Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

Predictive modeling of hypoxic head and neck cancers during fractionated radiotherapy with gold nanoparticle radiosensitization.

PURPOSE: Intrinsic radioresistance and increased proliferation rates in head and neck cancers (HNCs) are associated with negative radiotherapy (RT) treatment responses. The use of gold nanoparticles (AuNPs) as radiosensitizers could enable total radiation dose reduction and lowered radiation toxicity. AuNP radiosensitization may overcome hypoxia-induced radioresistance and treatment-induced accelerated repopulation of cancer cells in HNCs, improving radiotherapy outcomes. METHODS: Tumor control was determined by considering individual cancer cell responses in probabilistic computational simulations using HYP-RT software for clinical radiotherapy doses and fractionation schedules along with three different nanoparticle administration schedules. Antagonistic tumor hypoxia and rapid tumor regrowth due to accelerated repopulation of cancers cells were taken into consideration. RESULTS: Simulations indicate that tumors that are conventionally uncontrollable can be controlled with AuNP radiosensitization. In simulations where the absence of AuNPs required radiotherapy doses above standard clinical prescriptions, reoccurring AuNP administration allowed for radiation dose reductions below standard clinical dose prescriptions. For example, considering a 2 Gy per fraction radiotherapy schedule, tumor control was achieved with 57.2 ± 5.1 Gy (P = <0.0001) for weekly AuNP administration and 53.0 ± 4.0 Gy (P = <0.0001) for biweekly AuNP administration compared to 69.9 ± 5.8 Gy with no radiosensitization. CONCLUSIONS: AuNPs decreased the predicted RT total doses required to achieve tumor control via total stem cell elimination, offering an optimistic prediction and method for which hypoxia-induced and rapidly growing radioresistant tumors are treated more effectively. Outcomes are also shown to be sensitive to the RT schedule with data for hyperfractionated RT indicating the greatest benefits from radiosensitization.

In silico modeling of cellular probabilistic nanoparticle radiosensitization in head and neck cancers.

Background: The use of gold nanoparticles (AuNPs) as radiosensitizers may offer a new approach in the treatment of head and neck cancers; minimizing treatment-associated toxicities and improving patient outcomes. AuNPs promote localized dose deposition; permitting improved local control and/or dose reduction. Aim: This work aimed to address the theoretical optimization of radiation doses, fractionation and nanoparticle injection schedules to maximize therapeutic benefits. Materials & methods: Probabilistic nanoparticle sensitization factors were incorporated into the individual cell-based HYP-RT computer model of tumor growth and radiotherapy. Results: Total dose outcomes across all radiation therapy treatment regimens were found to be significantly reduced with the presence of AuNPs, with bi-weekly injections showing the most decrease. Conclusion: Outcomes suggest the need for regular AuNP administration to permit effective radiosensitization.

Impact of Globodera ellingtonae on yield of potato (Solanum tuberosum).

