Our visual system can link components of contours and segregate contours from complex backgrounds based on geometric grouping rules. This is an important intermediate step in object recognition. The ...substrate for contour integration may be based on contextual interactions and intrinsic horizontal connections seen in primary visual cortex (V1). We examined the perceptual rules governing contour saliency to determine whether the spatial extents of contextual interactions and horizontal connections match those mediating saliency. To quantify these rules, we used stimuli composed of randomly oriented nonoverlapping line segments. Salient contours within this complex background were formed by colinear alignment of nearby segments. Contour detectability was measured using a 2-interval-forced-choice design. Contour detectability deteriorated with increasing spacing between contour elements and improved as the number of colinear line elements was increased. At short contour spacing, the detectability reached a plateau with alignment of a few line segments that together formed a contour subtending several visual degrees. At intermediate spacing, saliency built up progressively with a greater number of colinear lines, extending up to 30 degrees. When contour spacing was beyond a critical range (about 2 degrees ), however, the detectability dropped to chance levels, regardless of the number of colinear lines. Contour detectability was found to be a function not only of the relative spacing of contour elements with respect to the noise elements but also of the average density of the overall pattern. Furthermore, training significantly improved contour detection, increasing the critical spacing of line elements beyond which contours were no longer detectable. Our data suggest that global contour integration is based on mechanisms of limited spatial extent, comparable to the interactions observed in V1. These interactions can cascade over larger distances provided the spacing of stimulus elements is kept within a limited range.
Abstract Aims UK guidance was recently developed for the treatment of anal cancer using intensity-modulated radiotherapy (IMRT). We audited the current use of radiotherapy in UK cancer centres for ...the treatment of anal cancer against such guidance. We describe the acute toxicity of IMRT in comparison with patient population in the audit treated with two-phase conformal radiotherapy and the previous published data from two-phase conformal radiotherapy, in the UK ACT2 trial. Materials and methods A Royal College of Radiologists' prospective national audit of patients treated with radiotherapy in UK cancer centres was carried out over a 6 month period between February and July 2015. Results Two hundred and forty-two cases were received from 40/56 cancer centres (71%). In total, 231 (95%) underwent full dose radiotherapy with prophylactic nodal irradiation. Of these, 180 (78%) received IMRT or equivalent, 52 (22%) two-phase conformal (ACT2) technique. The number of interruptions in radiotherapy treatment in the ACT2 trial was 15%. Interruptions were noted in 7% (95% confidence interval 0–14%) of courses receiving two-phase conformal and 4% (95% confidence interval 1–7%) of those receiving IMRT. The percentage of patients completing the planned radiotherapy dose, irrelevant of gaps, was 90% (95% confidence interval 82–98%) and 96% (95% confidence interval 93–99%), in two-phase conformal and IMRT respectively. The toxicity reported in the ACT2 trial, in patients receiving two-phase conformal in the audit and in patients receiving IMRT in the audit was: any toxic effect 71%, 54%, 48%, non-haematological 62%, 49%, 40% and haematological 26%, 13%, 18%, respectively. Conclusions IMRT implementation for anal cancer is well underway in the UK with most patients receiving IMRT delivery, although its usage is not yet universal. This audit confirms that IMRT results in reduced acute toxicity and minimised treatment interruptions in comparison with previous two-phase conformal techniques.
Androgen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and ...oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer.
The PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE NCT00268476 platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately.
Recruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of -3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3-13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80-1.53; P = 0.54). Oncological outcomes are awaited.
Efficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure - overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway.
Reactor neutrino experiments have seen major improvements in precision in recent years. With the experimental uncertainties becoming lower than those from theory, carefully considering all sources of ...ν¯e is important when making theoretical predictions. One source of ν¯e that is often neglected arises from the irradiation of the nonfuel materials in reactors. The ν¯e rates and energies from these sources vary widely based on the reactor type, configuration, and sampling stage during the reactor cycle and have to be carefully considered for each experiment independently. In this article, we present a formalism for selecting the possible ν¯e sources arising from the neutron captures on reactor and target materials. We apply this formalism to the High Flux Isotope Reactor (HFIR) at Oak Ridge National Laboratory, the ν¯e source for the the Precision Reactor Oscillation and Spectrum Measurement (PROSPECT) experiment. Overall, we observe that the nonfuel ν¯e contributions from HFIR to PROSPECT amount to 1% above the inverse β decay threshold with a maximum contribution of 9% in the 1.8–2.0 MeV range. Nonfuel contributions can be particularly high for research reactors like HFIR because of the choice of structural and reflector material in addition to the intentional irradiation of target material for isotope production. We show that typical commercial pressurized water reactors fueled with low-enriched uranium will have significantly smaller nonfuel ν¯e contribution.
