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BACKGROUND: The aim of the present study was to develop a novel 64Cu-labeled cyclic peptide ([64Cu]Cu-FAP-NOX) that targets fibroblast activation protein (FAP) and may offer advantages in terms of image contrast, imaging time window, and low uptake in normal tissues. METHODS: The novel cyclic peptide featuring with a N-oxalyl modified tail was constructed and conjugated to NOTA for 64Cu labeling. Biochemical and cellular assays were performed with A549.hFAP cells. The performance of [64Cu]Cu-FAP-NOX was compared to that of two established tracers ([64Cu]Cu-FAPI-04 and [68Ga]Ga-FAP-2286) and three different NOTA-conjugates in HEK-293T.hFAP xenograft mice using micro-PET imaging. Ex vivo biodistribution studies were performed to confirm the FAP specificity and to validate the PET data. Furthermore, a first-in-human study of this novel tracer was conducted on one patient with lung cancer. RESULTS: Compared to [64Cu]Cu-FAPI-04, [64Cu]Cu-FAP-NOX demonstrated faster and higher rates of cellular uptake and internalization in A549.hFAP cells, but lower rates of cellular efflux. All six radiotracers were rapidly taken up by the tumor within the first 4 h post-injection. However, [64Cu]Cu-FAP-NOX had more intense tumor accumulation and slower washout from the target. The ratios of the tumor to normal tissue (including kidneys and muscles) increased significantly over time, with [64Cu]Cu-FAP-NOX reaching the highest ratio among all tracers. In the patient, [64Cu]Cu-FAP-NOX PET showed a comparable result to FDG PET in the primary malignant lesion while exhibiting higher uptake in pleural metastases, consistent with elevated FAP expression as confirmed by immunohistochemistry. CONCLUSION: [64Cu]Cu-FAP-NOX is a promising FAP-targeted tracer with a highly flexible imaging time window, as evidenced by preclinical evaluation encompassing biodistribution and micro-PET studies, along with a successful patient application. Furthermore, [64Cu]Cu-FAP-NOX showed enhanced image contrast and favorable pharmacokinetic properties for FAP PET imaging, warranting translation into large cohort studies.
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PURPOSE: Fibroblast-activated protein (FAP) is highly expressed in cancer-associated fibroblasts (CAFs) of many solid cancers, but low or absent in normal tissues. Our study aimed to develop a novel FAP-specific tracer, namely [18F]FAP-2286, and evaluated its performance in comparison with well-established agents such as [18F]FAPI-42 and [68Ga]Ga-FAP-2286 in preclinical research, as well as 2-[18F]FDG in pilot clinical study. METHODS: [18F]FAP-2286 was manually synthesized in accordance with Good Manufacturing Practice (GMP). Subsequent investigations encompassed cell uptake, competitive binding affinity, internalization and efflux assays using HT-1080hFAP cell lines. PET imaging and biodistribution studies were conducted in HEK-293ThFAP, A549hFAP, HT-1080hFAP tumor-bearing mice as well as HEK-293T, A549 and HT-1080 control groups. Furthermore, clinical evaluation of [18F]FAP-2286 was performed in fifteen patients with various cancers compared to 2-[18F]FDG PET. RESULTS: The radiolabeling yield of [18F]FAP-2286 was 30.53 ± 5.20%, with a radiochemical purity exceeding 97%. In cell assays, [18F]FAP-2286 showed specific uptake, high internalization fraction and low cellular efflux. Rapid tumor uptake and satisfactory tumor retention was observed on micro-PET imaging and cancer patients. Meanwhile, the clinical research demonstrated that [18F]FAP-2286 may represent an alternative for low glucose-metabolism malignant tumors PET imaging such as gastric cancers. CONCLUSION: [18F]FAP-2286 showed superior imaging quality including rapid and high target uptake and satisfactory retention in both tumor-bearing mice and cancer patients. It may emerge as a promising candidate for early or delayed phase imaging and 2-[18F]FDG non-avid cancers PET scan.