Globodera ellingtonae was described from Oregon and Idaho in 2012. Due to the close phylogenetic relationship of this nematode to the potato cyst nematodes G. pallida and G. rostochiensis, and evidence that G. ellingtonae reproduces on potato (Solanum tuberosum), potential damaging effects to potato by this nematode are of great concern. To evaluate the pathogenic effects of G. ellingtonae on potato, five field and two microplot trials were conducted over a four-year period including comparisons of a range of G. ellingtonae initial population densities (Pi) and potato cultivars. In two field trials, potato 'Russet Burbank' was inoculated with Pi of G. ellingtonae ranging from 0 to 80 eggs/g soil; a similar trial was conducted with potato 'Désirée.' In another field trial, potato cultivars varying in maturity lengths were either inoculated (80 eggs/g soil) or not with G. ellingtonae. In a final field trial, 'Ranger Russet' was inoculated with Pi of G. ellingtonae ranging from 0 to 360 eggs/g soil. Additionally, Russet Burbank was inoculated with G. ellingtonae Pi ranging from 0 to 169 eggs/g soil in microplots. In all trials, data on tuber yield, aboveground biomass, final eggs/cyst, final population densities (Pf), and reproduction factor (RF = Pf/Pi) were collected. In only two of six trials conducted with increasing levels of Pi, was there a significant negative correlation between Pi of G. ellingtonae and yield of potato. Based on the linear regression model of tuber yield on logPi for Russet Burbank, 30.5 to 40.9% yield loss was predicted at a Pi of 40 and 80 eggs/g soil, respectively, and for Ranger Russet, 16.5 and 19.7% yield loss was predicted at a Pi of 40 and 80 eggs/g soil, respectively. None of the potato cultivars inoculated with 80 G. ellingtonae eggs/g soil had significantly reduced yields compared to non-inoculated plants. Reproduction factor values across trials ranged from 4.0 to 8.3 when inoculated with Pi of 40 eggs/g soil, demonstrating that the nematode successfully invaded and reproduced on potato in all trials. Care should be taken in extrapolating the results from these experiments conducted in Oregon to probable effects of G. ellingtonae on potato in other environments.KeywordsPotato, Damage, Globodera, Regression.Globodera ellingtonae was described from Oregon and Idaho in 2012. Due to the close phylogenetic relationship of this nematode to the potato cyst nematodes G. pallida and G. rostochiensis, and evidence that G. ellingtonae reproduces on potato (Solanum tuberosum), potential damaging effects to potato by this nematode are of great concern. To evaluate the pathogenic effects of G. ellingtonae on potato, five field and two microplot trials were conducted over a four-year period including comparisons of a range of G. ellingtonae initial population densities (Pi) and potato cultivars. In two field trials, potato 'Russet Burbank' was inoculated with Pi of G. ellingtonae ranging from 0 to 80 eggs/g soil; a similar trial was conducted with potato 'Désirée.' In another field trial, potato cultivars varying in maturity lengths were either inoculated (80 eggs/g soil) or not with G. ellingtonae. In a final field trial, 'Ranger Russet' was inoculated with Pi of G. ellingtonae ranging from 0 to 360 eggs/g soil. Additionally, Russet Burbank was inoculated with G. ellingtonae Pi ranging from 0 to 169 eggs/g soil in microplots. In all trials, data on tuber yield, aboveground biomass, final eggs/cyst, final population densities (Pf), and reproduction factor (RF = Pf/Pi) were collected. In only two of six trials conducted with increasing levels of Pi, was there a significant negative correlation between Pi of G. ellingtonae and yield of potato. Based on the linear regression model of tuber yield on logPi for Russet Burbank, 30.5 to 40.9% yield loss was predicted at a Pi of 40 and 80 eggs/g soil, respectively, and for Ranger Russet, 16.5 and 19.7% yield loss was predicted at a Pi of 40 and 80 eggs/g soil, respectively. None of the potato cultivars inoculated with 80 G. ellingtonae eggs/g soil had significantly reduced yields compared to non-inoculated plants. Reproduction factor values across trials ranged from 4.0 to 8.3 when inoculated with Pi of 40 eggs/g soil, demonstrating that the nematode successfully invaded and reproduced on potato in all trials. Care should be taken in extrapolating the results from these experiments conducted in Oregon to probable effects of G. ellingtonae on potato in other environments.KeywordsPotato, Damage, Globodera, Regression.

Stochastic multicellular modeling of x-ray irradiation, DNA damage induction, DNA free-end misrejoining and cell death.

