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re may rapidly become a reference method for NGS-based testing of MSI in CRC, especially in mCRC, where accurate MSI status is required before the prescription of ICI.
In contrast to MSISensor, the new MSICare test we propose performs at least as efficiently as the reference method, MSI polymerase chain reaction, to detect MSI in CRC regardless of the defective MMR protein under both WES and targeted NGS conditions. We suggest MSICare may rapidly become a reference method for NGS-based testing of MSI in CRC, especially in mCRC, where accurate MSI status is required before the prescription of ICI.Current approaches for generating high-quality research evidence for technology-based interventions in the field of disability and rehabilitation are inappropriate. Prevailing approaches often focus on randomized controlled trials as standard and apply clinical trial practices designed for pharmaceuticals; such approaches are unsuitable for technology-based interventions and are counterproductive to the goals of supporting people with disabilities and creating benefits for society. This communication is designed to (1) advocate for the use of alternative approaches to generating evidence in the development and evaluation of technology-based interventions; (2) propose an alternative framework and guiding principles; and (3) stimulate action by multiple disciplines and sectors to discuss, adopt, and promote alternative approaches. Our Framework for Accelerated and Systematic Technology-based intervention development and Evaluation Research (FASTER) is informed by established innovation design processes, complex intervention development, evaluation, and implementation concepts as well as our collective experiences in technology-based interventions research and clinical rehabilitation practice. FASTER is intended to be meaningful, timely, and practical for researchers, technology developers, clinicians, and others who develop these interventions and seek evidence. We incorporate research methods and designs that better align with creating technology-based interventions and evidence for integration into practice. We propose future activities to improve the generation of research evidence, enable the selection of research methods and designs, and create standards for evidence evaluation to support rigor and applicability for technology-based interventions. With this communication we aim to improve and advance technology-based intervention integration from conception to use, thus responsibly accelerating innovation to have greater positive benefit for people and society.
To provide a novel overview of the literature and to summarise the evidence for the effects of aerobic exercise (AE) on serum biomarkers neuroplasticity and brain repair in stroke survivors.
We conducted a systematic review and searched MEDLINE, EMBASE and Cochrane CENTRAL using terms related to AE, neuroplasticity, brain repair, and stroke.
Titles, abstracts, and selected full texts were screened by two independent reviewers against the following inclusion criteria studies including adult stroke survivors, completing an AE intervention working within the AE capacity, with at least one blood biomarker outcome of interest measured.
Two independent reviewers extracted data and assessed risk of bias using Risk of Bias In Non-randomised Studies - of Interventions (ROBINS-I) and Cochrane's Risk of Bias 2 (RoB 2) tools.
Nine studies (n=215 participants) were included, reporting on the following outcomes brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), cortisol, interleukin-6 (IL-6) and myeloperoxidase (MPO). A single bout of high-intensity interval training significantly increased BDNF, IGF-1 and VEGF levels, and a 40-45-minute, 24-session, continuous eight-week AE training program significantly increased BDNF levels. No significant difference in response to any other AE intervention was found in other serum biomarkers.
AE can significantly increase BDNF, IGF-1 and VEGF across different AE protocols in stroke survivors. However, more research is needed to determine the optimal exercise intensity and modalities, specifically in acute and subacute stroke survivors, and how this may relate to functional outcomes.
AE can significantly increase BDNF, IGF-1 and VEGF across different AE protocols in stroke survivors. However, more research is needed to determine the optimal exercise intensity and modalities, specifically in acute and subacute stroke survivors, and how this may relate to functional outcomes.Mammalian Na+/H+ exchanger isoform one (NHE1) is a plasma membrane protein responsible for pH regulation in mammalian cells. Excess activity of the protein promotes heart disease and is a trigger of metastasis in cancer. Inhibitors of the protein exist but problems in specificity have delayed their clinical application. Here we examined amino acids involved in two modeled inhibitor binding sites (A, B) in human NHE1. Twelve mutations (Asp159, Phe348, Ser351, Tyr381, Phe413, Leu465, Gly466, Tyr467, Leu468, His473, Met476, Leu481) were made and characterized. Mutants S351A, F413A, Y467A, L468A, M476A and L481A had 40-70% of wild type expression levels, while G466A and H473A expressed 22% ~ 30% of the wild type levels. Most mutants, were targeted to the cell surface at levels similar to wild type NHE1, approximately 50-70%, except for F413A and G466A, which had very low surface targeting. Most of the mutants had measurable activity except for D159A, F413A and G466A. Resistance to inhibition by EMD87580 was elevated in mutants F438A, L465A and L468A and reduced in mutants S351A, Y381A, H473A, M476A and L481A. All mutants with large alterations in inhibitory properties showed reduced Na+ affinity. The greatest changes in activity and inhibitor sensitivity were in mutants present in binding site B which is more closely associated with TM4 and C terminal of extracellular loop 5, and is situated between the putative scaffolding domain and transport domain. The results help define the inhibitor binding domain of the NHE1 protein and identify new amino acids involved in inhibitor binding.Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, attenuates inflammation. The present study aimed to study the mechanisms underlying cynandione A-induced antiinflammation. Treatment with cynandione A and the specific α7 nicotinic acetylcholine receptor (α7 nAChR) agonist PHA-543613 remarkably reduced overexpression of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 cells and primary peritoneal macrophages, and endotoxemic mice. Both cynandione A and PHA-543613 also stimulated IL-10 expression in naïve and LPS-treated macrophages and endotoxemic mice. Cynandione A- and PHA-543613-inhibited proinflammatory cytokine expression was completely blocked by the α7 nAChR antagonist methyllycaconitine and the IL-10 antibody. The stimulatory effect of cynandione A and PHA-543613 on IL-10 expression were suppressed by methyllycaconitine and knockdown of α7 nAChRs using siRNA/α7 nAChR. Cynandione A significantly stimulated STAT3 phosphorylation, which was attenuated by methyllycaconitine and the IL-10 neutralizing antibody. The STAT3 activation inhibitor NSC74859 also blocked cynandione A-inhibited proinflammatory cytokine expression. Taken together, our results, for the first time, demonstrate that cynandione A and PHA-543613 inhibit inflammation through macrophageal α7 nAChR activation and subsequent IL-10 expression.Radiotherapy interventions are rapidly evolving and improving, holding promise for better patient outcomes, yet at the possible detriment of higher societal costs. The ESTRO-HERO value-based radiotherapy project aims to develop a framework defining and assessing the value of radiotherapy innovations, to support clinical implementation and equitable access, within a sustainable healthcare system.
