Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its ¹⁸F-isotopologue ([¹⁸F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [¹⁸F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [¹⁸F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.

PURPOSE: A major question remaining in approaches to tissue engineering and organ replacement is the role of native mobilized native cells in the regeneration process of damaged tissues and organs. The goal of this study was to compare the cell mobilizing effects of the chemokine CXCL12 and cell therapy on the urinary sphincter of nonhuman primates (NHP) with chronic intrinsic urinary sphincter dysfunction. METHODS: Either autologous lenti-M-cherry labeled skeletal muscle precursor cells (skMPCs) or CXCL12 were injected directly into the sphincter complex of female NHPs with or without surgery-induced chronic urinary sphincter dysfunction (n=4/treatment condition). All monkeys had partial bone marrow transplantation with autologous lenti-green fluorescent protein (GFP) bone marrow cells prior to treatment. Labeled cells were identified, characterized and quantified using computer-assisted immunohistochemistry 6 months posttreatment. RESULTS: GFP-labeled bone marrow cells (BMCs) were identified in the bone marrow and both BMCs and skMPCs were found in the urinary sphincter at 6-month postinjection. BMCs and skMPCs were present in the striated muscle, smooth muscle, and lamina propria/urothelium of the sphincter tissue. Sphincter injury increased the sphincter content of BMCs when analyzed 6-month postinjection. CXCL12 treatment, but not skMPCs, increased the number of BMCs in all layers of the sphincter complex (P < 0.05). CXCL12 only modestly (P=0.15) increased the number of skMPCs in the sphincter complex. CONCLUSIONS: This dual labeling methodology now provides us with the tools to measure the relative number of locally injected cells versus bone marrow transplanted cells. The results of this study suggest that CXCL12 promotes mobilization of cells to the sphincter, which may contribute more to sphincter regeneration than injected cells.
Bone Marrow ; Bone Marrow Cells ; Bone Marrow Transplantation ; Cell- and Tissue-Based Therapy ; Chemokine CXCL12 ; Chemokines ; Female ; Haplorhini ; Humans ; Immunohistochemistry ; Muscle, Skeletal ; Muscle, Smooth ; Muscle, Striated ; Primates* ; Regeneration ; Stem Cells ; Tissue Engineering

PURPOSE: The Paprosky classification system of acetabular defects is complex and its reliability has been questioned. The purpose of this study was to evaluate the effectiveness of different radiologic imaging modalities in classifying acetabular defects in revision total hip arthroplasty (THA) and their value of at different levels of training. MATERIALS AND METHODS: Bone defects in 8 revision THAs were classified by 2 fellowship-trained adult reconstruction surgeons. A timed presentation with representative images for each case (X-ray, two-dimensional computed tomography [CT] and three-dimensional [3D] reconstructions) was shown to 35 residents from the first postgraduate year of training year of training (PGY-1 to PGY-5), 2 adult reconstruction fellows and 2 attending orthopaedic surgeons. The Paprosky classification of bone defects was recorded. The influence of image modality and level of training on classification were analyzed using chi-square analysis (alpha=0.05). RESULTS: Overall correct classification was 30%. The level of training had no influence on correct classification (P=0.531). Using X-ray led to 37% correctly identified defects, CT scans to 33% and 3D reconstructions to 20% of correct answers (P < 0.001). There was no difference in correct classification based defect type (P < 0.001). Regardless of level of training or imaging, 64% of observers recognized type 1 defects, compared to only 16% correct recognition of type 3B defects. CONCLUSION: Using plain X-rays led to an increased number of correct classification, while regular CT scan and 3D CT reconstructions did not improve accuracy. The classification system of acetabular defects can be used for treatment decisions; however, advanced imaging may not improve its utilization.
Acetabulum* ; Adult ; Arthroplasty, Replacement, Hip ; Classification ; Humans ; Internship and Residency* ; Pelvis* ; Reoperation ; Surgeons ; Tomography, X-Ray Computed

This paper aims to describe the knowledge, attitudes, and practices of first-stroke patients regarding sex. It also aims to describe the socio demographic and clinical profiles of first-stoke patients. It is hope of the investigators to come up with recommendations that will respond to the needs of stroke patients as well as the caring physician.
Human ; Male ; Female ; Aged ; Middle Aged ; Adult ; STROKE ; SEXUAL BEHAVIOR ;