Increased abundance of tumour-associated neutrophils in HPV-negative compared to HPV-positive oropharyngeal squamous cell carcinoma is mediated by IL-1R signalling

The incidence of human papillomavirus (HPV)-associated cancer is increasing and HPV is now implicated in the aetiology of more than 60% of all oropharyngeal squamous cell carcinomas (OPSCC). In OPSCC, innate immune cells such as neutrophils and macrophages generally correlate with poor prognosis, whilst adaptive immune cells, such as lymphocytes, tend to correlate with improved prognosis. This may, in part, be due to differences in the immune response within the tumour microenvironment leading to the recruitment of specific tumour-associated leukocyte sub-populations. In this study, we aimed to examine if differences exist in the levels of infiltrated leukocyte sub-populations, with particular emphasis on tumour-associated neutrophils (TAN), and to determine the mechanism of chemokine-induced leukocyte recruitment in HPV-positive compared to HPV-negative OPSCC. Immunohistochemical analysis showed that HPV-negative OPSCC contained significantly more neutrophils than HPV-positive tumours, whilst levels of CD68+ macrophages and CD3+ lymphocytes were similar. Using a 3D tissue culture model to represent tumour-stromal interactions, we demonstrated that HPV-negative tumour-stromal co-cultures expressed significantly higher levels of CXCL8, leading to increased neutrophil recruitment compared to their HPV-positive counterparts. HPV-negative OPSCC cells have previously been shown to express higher levels of IL-1 than their HPV-positive counterparts, indicating that this cytokine may be responsible for driving increased chemokine production in the HPV-negative 3D model. Inhibition of IL-1R in the tumour-stromal models using the receptor-specific antagonist, anakinra, dramatically reduced chemokine secretion and significantly impaired neutrophil and monocyte recruitment, suggesting that this tumour-stromal response is mediated by the IL-1/IL-1R axis. Here, we identify a mechanism by which HPV-negative OPSCC may recruit more TAN than HPV-positive OPSCC. Since TAN are associated with poor prognosis in OPSCC, our study identifies potential therapeutic targets aimed at redressing the chemokine imbalance to reduce innate immune cell infiltration with the aim of improving patient outcome

Cross section measurements of the 3He(alpha, gamma) 7Be reaction using DRAGON at TRIUMF.

4 pags., 2 figs. -- Nuclear Physics in Astrophysics V 3–8 April 2011, Eilat, IsraelWe present our initial efforts with the DRAGON separator at TRIUMF facility towards obtaining the energy dependence of the astrophysical S-factor for 3He(¿, ¿)7Be reaction in the energy range of Ecm = 2 to 3 MeV that was recommended by the recent evaluations. A comparison between the existing data and our new complementary Madrid data, together with the recent theoretical calculations, is also given in the context of our ongoing work.This work has been supported by the UK STFC

The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer

Background: Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups. Methods: In total, 205 patients received neoadjuvant CT±ZOL (CT+ZOL, n=102; CT, n=103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n=195), outcome differences between groups were assessed adjusting for potential response modifiers. Results: Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT+ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95% confidence interval: 3.5–20.4 mm; P=0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT+ZOL group (P=0.146). There was no difference in axillary nodal involvement (P=0.6315). Conclusion: These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies

Population genomic diversity and structure in the golden bandicoot: a history of isolation, extirpation, and conservation

Published online: 08 October 2023. OnlinePublUsing genetic information to develop and implement conservation programs is vital for maintaining biodiversity and ecosystem resilience. Evaluation of the genetic variability within and among remnant populations can inform management of both natural and translocated populations to maximise species' adaptive potential, mitigate negative impacts of inbreeding, and subsequently minimise risk of extinction. Here we use reduced representation sequencing to undertake a genetic assessment of the golden bandicoot (Isoodon auratus), a threatened marsupial endemic to Australia. The currently recognised taxon consists of three subspecies distributed among multiple natural and translocated populations. After confirming the genetic distinctiveness of I. auratus from two closely related taxa, I. fusciventer and I. macrourus, we identified four genetic clusters within I. auratus. These clusters exhibited substantial genetic differentiation (pairwise FST values ranging from 0.18 to 0.65, pairwise DXY ranging from 0.1 to 0.168), reflecting long-term isolation of some populations on offshore islands and the influence of genetic drift. Mainland natural populations in the Kimberley region had the highest genetic diversity and the largest contribution to overall allelic and gene diversity compared to both natural and translocated island populations. A population translocated to Guluwuru Island in the Northern Territory had the lowest genetic diversity. Our data suggest that island populations can appear genetically unique due to genetic drift and this needs to be taken into account when considering genetic diversity in conservation efforts to maintain overall genetic diversity of the species. We effectively demonstrate how genomic information can guide practical conservation planning, especially when declining species are represented by multiple isolated populations.Kate Rick, Margaret Byrne, Skye Cameron, Steve J. B. Cooper, Judy Dunlop, Brydie Hill, Cheryl Lohr, Nicola J. Mitchell, Craig Moritz, Kenny J. Travouillon, Brenton von Takach and Kym Ottewel

Population genomics of a predatory mammal reveals patterns of decline and impacts of exposure to toxic toads