This study aimed to assess the smallest clinical target volume (CTV) to planned target volume (PTV) margins for esophageal cancer radiotherapy using daily online registration to the bony anatomy that yield full dosimetric coverage over the course of treatment.
29 esophageal cancer patients underwent six T2-weighted MRI scans at weekly intervals. An online bone-match image-guided radiotherapy treatment of five fractions was simulated for each patient. Multiple conformal treatment plans with increasing margins around the CTV were created for each patient. Then, the dose was warped to obtain an accumulated dose per simulated fraction. Full target coverage by 95% of the prescribed dose was assessed as a function of margin expansion in six directions. If target coverage in a single direction was accomplished, then the respective margin remained fixed for the subsequent dose plans. Margins in uncovered directions were increased in a new dose plan until full target coverage was achieved.
The smallest set of CTctively, are sufficient to account for interfraction tumor variations over the course of treatment when applying a daily online bone match. However, two patients with extreme esophageal interfraction motion were insufficiently covered with these margins and were identified as patients requiring replanning to achieve full target coverage.
To quantitate the accuracy, reproducibility and prostate motion mitigation efficacy rendered by a target immobilization method used in an intermediate-risk prostate cancer dose-escalated 5×9Gy SBRT study.
An air-inflated (150cm
) endorectal balloon and Foley catheter with three electromagnetic beacon transponders (EBT) were used to mitigate and track intra-fractional target motion. A 2mm margin was used for PTV expansion, reduced to 0mm at the interface with critical OARs. EBT-detected≥2mm/5s motions mandated treatment interruption and target realignment prior to completion of planned dose delivery. Geometrical uncertainties were measured with an in-house ESAPI script.
Quantitative data were obtained in 886 sessions from 189 patients. Mean PTV dose was 45.8±0.4Gy (D95=40.5±0.4Gy). Tanzisertib mouse A mean of 3.7±1.7 CBCTs were acquired to reach reference position. Mean treatment time was 19.5±12min, 14.1±11 and 5.4±5.9min for preparation and treatment delivery, respectively. Target motion of 0, 1-2 and >2mm/10min were observed in 59%, 30% and 11% of sessions, respectively. Temporary beam-on hold occurred in 7.4% of sessions, while in 6% a new reference CBCT was required to correct deviations. Hence, all sessions were completed with application of the planned dose. Treatment preparation time>15min was significantly associated with the need of a second reference CBCT. Overall systematic and random geometrical errors were in the order of 1mm.
The prostate immobilization technique explored here affords excellent accuracy and reproducibility, enabling normal tissue dose sculpting with tight PTV margins.
The prostate immobilization technique explored here affords excellent accuracy and reproducibility, enabling normal tissue dose sculpting with tight PTV margins.
To train a deep neural network for correcting abdominal and pelvic cone-beam computed tomography (CBCT) of children and young adults in the presence of diverse patient size, anatomic extent, and scan parameters.
Pretreatment CBCT and planning/repeat CT image pairs from 64 children and young adults treated with proton therapy (aged 1-23years) were analyzed. To evaluate the impact of anatomic extent in CBCT and data size in the training data, we compared the performance of three cycle-consistent generative adversarial network models that were separately trained by three datasets comprising abdominal (n=21), pelvic (n=29), and combined abdominal-pelvic image pairs (n=50), respectively. The maximum body width of each patient was normalized to a fixed width before training and model application to reduce the impact of variations in body size. The corrected CBCT images by the three models were comparatively evaluated against the repeat CT closest in time to the CBCT (median gap, 0days; range, 0-6days) in HU accuracy, estimated dose distribution, and proton range.