The repair or misrepair of DNA double-strand breaks (DSBs) largely determines whether a cell will survive radiation insult or die. A new computational model of multicellular, track structure-based and pO2-dependent radiation-induced cell death was developed and used to investigate the contribution to cell killing by the mechanism of DNA free-end misrejoining for low-LET radiation. A simulated tumor of 1224 squamous cells was irradiated with 6 MV x-rays using the Monte Carlo toolkit Geant4 with low-energy Geant4-DNA physics and chemistry modules up to a uniform dose of 1 Gy. DNA damage including DSBs were simulated from ionizations, excitations and hydroxyl radical interactions along track segments through cell nuclei, with a higher cellular pO2 enhancing the conversion of DNA radicals to strand breaks. DNA free-ends produced by complex DSBs (cDSBs) were able to misrejoin and produce exchange-type chromosome aberrations, some of which were asymmetric and lethal. A sensitivity analysis was performed and conditions of full oxia and anoxia were simulated. The linear component of cell killing from misrejoining was consistently small compared to values in the literature for the linear component of cell killing for head and neck squamous cell carcinoma (HNSCC). This indicated that misrejoinings involving DSBs from the same x-ray (including all associated secondary electrons) were rare and that other mechanisms (e.g. unrejoined ends) may be important. Ignoring the contribution by the indirect effect toward DNA damage caused the DSB yield to drop to a third of its original value and the cDSB yield to drop to a tenth of its original value. Track structure-based cell killing was simulated in all 135306 viable cells of a 1 mm3 hypoxic HNSCC tumor for a uniform dose of 1 Gy.

Monte Carlo Simulation of the Oxygen Effect in DNA Damage Induction by Ionizing Radiation.

DNA damage induced by ionizing radiation exposure is enhanced in the presence of oxygen (the "oxygen effect"). Despite its practical importance in radiotherapy, the oxygen effect has largely been excluded from models that predict DNA damage from radiation tracks. A Monte Carlo-based algorithm was developed in MATLAB software to predict DNA damage from physical and chemical tracks through a cell nucleus simulated in Geant4-DNA, taking into account the effects of cellular oxygenation (pO2) on DNA radical chemistry processes. An initial spatial distribution of DNA base and sugar radicals was determined by spatially clustering direct events (that deposited at least 10.79 eV) and hydroxyl radical (•OH) interactions. The oxygen effect was modeled by increasing the efficiency with which sugar radicals from direct-type effects were converted to strand breaks from 0.6 to 1, the efficiency with which sugar radicals from the indirect effect were converted to strand breaks from 0.28 to 1 and the efficiency of base-to-sugar radical transfer from •OH-mediated base radicals from 0 to 0.03 with increasing pO2 from 0 to 760 mmHg. The DNA damage induction algorithm was applied to tracks from electrons, protons and alphas with LET values from 0.2 to 150 keV/µm under different pO2 conditions. The oxygen enhancement ratio for double-strand break induction was 3.0 for low-LET radiation up to approximately 15 keV/µm, after which it gradually decreased to a value of 1.3 at 150 keV/µm. These values were consistent with a range of experimental data published in the literature. The DNA damage yields were verified using experimental data in the literature and results from other theoretical models. The spatial clustering approach developed in this work has low memory requirements and may be suitable for particle tracking simulations with a large number of cells.

Simulation of head and neck cancer oxygenation and doubling time in a 4D cellular model with angiogenesis.

Tumor oxygenation has been correlated with treatment outcome for radiotherapy. In this work, the dependence of tumor oxygenation on tumor vascularity and blood oxygenation was determined quantitatively in a 4D stochastic computational model of head and neck squamous cell carcinoma (HNSCC) tumor growth and angiogenesis. Additionally, the impacts of the tumor oxygenation and the cancer stem cell (CSC) symmetric division probability on the tumor volume doubling time and the proportion of CSCs in the tumor were also quantified. Clinically relevant vascularities and blood oxygenations for HNSCC yielded tumor oxygenations in agreement with clinical data for HNSCC. The doubling time varied by a factor of 3 from well oxygenated tumors to the most severely hypoxic tumors of HNSCC. To obtain the doubling times and CSC proportions clinically observed in HNSCC, the model predicts a CSC symmetric division probability of approximately 2% before treatment. To obtain the doubling times clinically observed during treatment when accelerated repopulation is occurring, the model predicts a CSC symmetric division probability of approximately 50%, which also results in CSC proportions of 30-35% during this time.