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Fluorodesoxiglucosa F18 , Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Animales , Ratones , Fluorodesoxiglucosa F18/farmacocinética , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Masculino , Femenino , Línea Celular Tumoral , Células HEK293 , Distribución Tisular , Persona de Mediana Edad , Radiofármacos/farmacocinética , Anciano , Proteínas de la Membrana , EndopeptidasasRESUMEN
PURPOSE: This is a first-in-human study to evaluate the radiation dosimetry of a new prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical, [18F]AlF-P16-093, and also initial investigation of its ability to detect PSMA-positive tumors using PET scans in a cohort of prostate cancer (PCa) patients. METHODS: The [18F]AlF-P16-093 was automatically synthesized with a GE TRACERlab. A total of 23 patients with histopathologically proven PCa were prospectively enrolled. Dosimetry and biodistribution study investigations were carried out on a subset of six (6) PCa patients, involving multiple time-point scanning. The mean absorbed doses were estimated with PMOD and OLINDA software. RESULTS: [18F]AlF-P16-093 was successfully synthesized, and radiochemical purity was > 95%, and average labeling yield was 36.5 ± 8.3% (decay correction, n = 12). The highest tracer uptake was observed in the kidneys, spleen, and liver, contributing to an effective dose of 16.8 ± 1.3 µSv/MBq, which was ~ 30% lower than that of [68Ga]Ga-P16-093. All subjects tolerated the PET examination well, and no reportable side-effects were observed. The PSMA-positive tumors displayed rapid uptake, and they were all detectable within 10 min, and no additional lesions were observed in the following multi-time points scanning. Each patient had at least one detectable tumor lesion, and a total of 356 tumor lesions were observed, including intraprostatic, lymph node metastases, bone metastases, and other soft tissue metastases. CONCLUSIONS: We report herein a streamlined method for high yield synthesis of [18F]AlF-P16-093. Preliminary study in PCa patients has demonstrated its safety and acceptable radiation dosimetry. The initial diagnostic study indicated that [18F]AlF-P16-093 PET/CT is efficacious and potentially useful for a widespread application in the diagnosis of PCa patients.
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Antígenos de Superficie , Glutamato Carboxipeptidasa II , Neoplasias de la Próstata , Radiometría , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Anciano , Glutamato Carboxipeptidasa II/metabolismo , Persona de Mediana Edad , Antígenos de Superficie/metabolismo , Distribución Tisular , Radiofármacos/farmacocinética , Radiofármacos/química , Radioisótopos de Flúor/química , Anciano de 80 o más Años , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
B/T mixed phenotype acute leukemia (MPAL), which represents only 2-3% of all MPAL cases, is classified as a high-risk leukemia subtype. Adults diagnosed with B/T MPAL have a notably low 3-year survival rate, estimated at 20-40%. The rarity and undercharacterization of B/T MPAL present substantial challenges in identifying an optimal treatment protocol. This report aims to shed light on this issue by presenting a case in which a patient with a complex karyotype was treated using a combination of venetoclax, azacitidine, and blinatumomab. This novel, chemo-free regimen resulted in the patient achieving both hematologic and molecular complete remission, with no severe organ or hematological toxicity observed. Notably, the patient continued to maintain molecular remission for 1 year following the transplantation. Based on these findings, the combination of venetoclax, azacitidine, and blinatumomab could be considered a potential therapeutic approach for B/T MPAL patients, meriting further investigation.