Effective transvascular delivery of therapeutic oligonucleotides to the brain presents a major hurdle to the development of gene silencing technologies for treatment of genetically defined ...neurological disorders. Distribution to the brain after systemic administrations is hampered by the low permeability of the blood-brain barrier (BBB) and the rapid clearance kinetics of these drugs from the blood. Here we show that transient osmotic disruption of the BBB enables transvascular delivery of hydrophobically modified small interfering RNA (hsiRNA) to the rat brain. Intracarotid administration of 25% mannitol and hsiRNA conjugated to phosphocholine-docosahexanoic acid (PC-DHA) resulted in broad ipsilateral distribution of PC-DHA-hsiRNAs in the brain. PC-DHA conjugation enables hsiRNA retention in the parenchyma proximal to the brain vasculature and enabled active internalization by neurons and astrocytes. Moreover, transvascular delivery of PC-DHA-hsiRNAs effected Htt mRNA silencing in the striatum (55%), hippocampus (51%), somatosensory cortex (52%), motor cortex (37%), and thalamus (33%) 1 week after administration. Aside from mild gliosis induced by osmotic disruption of the BBB, transvascular delivery of PC-DHA-hsiRNAs was not associated with neurotoxicity. Together, these findings provide proof-of-concept that temporary disruption of the BBB is an effective strategy for the delivery of therapeutic oligonucleotides to the brain.
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Godinho et al. demonstrate the utility of transient blood-brain barrier (BBB) disruption using hyperosmolar mannitol as a delivery strategy for fully modified lipid-conjugated hydrophobic siRNAs (hsiRNAs). Phosphocholine-docosahexanoic acid (PC-DHA)-conjugated hsiRNAs broadly distribute in the brain after BBB disruption, enabling potent gene silencing without major neurotoxicity.
Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody ...targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC.
Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% 95% confidence interval (CI) 7.6% to 22.5%, with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class.
Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.
•Retifanlimab (PD-1 inhibitor) monotherapy demonstrated encouraging results in patients with platinum-refractory SCAC.•Clinically meaningful antitumor activity was reported with ORR of 13.8% and stable disease in 35.1%, for a DCR of 48.9%.•Observed responses in advanced SCAC were durable (median 9.5 months).•Acceptable safety profile consistent with that reported for the PD-(L)1 inhibitor class.•Promising results warrant further investigation of retifanlimab in advanced SCAC as well as earlier stages of disease.
Abstract Aims Treatment decisions for men aged 70 years or over with localised prostate cancer need to take into account the risk of death from competing causes and fitness for the proposed ...treatment. Objective assessments such as those included in a comprehensive geriatric assessment (CGA) might help to inform the decision-making process. The aim of this study was to describe the CGA scores of a cohort of older men with prostate cancer, evaluate potential screening tools in this population and assess whether any CGA component predicts significant acute radiotherapy toxicity. Materials and methods This was a prospective cohort study undertaking pretreatment CGA, Vulnerable Elders Survey (VES-13) and G8 assessment in patients aged 70 years and over with localised prostate cancer planned to undergo radical external beam radiotherapy. Results In total, 178 participants were recruited over a 3 year period and underwent a CGA. Fifty-five (30.1%) participants were defined as having health needs identified by their CGA. Both VES-13 and G8 screening tools showed a statistically significant association with CGA needs ( P < 0.001 and X2 = 15.02, P < 0.001, respectively), but their sensitivity was disappointing. There was no association between a CGA (or its components) and significant acute radiotherapy toxicity. Conclusions Many older men with localised prostate cancer are vulnerable according to a CGA. The screening tools evaluated were not sufficiently sensitive to identify this group. CGA outcome does not predict for significant acute radiotherapy toxicity.