The Draft Genome of Globodera ellingtonae.

Globodera ellingtonae is a newly described potato cyst nematode (PCN) found in Idaho, Oregon, and Argentina. Here, we present a genome assembly for G. ellingtonae, a relative of the quarantine nematodes G. pallida and G. rostochiensis, produced using data from Illumina and Pacific Biosciences DNA sequencing technologies.

Draft Transcriptome of Globodera ellingtonae.

Globodera ellingtonae is a newly described cyst nematode found in Idaho, Oregon, and Argentina. Here we present the first transcriptome assembly of G. ellingtonae, providing a valuable resource for comparing the evolution of expressed genes between potato cyst nematode species.

A review of the development of tumor vasculature and its effects on the tumor microenvironment.

BACKGROUND: The imbalance of angiogenic regulators in tumors drives tumor angiogenesis and causes the vasculature to develop much differently in tumors than in normal tissue. There are several cancer therapy techniques currently being used and developed that target the tumor vasculature for the treatment of solid tumors. This article reviews the aspects of the tumor vasculature that are relevant to most cancer therapies but particularly to vascular targeting techniques. MATERIALS AND METHODS: We conducted a review of identified experiments in which tumors were transplanted into animals to study the development of the tumor vasculature with tumor growth. Quantitative vasculature morphology data for spontaneous human head and neck cancers are reviewed. Parameters assessed include the highest microvascular density (h-MVD) and the relative vascular volume (RVV). The effects of the vasculature on the tumor microenvironment are discussed, including the distributions of hypoxia and proliferation. RESULTS: Data for the h-MVD and RVV in head and neck cancers are highly varied, partly due to methodological differences. However, it is clear that the cancers are typically more vascularized than the corresponding normal tissue. The commonly observed chronic hypoxia and acute hypoxia in these tumors are due to high intratumor heterogeneity in MVD and lower than normal blood oxygenation levels through the abnormally developed tumor vasculature. Hypoxic regions are associated with decreased cell proliferation. CONCLUSION: The morphology of the vasculature strongly influences the tumor microenvironment, with important implications for tumor response to medical intervention such as radiotherapy. Quantitative vasculature morphology data herein may be used to inform computational models that simulate the spatial tumor vasculature. Such models may play an important role in exploring and optimizing vascular targeting cancer therapies.

Development of an in silico stochastic 4D model of tumor growth with angiogenesis.

PURPOSE: A stochastic computer model of tumour growth with spatial and temporal components that includes tumour angiogenesis was developed. In the current work it was used to simulate head and neck tumour growth. The model also provides the foundation for a 4D cellular radiotherapy simulation tool. METHODS: The model, developed in Matlab, contains cell positions randomised in 3D space without overlap. Blood vessels are represented by strings of blood vessel units which branch outwards to achieve the desired tumour relative vascular volume. Hypoxic cells have an increased cell cycle time and become quiescent at oxygen tensions less than 1 mmHg. Necrotic cells are resorbed. A hierarchy of stem cells, transit cells and differentiated cells is considered along with differentiated cell loss. Model parameters include the relative vascular volume (2-10%), blood oxygenation (20-100 mmHg), distance from vessels to the onset of necrosis (80-300 µm) and probability for stem cells to undergo symmetric division (2%). Simulations were performed to observe the effects of hypoxia on tumour growth rate for head and neck cancers. Simulations were run on a supercomputer with eligible parts running in parallel on 12 cores. RESULTS: Using biologically plausible model parameters for head and neck cancers, the tumour volume doubling time varied from 45 ± 5 days (n = 3) for well oxygenated tumours to 87 ± 5 days (n = 3) for severely hypoxic tumours. CONCLUSIONS: The main achievements of the current model were randomised cell positions and the connected vasculature structure between the cells. These developments will also be beneficial when irradiating the simulated tumours using Monte Carlo track structure methods.