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Anticuerpos Biespecíficos , Azacitidina , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia , Sulfonamidas , Adulto , Humanos , Azacitidina/uso terapéutico , Leucemia/terapia , Enfermedad AgudaRESUMEN
OBJECTIVE: To investigate the feasibility and effectiveness of applying intraoperative ultrasound (IOUS) to evaluate spinal canal expansion in patients undergoing French-door cervical laminoplasty (FDCL). MATERIALS AND METHODS: Twenty-five patients who underwent FDCL for multilevel degenerative cervical myelopathy were prospectively recruited. Formulae describing the relationship between laminoplasty opening angle (LOA) and laminoplasty opening size, the increase in sagittal canal diameter and the spinal canal area were deduced with trigonometric functions. The LOA was measured with IOUS imaging during surgery, and other spinal canal parameters were assessed. Actual spinal canal enlargement was verified on postoperative CT images. Linear correlation analysis and BlandâAltman analysis were used to evaluate correlation and agreement between the intraoperative and postoperative measurements. RESULTS: The LOA at C5 measured with IOUS was 27.54 ± 3.12°, and it was 27.23 ± 3.02° on postoperative CT imaging. Linear correlation analysis revealed a significant correlation between IOUS and postoperative CT measurements (r = 0.88; p < 0.01). Bland-Altman plots showed good agreement between these two methods, with a mean difference of 0.30°. For other spinal canal expansion parameter measurements, correlation analysis showed a moderate to a high degree of correlation (p < 0.01), and Bland-Altman analysis indicated good agreement. CONCLUSION: In conclusion, during the French-door cervical laminoplasty procedure, application of IOUS can accurately evaluate spinal canal expansion. This innovative method may be helpful in improving surgical accuracy by enabling the operator to measure and determine canal enlargement during surgery, leading to ideal clinical outcomes and fewer postoperative complications. CLINICAL RELEVANCE STATEMENT: The use of intraoperative ultrasonography to assess spinal canal expansion following French-door cervical laminoplasty may improve outcomes for patients undergoing this procedure by providing more accurate measurements of spinal canal expansion. KEY POINTS: ⢠Spinal canal expansion after French-door cervical laminoplasty substantially influences operative prognosis; insufficient or excessive lamina opening may result in unexpected outcomes. ⢠Prediction of spinal canal expansion during surgery was previously impracticable, but based on this study, intraoperative ultrasonography offers an innovative approach and strongly agrees with postoperative CT measurement. ⢠Since this is the first research to offer real-time canal expansion guidance for cervical laminoplasty, it may improve the accuracy of the operation and produce ideal clinical outcomes with fewer postoperative complications.
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Laminoplastia , Enfermedades de la Médula Espinal , Humanos , Laminoplastia/efectos adversos , Laminoplastia/métodos , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/cirugía , Canal Medular/diagnóstico por imagen , Canal Medular/cirugía , Ultrasonografía , Complicaciones Posoperatorias/etiología , Resultado del Tratamiento , Enfermedades de la Médula Espinal/diagnóstico por imagen , Enfermedades de la Médula Espinal/cirugía , Enfermedades de la Médula Espinal/complicaciones , Estudios RetrospectivosRESUMEN
OBJECTIVES: To evaluate the ability of intraoperative CEUS to predict neurological recovery in patients with degenerative cervical myelopathy (DCM). METHODS: Twenty-six patients with DCM who underwent laminoplasty and intraoperative ultrasound (IOUS) were included in this prospective study. The modified Japanese Orthopaedic Association (mJOA) scores and MRI were assessed before surgery and 12 months postoperatively. The anteroposterior diameter (APD), maximum spinal cord compression (MSCC), and area of signal changes in the cord at the compressed and normal levels were measured and compared using MRI and IOUS. Conventional blood flow and CEUS indices (time to peak, ascending slope, peak intensity (PI), and area under the curve (AUC)) at different levels during IOUS were calculated and analysed. Correlations between all indicators and the neurological recovery rate were evaluated. RESULTS: All patients underwent IOUS and intraoperative CEUS, and the total recovery rate was 50.7 ± 33.3%. APD and MSCC improved significantly (p < 0.01). The recovery rate of the hyperechoic lesion group was significantly worse than that of the isoechoic group (p = 0.016). 22 patients were analysed by contrast analysis software. PI was higher in the compressed zone than in the normal zone (24.58 ± 3.19 versus 22.43 ± 2.39, p = 0.019). ΔPI compress-normal and ΔAUC compress-normal of the hyperechoic lesion group were significantly higher than those of the isoechoic group (median 2.19 versus 0.55, p = 0.017; 135.7 versus 21.54, p = 0.014, respectively), and both indices were moderately negatively correlated with the recovery rate (r = - 0.463, p = 0.030; r = - 0.466, p = 0.029). CONCLUSIONS: Signal changes and microvascular perfusion evaluated using CEUS during surgery are valuable predictors of cervical myelopathy prognosis. CLINICAL RELEVANCE STATEMENT: In the spinal cord compression area of degenerative cervical myelopathy, especially in the hyperechoic lesions, intraoperative CEUS showed more significant contrast agent perfusion than in the normal area, and the degree was negatively correlated with the neurological prognosis. KEY POINTS: ⢠Recovery rates in patients with hyperechoic findings were lower than those of patients without lesions detected during intraoperative ultrasound. ⢠The peak intensity of CEUS was higher in compressed zones than in the normal parts of the spinal cord. ⢠Quantitative CEUS comparisons of the peak intensity and area under the curve at the compressed and normal levels of the spinal cord revealed differences that were inversely correlated to the recovery rate.
