Exploiting biological and physical determinants of radiotherapy toxicity to individualise treatment.

This is the final version of the article. It first appeared from the British Institute of Radiology via http://dx.doi.org/10.1259/bjr.20150172The recent advances in radiation delivery can improve tumour control probability and reduce treatment related toxicity. The use of intensity-modulated radiotherapy (IMRT) in particular can reduce normal tissue toxicity, an objective in its own right, and can allow safe dose escalation in selected cases. Ideally IMRT should be combined with image guidance to verify the position of the target, since patients, target and organs at risk can move day-to-day. Daily image guidance scans can be used to identify the position of normal tissue structures, and potentially to compute the daily delivered dose. Fundamentally, it is still the tolerance of the normal tissues which limits radiotherapy dose and therefore tumour control. However, the dose response relationships for both tumour and normal tissues are relatively steep, meaning that small dose differences can translate into clinically relevant improvements. Differences exist between individuals in the severity of toxicity experienced for a given dose of radiotherapy. Some of this difference may be the result of differences between the planned dose and the accumulated dose (DA). However, some may be due to intrinsic differences in radiosensitivity of the normal tissues between individuals. This field has been developing rapidly, with the demonstration of definite associations between genetic polymorphisms and variation in toxicity recently described. It might be possible to identify more resistant patients who would be suitable for dose escalation, as well as more sensitive patients for whom toxicity could be reduced or avoided. Daily differences in delivered dose have been investigated within the VoxTox research programme, using the rectum as an example organ at risk. In prostate cancer patients receiving curative radiotherapy, considerable daily variation in rectal position and dose can be demonstrated, although the median position matches the planning scan well. Overall, in 10 patients, the mean difference between planned and accumulated rectal equivalent uniform doses (EUDs) was -2.7 Gy (5%), and a dose reduction was seen in 7/10 cases. If dose escalation were performed to take rectal dose back to the planned level, this should increase the mean tumour control probability (TCP) (as biochemical progression-free survival) by 5%. Combining radiogenomics with individual estimates of DA might identify almost half of patients undergoing radical radiotherapy who might benefit from either dose escalation, suggesting improved tumour cure, or reduced toxicity, or both.JS is supported by Cancer Research UK through the Cambridge Cancer Centre. NGB is supported by the NIHR Cambridge Biomedical Research Centre. The VoxTox Research Programme is funded by Cancer Research UK

No effect of repeated post-resistance exercise cold or hot water immersion on in-season body composition and performance responses in academy rugby players: a randomised controlled cross-over design

Following resistance exercise, uncertainty exists as to whether the regular application of cold water immersion attenuates lean muscle mass increases in athletes. The effects of repeated post-resistance exercise cold versus hot water immersion on body composition and neuromuscular jump performance responses in athletes were investigated. Male, academy Super Rugby players (n = 18, 19.9 ± 1.5 y, 1.85 ± 0.06 m, 98.3 ± 10.7 kg) participated in a 12-week (4-week × 3-intervention, i.e., control [CON], cold [CWI] or hot [HWI] water immersion) resistance exercise programme, utilising a randomised cross-over pre-post-design. Body composition measures were collected using dual-energy X-ray absorptiometry prior to commencement and every fourth week thereafter. Neuromuscular squat (SJ) and counter-movement jump (CMJ) performance were measured weekly. Linear mixed-effects models were used to analyse main (treatment, time) and interaction effects. There were no changes in lean (p = 0.960) nor fat mass (p = 0.801) between interventions. CON (p = 0.004) and CWI (p = 0.003) increased (g = 0.08-0.19) SJ height, compared to HWI. There were no changes in CMJ height (p = 0.482) between interventions. Repeated post-resistance exercise whole-body CWI or HWI does not attenuate (nor promote) increases in lean muscle mass in athletes. Post-resistance exercise CON or CWI results in trivial increases in SJ height, compared to HWI. During an in-season competition phase, our data support the continued use of post-resistance exercise whole-body CWI by athletes as a recovery strategy which does not attenuate body composition increases in lean muscle mass, while promoting trivial increases in neuromuscular concentric-only squat jump performance. [Abstract copyright: © 2022. The Author(s).