Control of Globodera spp. Using Brassica juncea Seed Meal and Seed Meal Extract.

The eradication program for the potato cyst nematode (PCN), Globodera pallida, in the Northwest of the United States revolves around the use of soil fumigation. Alternative, integrated strategies are needed to continue to battle this invasive nematode. Laboratory, greenhouse, and field experiments were conducted with G. pallida and another cyst nematode found in the United States, Globodera ellingtonae, to evaluate the efficacy of a new formulated Brassica juncea seed meal extract, as well as a traditional B. juncea seed meal, as alternate eradication strategies. This is the first report on the efficacy of B. juncea seed meal extract against plant-parasitic nematodes. Rates of B. juncea seed meal greater than 2.2 t/ha and 4.5 t/ha for G. pallida and G. ellingtonae, respectively, were required for egg hatch suppression, as determined by a potato root diffusate (PRD) bioassay. Reproduction of G. pallida on potato after exposure to B. juncea seed meal at a rate of 2.2 t/ha was also significantly reduced. In the field, 8.9 t/ha B. juncea seed meal almost eliminated egg hatch of G. ellingtonae. Rates needed for Globodera spp. suppression were greatly reduced when using the B. juncea seed meal extract. When compared side-by-side, half as much B. juncea seed meal extract, 1.1 t/ha, was required to suppress G. ellingtonae egg hatch to the same extent as B. juncea seed meal. Exposure of G. pallida to B. juncea seed meal extract at 4.5 t/ha reduced egg hatch by 90% compared with a nonamended control. The ability to reduce the amount of material being applied to soil by using an extract has the potential for integration into a G. pallida eradication program.

Developmental Dynamics of Globodera ellingtonae in Field-Grown Potato.

Globodera ellingtonae is a recently described nematode parasite of potato, which is closely related to the economically significant potato cyst nematodes G. rostochiensis and G. pallida. Because of the close relationship of G. ellingtonae to the potato cyst nematodes, a greater understanding of its biology is critical. Two experiments were conducted in Oregon to explore the developmental biology of G. ellingtonae in field-grown potato. The first experiment was conducted in 2013 and 2014 to determine the developmental timing of G. ellingtonae life stages and reproduction by inoculating potato with soil containing cysts followed by weekly collection of soil and root samples. Life stages; second-stage juveniles (J2) in soil and roots, third-stage juveniles (J3) and fourth-stage (J4) females and males in roots, males and females or cysts in soil, and egg number and developmental state were quantified. Normalizing across years using accumulated developmental degree days above 6°C (DD6), J2 of G. ellingtonae were found in soil from 41 to 588 DD6; two peaks of J2 invasion of roots were observed. The first adult females were observed at 387 and 449 DD6 in 2013 and 2014, respectively. The next generation of eggs was first observed from 675 to 854 DD6 and 50% egg development (containing a vermiform juvenile) occurred at approximately 920 DD6. A second J2 hatch was observed in both years at 927 to 1,073 DD6. The developmental dynamics of G. ellingtonae observed here are similar to those reported for G. rostochiensis and G. pallida from several geographical locations. In the second experiment, the effect of potato and bare soil on G. ellingtonae egg hatch was evaluated; in 2014 and 2015, packages containing cysts in soil were buried under potato or in bare soil at the time of planting and eggs per cyst determined weekly. Across years, a significant reduction in eggs per cysts under potato (>50%) was observed 35 days after planting (DAP) and, at 63 DAP, eggs per cyst were reduced by 76 to 96% compared with initial egg per cyst densities. In bare soil, the maximum reduction in densities of eggs per cyst was 55 to 73%. This annual reduction in egg numbers of G. ellingtonae in bare soil is similar to that reported for G. pallida and G. rostochiensis.

The mitochondrial genome of Globodera ellingtonae is composed of two circles with segregated gene content and differential copy numbers.