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Médula Cervical , Compresión de la Médula Espinal , Enfermedades de la Médula Espinal , Humanos , Compresión de la Médula Espinal/patología , Estudios Prospectivos , Médula Cervical/diagnóstico por imagen , Médula Cervical/cirugía , Médula Cervical/patología , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/cirugía , Vértebras Cervicales/patología , Médula Espinal/patología , Enfermedades de la Médula Espinal/diagnóstico por imagen , Enfermedades de la Médula Espinal/cirugía , Enfermedades de la Médula Espinal/patología , Imagen por Resonancia Magnética , Resultado del TratamientoRESUMEN
OBJECTIVES: To investigate the potential utility of [18F]fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) for evaluating pulmonary artery (PA) masses, and compare it with [18F]fluorodeoxyglucose (FDG) PET/CT. METHODS: Participants with clinically suspected PA malignancy were prospectively enrolled and underwent dual-tracer PET/CT ([18F]FAPI-42 and [18F]FDG) imaging. Visual analysis and semi-quantitative parameters were compared between the two types of radiotracers. The tissue specimen underwent immunohistochemical staining to verify FAP expression in the tissue. RESULTS: Thirty-three patients (18 males/15 females; mean age 53.1 ± 15.4 years) were enrolled. All 21 patients with malignant PA masses were FDG-positive (100%), whereas 20 out of 21 patients were FAPI-positive (95.2%). All 12 patients with benign PA masses were both negative in FDG and FAPI PET. The mean maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) of FAPI and FDG in malignant PA masses were significantly higher than those of benign masses. Although there was no significant difference in SUVmax between FDG and FAPI in malignant PA masses (11.36 vs. 9.18, p = 0.175), the TBR (liver) and TBR (left ventricle) were more favorable for FAPI than for FDG (13.04 vs. 5.17, p < 0.001); (median: 7.75 vs. 2.75, p = 0.007). Immunohistochemical analysis (n = 16) validated that the level of FAP expression corresponded strongly to the uptake of FAPI in PET/CT scans (rs = 0.712, p = 0.002). For clinical management, FAPI PET found more metastatic lesions than FDG PET in 4 patients, with 2 patients upgrading and 1 patient changing treatment decisions. CONCLUSIONS: FAPI PET/CT is feasible in the diagnosis of PA masses. Although not superior to FDG PET/CT, FAPI PET/CT showed better target-to-background contrast. CLINICAL RELEVANCE STATEMENT: This study found that FAPI PET/CT is not superior to FDG PET/CT in diagnosing PA masses, but FAPI PET/CT displays better target-to-background contrast and more positive lesions, which may help improve disease management. KEY POINTS: Pulmonary malignancies lack specificity in clinical manifestations, laboratory tests, and routine imaging examinations. FAPI PET/CT is not diagnostically better than FDG PET/CT but displays better target-to-background contrast and more positive lesions. Dual-tracer PET/CT ([18F]FAPI-42 and [18F]FDG) imaging improves clinical management of pulmonary artery masses.
