Background Intracellular aggregation of TDP-43 is found in most patients with amyotrophic lateral sclerosis (ALS), 45% of patients with frontotemporal dementia (FTD) and 30-50% of patients with clinical diagnosis of A...
Background Intracellular aggregation of TDP-43 is found in most patients with amyotrophic lateral sclerosis (ALS), 45% of patients with frontotemporal dementia (FTD) and 30-50% of patients with clinical diagnosis of Alzheimer’s disease. Sensitive fluid or imaging biomarkers of TDP-43 pathology are currently not available. Direct detection of TDP-43 aggregates by positron emission tomography (PET) holds promise for a more accurate diagnosis, patient stratification and assessment of therapeutic efficacy in clinical trials. Methods Using ACI’s Morphomer ® small molecule library focused on brain penetrant and beta sheet binding compounds, initial hits were identified, and iterative medicinal chemistry applied to discover compounds with optimized properties. Radiobinding and autoradiography experiments on FTLD-TDP brain samples were used to evaluate affinity and target engagement. These techniques were also used to assess selectivity over other aggregation-prone proteins using brain material from Alzheimer’s (AD) and Parkinson’s disease (PD) cases. Brain pharmacokinetic (PK) profile was obtained in mice, followed by assessment of brain uptake, distribution and washout for selected 18F radiolabeled compounds in non-human primates (NHP). Results Several chemical series showing nanomolar binding affinity to aggregated TDP-43 from patient brain samples were identified. The specificity of binding was further confirmed by high resolution autoradiography enabling visualization of target engagement on TDP-43 inclusions in FTLD-TDP brain sections. In addition, the most advanced compounds differentiated FTLD-TDP from control by classical autoradiography on patient brain sections. Selectivity over amyloid beta, alpha-synuclein and Tau was observed. The compounds with the most favorable brain penetrantion properties demonstrated fast and substantial brain uptake and fast and complete washout in NHPs. Conclusions First-in-class TDP-43 PET ligands have been discovered with the potenti
Purpose: To develop a new method to investigate the effect of local pelvic bone marrow (BM) radiation dose on acute hematologic toxicity (HT) in cervical cancer patients undergoing concurrent chemoradiation therapy (C...
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Purpose: To develop a new method to investigate the effect of local pelvic bone marrow (BM) radiation dose on acute hematologic toxicity (HT) in cervical cancer patients undergoing concurrent chemoradiation therapy (CRT), with the ultimate goal of optimizing BM-sparing radiation techniques. Method and Materials: We analyzed 24 cervical cancer patients treated with concurrent cisplatin (40mg/m2/week) and pelvic IMRT. The white blood cell count (WBC) nadir, defined as the lowest value occurring between the start of CRT and two weeks following IMRT, was used as the indicator of acute HT. The pelvic bone region included the os coxae, lower lumbar vertebrae, sacrum, acetabulae, and proximal femora. BM doses were standardized in two steps: pelvic bone registration followed by dose remapping. Simulation CT images were registered to a common (canonical) template using the optical flow based deformable image registration developed by Yang et al.[2]. The deformation field was used to remap the dose distribution back to the deformed pelvic bones. We generated a data structure called a “dose-array” that reserves the spatial information of each dose value. The position of an element inside array can be used to trace its location in 3D. Results: Substantial variation of BM dose distribution among the 24 patients was observed. Patients were classified based on their WBC nadir value (⩾ vs. < 2000/μL) into two groups (n=15 vs. n=9, respectively), and the average pelvic BM 3-D dose distribution was compared visually. Results suggested that patients receiving higher doses to the lower lumbar spine, upper sacrum, and medial ilium, were more likely to develop acute HT. Conclusion: We have developed a novel method to study the impact of BM radiation dose on acute HT. Our next step is to implement both unsupervised and supervised classification models to analyze radiation effects, for use in IMRT plan optimization.
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