We hypothesized that stearoyl-CoA desaturase (SCD) enzyme activity would not correlate with fatty acid indices of SCD activity in steers fed different grains. Forty-five Angus steers (358 ± 26 kg BW) ...were individually fed for 107 d diets differing in whole cottonseed (WCS) supplementation (0, 5, or 15% of DM) and grain source (rolled corn, flaxseed plus rolled corn, or ground sorghum grain) in a 3 x 3 factorial arrangement. Flaxseed- and corn-fed steers had greater (P < 0.01) G:F (0.119 and 0.108, respectively) than sorghum-fed steers (0.093). Marbling score was decreased by WCS (P = 0.04), and LM area was decreased (P < 0.01) by sorghum. Plasma 14:0, 16:0, 16:1n-7, and 18:2n-6 were greatest in corn-fed steers, whereas plasma 18:3n-3 and 20:5n-3 were greatest in the flax-seed-fed steers (P < 0.01). Plasma 18:1trans-11 was least in sorghum-fed steers, and plasma cis-9,trans-11 CLA was barely detectable, in spite of high intestinal mucosal SCD enzyme activity (118 to 141 nmolbulletg tissue⁻¹bullet7 min⁻¹). Interfascicular (i.f.) and s.c. cis-9,trans-11 CLA remained unchanged (P >/= 0.25) by treatment, although 18:1trans-11 was increased (P </= 0.02) in steers fed corn or flaxseed. Steers fed flaxseed also had greater (P < 0.01) i.f. and s.c. concentrations of 18:3n-3 than steers fed the other grain sources. Oleic acid (18:1n-9) was least and total SFA were greatest (P < 0.01) in i.f. adipose tissue of steers fed 15% WCS. Lipogenesis from acetate in s.c. adipose tissue was greater (P < 0.01) in flaxseed-fed steers than in the corn- or sorghum-fed steers. Steers fed flaxseed or corn had larger i.f. mean adipocyte volumes (P < 0.01) than those fed sorghum and tended (P = 0.07) to have larger s.c. adipocyte volumes. Several fatty acid indices of SCD enzyme activity were decreased (P </= 0.03) by WCS in i.f. adipose tissue, including the 18:2cis-9,trans-11/ 18:1trans-11 ratio. The 18:2cis-9,trans-11/18:1trans-11 ratio also tended to be decreased (P = 0.09) in s.c. adipose tissue by flaxseed; however, SCD enzyme activities in i.f. and s.c. adipose tissue were not affected by dietary WCS (P >/= 0.47) or grain source (P >/= 0.37). Differences in SFA seemed to be independent of SCD enzyme activity in both adipose tissues, suggesting that duodenal concentrations of fatty acids were more important in determining tissue fatty acid concentrations than endogenous desaturation by SCD.
The visual system uses information about the relative depth of contours and surfaces to link and segment elements of visual scenes. The integration of form and depth information was studied in areas ...V1 and V2 of the alert macaque. Neurons in area V2 used contextual depth information to integrate occluded contours, signal the presence of object boundaries, and segment surfaces: (1) Amodal contour completion occurs when a contour passes behind an occluder. The basis of contour completion, the facilitation of neuronal responses to stimuli located within their receptive fields (RFs) by contextual lines lying outside their RFs, was blocked by orthogonal lines intersecting the contours but was recovered when the orthogonal line was placed in the near depth plane. (2) An illusory contour will modally complete separated elements located across an isoluminant field if the elements are placed in the near depth plane. V2 neurons responded when line segments were placed outside the RF in the near depth plane and a field of uniform luminance covered the RF. (3) Texture elements within a surface will "capture" the perceived depth consistent with the disparity of the surface's boundary, even when given no disparity themselves. V2 neurons responded to the center elements of a grating as if they contained disparity, even though disparity was present only for the grating's end elements located beyond the RF borders. These results, which were more common in V2 than in V1, demonstrate a role for V2 in the three-dimensional representation of surfaces in space.
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