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INTRODUCTION: Heterotopic ossification of the tendon and ligament (HOTL) is a chronic progressive disease that is usually accompanied by thickening and ossification of ligaments and high osteogenic activity of the surrounding ligament tissue. However, the molecular mechanism of maintaining the cellular phenotype of HOTL remains unclear. MATERIALS AND METHODS: We first constructed a model of HOTL, Enpp1flox/flox/EIIa-Cre mice, a novel genetic mouse system. Imaging, histological, and cell-level analyses were performed to investigate the progressive ossification of the posterior longitudinal ligament, Achilles tendons, and degeneration joints caused by Enpp1 deficiency. RESULTS: The results indicate that Enpp1 deficiency led to markedly progressive heterotopic ossification (HO), especially spine, and Achilles tendons, and was associated with progressive degeneration of the knees. The bone mass was decreased in the long bone. Furthermore, fibroblasts from Enpp1flox/flox/EIIa-Cre mice had greater osteogenic differentiation potential following induction by osteogenesis, accompanied by enhanced hedgehog (Hh) signaling. In addition, fibroblast cells show senescence, and aggravation of the senescence phenotype by further osteogenic induction. CONCLUSION: Our study indicated that with increasing age, mutations in Enpp1 promote ectopic ossification of spinal ligaments and endochondral ossification in tendons and further aggravate knee degeneration by upregulating hedgehog signaling.
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Rationale: Sustained activation of lung fibroblasts and the resulting oversynthesis of the extracellular matrix are detrimental events for patients with interstitial lung diseases (ILDs). Lung biopsy is a primary evaluation technique for the fibrotic status of ILDs, and is also a major risk factor for triggering acute deterioration. Fibroblast activation protein (FAP) is a long-known surface biomarker of activated fibroblasts, but its expression pattern and diagnostic implications in ILDs are poorly defined. Objectives: The present study aims to comprehensively investigate whether the expression intensity of FAP could be used as a potential readout to estimate or measure the amounts of activated fibroblasts in ILD lungs quantitatively. Methods: FAP expression in human primary lung fibroblasts as well as in clinical lung specimens was first tested using multiple experimental methods, including real-time quantitative PCR (qPCR), Western blot, immunofluorescence staining, deep learning measurement of whole slide immunohistochemistry, as well as single-cell sequencing. In addition, FAP-targeted positron emission tomography/computed tomography imaging PET/CT was applied to various types of patients with ILD, and the correlation between the uptake of FAP tracer and pulmonary function parameters was analyzed. Measurements and Main Results: Here, it was revealed, for the first time, FAP expression was upregulated significantly in the early phase of lung fibroblast activation event in response to a low dose of profibrotic cytokine. Single-cell sequencing data further indicate that nearly all FAP-positive cells in ILD lungs were collagen-producing fibroblasts. Immunohistochemical analysis validated that FAP expression level was closely correlated with the abundance of fibroblastic foci on human lung biopsy sections from patients with ILDs. We found that the total standard uptake value (SUV) of FAP inhibitor (FAPI) PET (SUVtotal) was significantly related to lung function decline in patients with ILD. Conclusions: Our results strongly support that in vitro and in vivo detection of FAP can assess the profibrotic activity of ILDs, which may aid in early diagnosis and the selection of an appropriate therapeutic window.