BACKGROUND: The evolution of animal mitochondrial (mt) genomes has resulted in a highly conserved structure: a single compact circular chromosome approximately 14 to 20 kb long. Within the last two decades exceptions to this conserved structure, such as the division of the genome into multiple chromosomes, have been reported in a diverse set of metazoans. We report on the two circle multipartite mt genome of a newly described cyst nematode, Globodera ellingtonae. RESULTS: The G. ellingtonae mt genome was found to be comprised of two circles, each larger than any other multipartite circular mt chromosome yet reported, and both were larger than the single mt circle of the model nematode Caenorhabditis elegans. The genetic content of the genome was disproportionately divided between the two circles, although they shared a ~6.5 kb non-coding region. The 17.8 kb circle (mtDNA-I) contained ten protein-coding genes and two tRNA genes, whereas the 14.4 kb circle (mtDNA-II) contained two protein-coding genes, 20 tRNA genes and both rRNA genes. Perhaps correlated with this division of genetic content, the copy number of mtDNA-II was more than four-fold that of mtDNA-I in individual nematodes. The difference in copy number increased between second-stage and fourth-stage juveniles. CONCLUSIONS: The segregation of gene types to different mt circles in G. ellingtonae could provide benefit by localizing gene functional types to independent transcriptional units. This is the first report of both two-circle and several-circle mt genomes within a single genus. The differential copy number associated with this multipartite mt organization could provide a model system for deconstructing mechanisms regulating mtDNA copy number both in somatic cells and during germline development.

The genome of the yellow potato cyst nematode, Globodera rostochiensis, reveals insights into the basis of parasitism and virulence.

BACKGROUND: The yellow potato cyst nematode, Globodera rostochiensis, is a devastating plant pathogen of global economic importance. This biotrophic parasite secretes effectors from pharyngeal glands, some of which were acquired by horizontal gene transfer, to manipulate host processes and promote parasitism. G. rostochiensis is classified into pathotypes with different plant resistance-breaking phenotypes. RESULTS: We generate a high quality genome assembly for G. rostochiensis pathotype Ro1, identify putative effectors and horizontal gene transfer events, map gene expression through the life cycle focusing on key parasitic transitions and sequence the genomes of eight populations including four additional pathotypes to identify variation. Horizontal gene transfer contributes 3.5 % of the predicted genes, of which approximately 8.5 % are deployed as effectors. Over one-third of all effector genes are clustered in 21 putative 'effector islands' in the genome. We identify a dorsal gland promoter element motif (termed DOG Box) present upstream in representatives from 26 out of 28 dorsal gland effector families, and predict a putative effector superset associated with this motif. We validate gland cell expression in two novel genes by in situ hybridisation and catalogue dorsal gland promoter element-containing effectors from available cyst nematode genomes. Comparison of effector diversity between pathotypes highlights correlation with plant resistance-breaking. CONCLUSIONS: These G. rostochiensis genome resources will facilitate major advances in understanding nematode plant-parasitism. Dorsal gland promoter element-containing effectors are at the front line of the evolutionary arms race between plant and parasite and the ability to predict gland cell expression a priori promises rapid advances in understanding their roles and mechanisms of action.

Stochastic Predictions of Cell Kill During Stereotactic Ablative Radiation Therapy: Do Hypoxia and Reoxygenation Really Matter?