A New Computational Tool for the Phenomenological Analysis of Multipassage Tumor Growth Curves

Multipassage experiments are performed by subcutaneous implantation in lab animals (usually mice) of a small number of cells from selected human lines. Tumor cells are then passaged from one mouse to another by harvesting them from a growing tumor and implanting them into other healthy animals. This procedure may be extremely useful to investigate the various mechanisms involved in the long term evolution of tumoral growth. It has been observed by several researchers that, contrary to what happens in in vitro experiments, there is a significant growth acceleration at each new passage. This result is explained by a new method of analysis, based on the Phenomenological Universalities approach. It is found that, by means of a simple rescaling of time, it is possible to collapse all the growth curves, corresponding to the successive passages, into a single curve, belonging to the Universality Class U2. Possible applications are proposed and the need of further experimental evidence is discussed

Phosphoenolpyruvate carboxylase dentified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism

Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in thePlasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery

Constraints on Nucleon Decay via "Invisible" Modes from the Sudbury Neutrino Observatory

Data from the Sudbury Neutrino Observatory have been used to constrain the lifetime for nucleon decay to ``invisible'' modes, such as n -> 3 nu. The analysis was based on a search for gamma-rays from the de-excitation of the residual nucleus that would result from the disappearance of either a proton or neutron from O16. A limit of tau_inv > 2 x 10^{29} years is obtained at 90% confidence for either neutron or proton decay modes. This is about an order of magnitude more stringent than previous constraints on invisible proton decay modes and 400 times more stringent than similar neutron modes.Comment: Update includes missing efficiency factor (limits change by factor of 2) Submitted to Physical Review Letter

Antibody-Based Detection and Inhibition of Vaginolysin, the Gardnerella vaginalis Cytolysin

Bacterial vaginosis (BV) is the most common vaginal infection worldwide and is associated with significant adverse sequelae. We have recently characterized vaginolysin (VLY), the human-specific cytotoxin produced by Gardnerella vaginalis and believed to play a critical role in the pathogenesis of BV and its associated morbidities. We hypothesize that novel antibody-based strategies may be useful for detection of VLY and for inhibition of its toxic effects on human cells. Using purified toxin as an immunogen, we generated polyclonal rabbit immune serum (IS) against VLY. A western blot of G. vaginalis lysate was probed with IS and a single band (57 kD) identified. Immunofluorescence techniques using IS detected VLY production by G. vaginalis. In addition, we have developed a sandwich ELISA assay capable of VLY quantification at ng/ml concentrations in the supernatant of growing G. vaginalis. To investigate the potential inhibitory role of IS on VLY-mediated cell lysis, we exposed human erythrocytes to VLY or VLY pretreated with IS and determined the percent hemolysis. Pretreatment with IS resulted in a significant reduction in VLY-mediated lysis. Similarly, both human cervical carcinoma cells and vaginal epithelial cells exhibited reduced cytolysis following exposure to VLY with IS compared to VLY alone. These results confirm that antibody-based techniques are an effective means of VLY detection. Furthermore, VLY antiserum functions as an inhibitor of VLY–CD59 interaction, mitigating cell lysis. These strategies may have a potential role in the diagnosis and treatment of BV

A Career in Surgical Oncology: Finding Meaning, Balance, and Personal Satisfaction

The practice of surgical oncology provides opportunities for both personal distress as well as personal satisfaction. While many surgical oncologists experience career burnout, others derive great meaning and satisfaction from their work. In this article, we review the literature on surgeon burnout, discuss potential personal and professional consequences, and consider steps individual surgeons can take to promote personal and professional satisfaction

Inversion of the balance between hydrophobic and hydrogen bonding interactions in protein folding and aggregation.

Identifying the forces that drive proteins to misfold and aggregate, rather than to fold into their functional states, is fundamental to our understanding of living systems and to our ability to combat protein deposition disorders such as Alzheimer's disease and the spongiform encephalopathies. We report here the finding that the balance between hydrophobic and hydrogen bonding interactions is different for proteins in the processes of folding to their native states and misfolding to the alternative amyloid structures. We find that the minima of the protein free energy landscape for folding and misfolding tend to be respectively dominated by hydrophobic and by hydrogen bonding interactions. These results characterise the nature of the interactions that determine the competition between folding and misfolding of proteins by revealing that the stability of native proteins is primarily determined by hydrophobic interactions between side-chains, while the stability of amyloid fibrils depends more on backbone intermolecular hydrogen bonding interactions