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Enfermedades Pulmonares Intersticiales , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Enfermedades Pulmonares Intersticiales/patología , Pulmón/patología , Fibrosis , Fibroblastos/metabolismoRESUMEN
PURPOSE: This study investigates the association between handgrip strength, walking pace, and the incidence of degenerative cervical myelopathy (DCM) using the UK Biobank dataset. METHODS: We analyzed data from 364,716 UK Biobank participants without prior neurological conditions. Handgrip strength was measured with a dynamometer, and walking pace was self-reported. Cox proportional hazards models assessed hazard ratios (HRs) and 95% confidence intervals (CIs) for DCM development. RESULTS: The cohort, with an average age of 56.2 years (SD, 8.1) and 47.4% male, was followed for a median of 12.6 years. During this period, 3,993 participants (1.1%) developed DCM. A significant inverse correlation was found between handgrip strength and DCM incidence (P for trend < 0.001), with decreasing HRs for DCM across quartiles of increasing grip strength: HRs were 0.70 (95% CI: 0.64-0.76), 0.62 (95% CI: 0.57-0.68), and 0.59 (95% CI: 0.54-0.66) for the second, third, and fourth quartiles, respectively. Participants with average or brisk walking paces had a lower DCM risk (HR, 0.55; 95% CI: 0.50-0.61 and HR, 0.48; 95% CI: 0.43-0.54) compared to slow walkers. The greatest risk reduction was in those with both higher handgrip strength and faster pace (HR, 0.39; 95% CI: 0.34-0.44). CONCLUSIONS: Handgrip strength and walking pace are inversely associated with DCM incidence, suggesting their potential as cost-effective screening tools for identifying individuals at risk for DCM.
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BACKGROUND AND PURPOSE: The spinal cord central echo complex (SCCEC) is a special ultrasonography-based intramedullary structure, but its clinical significance in degenerative cervical myelopathy (DCM) is undefined. This study aimed to explore the potential of the SCCEC in predicting postoperative neurological recovery in DCM. METHODS: Thirty-two DCM patients who underwent intraoperative ultrasonography-guided French-door laminoplasty were prospectively enrolled. The modified Japanese Orthopaedic Association (mJOA) score was evaluated preoperatively and 12 months postoperatively. SCCEC width (SCCEC-W), and anteroposterior diameter (APD) and transverse diameter (TD) of the spinal cord were measured on transverse ultrasonographic images, while the tissue widths from anterior and posterior borders of the spinal cord to the SCCEC were measured on sagittal ultrasonographic images. The APD of the spinal cord and occupying rate of the spinal canal were measured on preoperative magnetic resonance imaging (MRI). RESULTS: All patients achieved improvements in mJOA scores, with an average recovery rate (RR) of 68.69 ± 20.22%. Spearman correlation analysis revealed that SCCEC-W, and ratios between the SCCEC-W and APD/TD based on ultrasonography, correlated moderately with mJOA score RR, with coefficients of -0.527, -0.605 and -0.514, respectively. The ratio between SCCEC-W and ultrasonographic TD correlated moderately with preoperative APD of the spinal cord. The MRI measurements and ultrasonography-based tissue widths showed no significant correlation with mJOA score RR. CONCLUSIONS: The SCCEC may have predictive potential as an intraoperative indicator of neurological recovery in treating DCM. SCCEC-W may be related to spinal cord compression in DCM.
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Compresión de la Médula Espinal , Enfermedades de la Médula Espinal , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/patología , Vértebras Cervicales/cirugía , Humanos , Imagen por Resonancia Magnética/métodos , Médula Espinal/diagnóstico por imagen , Médula Espinal/patología , Médula Espinal/cirugía , Compresión de la Médula Espinal/patología , Compresión de la Médula Espinal/cirugía , Enfermedades de la Médula Espinal/diagnóstico por imagen , Enfermedades de la Médula Espinal/patología , Enfermedades de la Médula Espinal/cirugía , Resultado del Tratamiento , UltrasonografíaRESUMEN
INTRODUCTION: Heterotopic ossification of tendons and ligaments is a painful and debilitating disease with no effective treatment. Although aging has been reported to be correlated with the occurrence and development of this disease, the mechanism remains unknown. MATERIALS AND METHODS: In the present study, we generated Bmal1-/- mice, which disrupted the circadian clock and displayed premature aging, as an aging model to explore the role of Bmal1 in TGF-beta (ß)/BMP signaling in progressive heterotopic ossification of tendons and ligaments with aging. RESULTS: We first confirmed that BMAL1 expression is downregulated in human fibroblasts from ossification of the posterior longitudinal ligament using online datasets. Bmal1 deficiency in mice caused significantly progressive heterotopic ossification with aging starting at week 6, notably in the Achilles tendons and posterior longitudinal ligaments. Ossification of the Achilles tendons was accompanied by progressive motor dysfunction of the ankle joint. Histology and immunostaining showed markedly increased endochondral ossification in the posterior longitudinal ligaments and Achilles tendons of Bmal1-/- mice. Ligament-derived Bmal1-/- fibroblasts showed an osteoblast-like phenotype, upregulated osteogenic and chondrogenic markers, and activated TGFß/BMP signaling, which was enhanced by TGFß1 stimulation. Furthermore, Bmal1-/- mouse embryonic fibroblasts had a stronger potential for osteogenic differentiation with activation of TGFß/BMP signaling. CONCLUSIONS: These findings demonstrated that Bmal1 negatively regulates endochondral ossification in heterotopic ossification of tendons and ligaments with aging via TGFß/BMP signaling, thereby identifying a new regulatory mechanism in age-related heterotopic ossification of tendons and ligaments.