PURPOSE: To simulate stereotactic ablative radiation therapy on hypoxic and well-oxygenated in silico tumors, incorporating probabilistic parameter distributions and linear-quadratic versus linear-quadratic-cubic methodology and the evaluation of optimal fractionation schemes using biological effective dose (BEDα/ß=10 or 3) comparisons. METHODS AND MATERIALS: A temporal tumor growth and radiation therapy algorithm simulated high-dose external beam radiation therapy using stochastic methods. Realistic biological proliferative cellular hierarchy and pO2 histograms were incorporated into the 10(8)-cell tumor model, with randomized radiation therapy applied during continual cell proliferation and volume-based gradual tumor reoxygenation. Dose fractions ranged from 6-35 Gy, with predictive outcomes presented in terms of the total doses (converted to BED) required to eliminate all cells that could potentially regenerate the tumor. RESULTS: Well-oxygenated tumor control BED10 outcomes were not significantly different for high-dose versus conventional radiation therapy (BED10: 79-84 Gy; Equivalent Dose in 2 Gy fractions with α/ß of 10: 66-70 Gy); however, total treatment times decreased from 7 down to 1-3 weeks. For hypoxic tumors, an additional 28 Gy (51 Gy BED10) was required, with BED10 increasing with dose per fraction due to wasted dose in the final fraction. Fractions of 9 Gy compromised well for total treatment time and BED, with BED10:BED3 of 84:176 Gy for oxic and 132:278 Gy for non-reoxygenating hypoxic tumors. Initial doses of 12 Gy followed by 6 Gy further increased the therapeutic ratio. When delivering ≥9 Gy per fraction, applying reoxygenation and/or linear-quadratic-cubic cell survival both affected tumor control doses by a significant 1-2 fractions. CONCLUSIONS: The complex temporal dynamics of tumor oxygenation combined with probabilistic cell kinetics in the modeling of radiation therapy requires sophisticated stochastic modeling to predict tumor cell kill. For stereotactic ablative radiation therapy, high doses in the first week followed by doses that are more moderate may be beneficial because a high percentage of hypoxic cells could be eradicated early while keeping the required BED10 relatively low and BED3 toxicity to tolerable levels.

The Relationship between Temperature and Development in Globodera ellingtonae.

A new cyst nematode species, Globodera ellingtonae, was recently described from populations in Oregon and Idaho. This nematode has been shown to reproduce on potato. Because of this nematode's close relationship to the potato cyst nematodes, G. rostochiensis and G. pallida, an understanding of the risk of its potential spread, including prediction of potential geographical distribution, is required. To determine the development of G. ellingtonae under different temperatures, we conducted growth chamber experiments over a range of temperatures (10.0°C to 26.5°C) and tracked length of time to various developmental stages, including adult females bearing the next generation of eggs. Both the time to peak population densities of G. ellingtonae life stages and their duration in roots generally increased with decreasing temperature. Regression of growth rate to second-stage (J2) and third-stage (J3) juveniles on temperature yielded different base temperatures: 6.3°C and 4.4°C for J2 and J3, respectively. Setting a base temperature of 6°C allowed calculation of the degree-days (DD6) over which different life stages occurred. The largest population densities of J2 were found in roots between 50 and 200 DD6. Population densities of J3 peaked between 200 and 300 DD6. Adult males were detected in soil starting at 300 to 400 DD6 and remained detectable for approximately 500 DD6. By 784 to 884 DD6, half of the eggs in adult females contained vermiform juveniles. Given the similarity in temperature ranges for successful development between G. ellingtonae and G. rostochiensis, G. ellingtonae populations likely could survive in the same geographic range in which G. rostochiensis now occurs.

Hypoxia in head and neck cancer in theory and practice: a PET-based imaging approach.

Hypoxia plays an important role in tumour recurrence among head and neck cancer patients. The identification and quantification of hypoxic regions are therefore an essential aspect of disease management. Several predictive assays for tumour oxygenation status have been developed in the past with varying degrees of success. To date, functional imaging techniques employing positron emission tomography (PET) have been shown to be an important tool for both pretreatment assessment and tumour response evaluation during therapy. Hypoxia-specific PET markers have been implemented in several clinics to quantify hypoxic tumour subvolumes for dose painting and personalized treatment planning and delivery. Several new radiotracers are under investigation. PET-derived functional parameters and tracer pharmacokinetics serve as valuable input data for computational models aiming at simulating or interpreting PET acquired data, for the purposes of input into treatment planning or radio/chemotherapy response prediction programs. The present paper aims to cover the current status of hypoxia imaging in head and neck cancer together with the justification for the need and the role of computer models based on PET parameters in understanding patient-specific tumour behaviour.