Mammal declines across northern Australia are one of the major biodiversity loss events occurring globally. There has been no regional assessment of the implications of these species declines for genomic diversity. To address this, we conducted a species-wide assessment of genomic diversity in the northern quoll (Dasyurus hallucatus), an Endangered marsupial carnivore. We used next generation sequencing methods to genotype 10,191 single nucleotide polymorphisms (SNPs) in 352 individuals from across a 3220-km length of the continent, investigating patterns of population genomic structure and diversity, and identifying loci showing signals of putative selection. We found strong heterogeneity in the distribution of genomic diversity across the continent, characterized by (i) biogeographical barriers driving hierarchical population structure through long-term isolation, and (ii) severe reductions in diversity resulting from population declines, exacerbated by the spread of introduced toxic cane toads (Rhinella marina). These results warn of a large ongoing loss of genomic diversity and associated adaptive capacity as mammals decline across northern Australia. Encouragingly, populations of the northern quoll established on toad-free islands by translocations appear to have maintained most of the initial genomic diversity after 16 years. By mapping patterns of genomic diversity within and among populations, and investigating these patterns in the context of population declines, we can provide conservation managers with data critical to informed decision-making. This includes the identification of populations that are candidates for genetic management, the importance of remnant island and insurance/translocated populations for the conservation of genetic diversity, and the characterization of putative evolutionarily significant units

Precision Pion-Proton Elastic Differential Cross Sections at Energies Spanning the Delta Resonance

A precision measurement of absolute pi+p and pi-p elastic differential cross sections at incident pion laboratory kinetic energies from T_pi= 141.15 to 267.3 MeV is described. Data were obtained detecting the scattered pion and recoil proton in coincidence at 12 laboratory pion angles from 55 to 155 degrees for pi+p, and six angles from 60 to 155 degrees for pi-p. Single arm measurements were also obtained for pi+p energies up to 218.1 MeV, with the scattered pi+ detected at six angles from 20 to 70 degrees. A flat-walled, super-cooled liquid hydrogen target as well as solid CH2 targets were used. The data are characterized by small uncertainties, ~1-2% statistical and ~1-1.5% normalization. The reliability of the cross section results was ensured by carrying out the measurements under a variety of experimental conditions to identify and quantify the sources of instrumental uncertainty. Our lowest and highest energy data are consistent with overlapping results from TRIUMF and LAMPF. In general, the Virginia Polytechnic Institute SM95 partial wave analysis solution describes our data well, but the older Karlsruhe-Helsinki PWA solution KH80 does not.Comment: 39 pages, 22 figures (some with quality reduced to satisfy ArXiv requirements. Contact M.M. Pavan for originals). Submitted to Physical Review

Measurement of radiative proton capture on F 18 and implications for oxygen-neon novae reexamined

Background: The rate of the F18(p,γ)Ne19 reaction affects the final abundance of the radioisotope F18 ejected from novae. This nucleus is important as its abundance is thought to significantly influence the first-stage 511-keV and continuum γ-ray emission in the aftermath of novae. No successful measurement of this reaction existed prior to this work, and the rate used in stellar models had been calculated based on incomplete information from contributing resonances. Purpose: Of the two resonances thought to provide a significant contribution to the astrophysical reaction rate, located at Ec.m.=330 and 665 keV, the former has a radiative width estimated from the assumed analog state in the mirror nucleus, F19, while the latter resonance does not have an analog state assignment, resulting in an arbitrary radiative width being assumed. As such, a direct measurement was needed to establish what role this resonance plays in the destruction of F18 at nova temperatures. This paper extends and takes the place of a previous Letter which reported the strength of the Ec.m.=665 keV resonance. Method: The DRAGON recoil separator was used to directly measure the strength of the important 665-keV resonance in this reaction, in inverse kinematics, by observing Ne19 reaction products. A radioactive F18 beam was provided by the ISAC facility at TRIUMF. R-matrix calculations were subsequently used to evaluate the significance of the results at astrophysical energies. Results: We report the direct measurement of the F18(p,γ)Ne19 reaction with the reevaluation of several detector efficiencies and the use of an updated Ne19 level scheme in the reaction rate analysis. The strength of the 665-keV resonance (Ex=7.076 MeV) is found to be an order of magnitude weaker than currently assumed in nova models. An improved analysis of the previously reported data is presented here, resulting in a slightly different value for the resonance strength. These small changes, however, do not alter the primary conclusions. Conclusions: Reaction rate calculations definitively show that the 665-keV resonance plays no significant role in the destruction of F18 at nova temperatures

Constraining nova observables: direct measurements of resonance strengths in 33S(p,\gamma)34Cl

The 33S(p,\gamma)34Cl reaction is important for constraining predictions of certain isotopic abundances in oxygen-neon novae. Models currently predict as much as 150 times the solar abundance of 33S in oxygen-neon nova ejecta. This overproduction factor may, however, vary by orders of magnitude due to uncertainties in the 33S(p,\gamma)34Cl reaction rate at nova peak temperatures. Depending on this rate, 33S could potentially be used as a diagnostic tool for classifying certain types of presolar grains. Better knowledge of the 33S(p,\gamma)34Cl rate would also aid in interpreting nova observations over the S-Ca mass region and contribute to the firm establishment of the maximum endpoint of nova nucleosynthesis. Additionally, the total S elemental abundance which is affected by this reaction has been proposed as a thermometer to study the peak temperatures of novae. Previously, the 33S(p,\gamma)34Cl reaction rate had only been studied directly down to resonance energies of 432 keV. However, for nova peak temperatures of 0.2-0.4 GK there are 7 known states in 34Cl both below the 432 keV resonance and within the Gamow window that could play a dominant role. Direct measurements of the resonance strengths of these states were performed using the DRAGON recoil separator at TRIUMF. Additionally two new states within this energy region are reported. Several hydrodynamic simulations have been performed, using all available experimental information for the 33S(p,\gamma)34Cl rate, to explore the impact of the remaining uncertainty in this rate on nucleosynthesis in nova explosions. These calculations give a range of ~ 20-150 for the expected 33S overproduction factor, and a range of ~ 100-450 for the 32S/33S ratio expected in ONe novae.Comment: 12 pages, 8 figures, Accepted for publication in Physical Review