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Tendón Calcáneo , Osificación Heterotópica , Factores de Transcripción ARNTL/genética , Envejecimiento , Animales , Fibroblastos , Ratones , Osificación Heterotópica/genética , Osteogénesis , Factor de Crecimiento Transformador betaRESUMEN
OBJECTIVES: During French-door laminoplasty, a linear array transducer of IOUS was used to observe and record the spinal cord decompression. To acquire a higher-reliability method, and compare the in-observer and inter-observer reliability of two methods in evaluating the hyperechoic intensity of spinal cord ultrasound in degenerative cervical myelopathy (DCM). BACKGROUND: The intensity of spinal cord hyperechogenicity is considered as a potential predictor of neurological recovery in DCM after decompression, but the accuracy of gray value ratio (GVR) is affected by many factors. METHODS: Totally 28 patients (20 males and 8 females) who had been followed up for 12 months were included. Their mean age at surgery was 61.2 ± 10.8 years and the average symptom duration was 23.36 ± 22.11 months. The gray values of circles 1, 2 and 3 were recorded as Gcompression, Gnorml and Gsac, respectively. Circle 1 was drawn with the maximum brightness point within the spinal cord as the center, circle 2 with the same area was plotted on the spinal cord with uniform echogenicity, without compression and at least 1 cm away from the circle 1, and circle 3 was drawn on the dorsal dural sac at the same segment as circle 1. GVR was calculated as follows: GVR-A = Gcompression/Gnorml (method A), and GVR-B = Gcompression/Gsac (method B). The in-observer and inter-observer reliabilities of the two methods were compared. It is generally believed a reliability coefficient < 0.40 and > 0.75 indicate poor and good reliability respectively. The images-based GVR-B using this protocol demonstrates higher inter- and intraobserver reliabilities than GVR-A, and can be used as the basis for prognostic prediction and future studies. RESULTS: All examination acquisitions were successfully completed. GVR-A averaged 2.043 (0.318-5.56), and GVR-B averaged 0.578(0.06-1.41). GVR-B has better repeatability of gray value measurement, smaller relative standard deviation (RSD%) (0.298 vs. 0.32) and larger inter-group correlation coefficient compared with GVR-A. The mean value (MD) of the GVR difference calculated by GVR-B between the two clinicians was closer to 0. CONCLUSIONS: For DCM patients routinely using ultrasound for real-time cord visualization during spinal cord decompression by French-door laminoplasty, the images-based GVR-B using this protocol demonstrates better inter- and intraobserver reliabilities compared with GVR-A.
