a tracer of the projected large-scale structure. The large-scale-structure tracer used is a map of the cosmic infrared background derived from Planck satellite data, while the polarized CMB map comes from a combination of South Pole Telescope, bicep/Keck, and Planck data. We expand the bicep/Keck likelihood analysis framework to accept a lensing template and apply it to the bicep/Keck dataset collected through 2014 using the same parametric foreground modeling as in the previous analysis. From simulations, we find that the uncertainty on r is reduced by ∼10%, from σ(r)=0.024 to 0.022, which can be compared with a ∼26% reduction obtained when using a perfect lensing template or if there were zero lensing B-modes. Applying the technique to the real data, the constraint on r is improved from r0.05<0.090 to r0.05<0.082 (95% C.L.). This is the first demonstration of improvement in an r constraint through delensing.
This Letter reports one of the most precise measurements to date of the antineutrino spectrum from a purely 235U-fueled reactor, made with the final dataset from the PROSPECT-I detector at the High ...Flux Isotope Reactor. By extracting information from previously unused detector segments, this analysis effectively doubles the statistics of the previous PROSPECT measurement. Further, the reconstructed energy spectrum is unfolded into antineutrino energy and compared with both the Huber-Mueller model and a spectrum from a commercial reactor burning multiple fuel isotopes. A local excess over the model is observed in the 5–7 MeV energy region. Comparison of the PROSPECT results with those from commercial reactors provides new constraints on the origin of this excess, disfavoring at 2.0 and 3.7 standard deviations the hypotheses that antineutrinos from 235U are solely responsible and noncontributors to the excess observed at commercial reactors, respectively.
We report the discovery of endogenous viral elements (EVEs) from Hepadnaviridae, Bornaviridae and Circoviridae in the speckled rattlesnake, Crotalus mitchellii, the first viperid snake for which a ...draft whole genome sequence assembly is available. Analysis of the draft assembly reveals genome fragments from the three virus families were inserted into the genome of this snake over the past 50 Myr. Cross-species PCR screening of orthologous loci and computational scanning of the python and king cobra genomes reveals that circoviruses integrated most recently (within the last approx. 10 Myr), whereas bornaviruses and hepadnaviruses integrated at least approximately 13 and approximately 50 Ma, respectively. This is, to our knowledge, the first report of circo-, borna- and hepadnaviruses in snakes and the first characterization of non-retroviral EVEs in non-avian reptiles. Our study provides a window into the historical dynamics of viruses in these host lineages and shows that their evolution involved multiple host-switches between mammals and reptiles.
The PROSPECT and STEREO collaborations present a combined measurement of the pure 235U antineutrino spectrum, without site specific corrections or detector-dependent effects. The spectral ...measurements of the two highest precision experiments at research reactors are found to be compatible with χ2/ndf = 24.1/21, allowing a joint unfolding of the prompt energy measurements into antineutrino energy. This $\bar{ν}_e$ energy spectrum is provided to the community, and an excess of events relative to the Huber model is found in the 5-6 MeV region. When a Gaussian bump is fitted to the excess, the data-model χ2 value is improved, corresponding to a 2.4σ significance.
Concurrent chemoradiotherapy is the standard treatment for anal cancer. Following national UK implementation of intensity-modulated radiotherapy (IMRT), this prospective, national cohort evaluates ...the one-year oncological outcomes and patient-reported toxicity outcomes (PRO) after treatment.
A national cohort of UK cancer centers implementing IMRT was carried out between February to July 2015. Cancer centers provided data on oncological outcomes, including survival, and disease and colostomy status at one-year. EORTC-QLQ core (C30) and colorectal (CR29) questionnaires were completed at baseline and one-year followup. The PRO scores at baseline and one year were compared.
40 UK Cancer Centers returned data with a total of 187 patients included in the analysis. 92% received mitomycin with 5-fluorouracil or capecitabine. One-year overall survival was 94%; 84% were disease-free and 86% colostomy-free at one-year followup. At one year, PRO results found significant improvements in buttock pain, blood and mucus in stools, pain, constipation, appetite loss, and health anxiety compared to baseline. No significant deteriorations were reported in diarrhea, bowel frequency, and flatulence. Urinary symptom scores were low at one year. Moderate impotence symptoms at baseline remained at one year, and a moderate deterioration in dyspareunia reported.
With national anal cancer IMRT implementation, at this early pre-defined time point, one-year oncological outcomes were reassuring and resulted in good disease-related symptom control. one-year symptomatic complications following CRT for anal cancer using IMRT techniques appear to be relatively mild. These PRO results provide a basis to benchmark future studies.
•Significant improvements in pain, blood in stool and health anxiety at one-year.•No significant deterioration in bowel or urinary symptoms.•Moderate male and female sexual dysfunction reported.•94% one-year overall survival in a national cohort following anal cancer (chemo)IMRT.
Radiotherapy for breast cancer reduces disease recurrence and breast cancer mortality. However, it has also been associated with increased second cancer risks in exposed sites.
We evaluated long-term ...second cancer risks among 182 057 5-year survivors of locoregional invasive breast cancer diagnosed between 1973 and 2000 and reported to US NCI-SEER Program cancer registries. Multivariate Poisson regression was used to estimate the relative risk (RR) and excess cases of second cancer in women who had surgery and radiotherapy, compared with those who had surgery alone. Second cancer sites were grouped according to doses received from typical tangential breast fields.
By the end of 2005 (median follow-up=13.0 years), 15 498 second solid cancers had occurred, including 6491 contralateral breast cancers. The RRs for radiotherapy were 1.45 (95% confidence interval (CI)=1.33-1.58) for high-dose second cancer sites (1+ Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04-1.15) for contralateral breast cancer ( approximately 1 Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5-0.99 Gy, RR=0.89 (0.74-1.06)) or low doses (<0.5 Gy, RR=1.01 (0.95-1.07)). The estimated excess cases of cancer in women treated with radiotherapy were as follows: 176 (95% CI=69-284) contralateral breast cancers or 5% (2-8%) of the total in all 1+year survivors, and 292 (222-362) other solid cancers or 6% (4-7%) of the total.
Most second solid cancers in breast cancer survivors are not related to radiotherapy.
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