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Enfermedades de la Médula Espinal , Descompresión Quirúrgica , Femenino , Humanos , Masculino , Reproducibilidad de los Resultados , Enfermedades de la Médula Espinal/diagnóstico por imagen , Enfermedades de la Médula Espinal/cirugía , UltrasonografíaRESUMEN
BACKGROUND: Knee osteoarthritis (KOA) is a common disease based on degenerative pathological changes. Total knee arthroplasty (TKA) is an effective treatment for end-stage of KOA. However, only volume adaptation can be achieved with current knee prostheses, and it is difficult to achieve weight adaptation. This study focused on the weight difference of knee joints and initially explored the impact of this change on knee joint functional recovery and gait changes in patients after surgery. METHODS: From October 2015 to June 2019, patients who underwent primary unilateral TKA were enrolled in this prospective cohort study with the same brand of knee prostheses. General data were collected from patients who met the criteria. The resected bone and soft tissues were collected and weighed precisely during TKA, and multivariate regression analysis was used to determine the factors affecting the weight of the removed knee tissues. We compared the weight of excised tissues and the total weight of the knee prosthesis, and the weight difference was defined as the increased weight of the knee joint (IWKJ). All patients were evaluated by HSS score, gait analysis, and affected side knee X-ray at two weeks, three months, and the last follow-up after the operation. To further determine the influence of IWKJ on postoperative functional recovery, the relationship between IWKJ, HSS score, and gait analysis was analyzed by univariate regression. RESULTS: In total, 210 patients were eventually included in observation. All patients underwent postoperative follow-up for no less than two years. Multiple regression analysis showed that the course of the disease, body weight, and kellgren-Larencen stage(K-L stage)of the affected knee joint were independent factors affecting the weight of the removed knee tissues and were positively correlated with it. Univariate analysis showed that IWKJ was negatively correlated with HSS score at two weeks and three months after the operation. In addition, the values of spatiotemporal parameters and knee rotation ROM were negatively correlated with IWKJ two weeks after surgery, while outside food load response was positively correlated with IWKJ. Cadence, knee rotation ROM, and Ankle rotation ROM were negatively correlated with IWKJ, while outside food was positively correlated with IWKJ three months after surgery. At the last follow-up, only the hip rotation ROM was positively correlated with IWKJ. CONCLUSIONS: All Patients underwent TKA had varying degrees of increased knee weight. The increased weight was 298.98 ± 63.77 g. Patients' body weight, K-L staging, and disease duration are important factors that cause differences in resected knee tissue. Three months after the operation, the changes in knee joint weight had a negative correlation with the HSS score, which at the same time, it had varying degrees of linearity with gait parameters. However, the influence of weight diminished over time.
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Artroplastia de Reemplazo de Rodilla , Prótesis de la Rodilla , Osteoartritis de la Rodilla , Artroplastia de Reemplazo de Rodilla/efectos adversos , Peso Corporal , Marcha , Humanos , Articulación de la Rodilla/cirugía , Osteoartritis de la Rodilla/cirugía , Estudios Prospectivos , Rango del Movimiento Articular , Recuperación de la Función , Resultado del TratamientoRESUMEN
OBJECTIVES: In this study, we investigated the time course in the cerebrospinal fluid (CSF) advanced oxidation protein products (AOPPs) levels in patients with aneurysmal subarachnoid hemorrhage (aSAH), and ascertained the relationship between the levels of AOPPs and early brain injury (EBI), hydrocephalus and prognosis of patients with aSAH. METHODS: We measured the CSF AOPPs levels in 50 patients with aSAH at 1-3 d, 4-6 d, 7-9 d, and 10-12 d after hemorrhage. The modified Fisher grades, Hunt-Hess grades, CSF IL-6 levels, peripheral blood count of white blood cells, cerebral edema scores and hydrocephalus were used to assess the severity of brain injury. Modified Rankin Scale (mRS) scores were used to assess the prognosis. Patients with mRS scores greater than 2 were considered to have a poor outcome. RESULTS: CSF AOPPs levels were significantly higher in patients with aSAH with poor prognosis, compared to patients with good prognosis and peaked in the early stage. Among patients with aSAH, the levels of CSF AOPPs on days 1-3 were significantly correlated with modified Fisher grades, Hunt-Hess grades, CSF IL-6 levels, peripheral blood count of white blood cells, and cerebral edema scores. Also, in patients with hydrocephalus, early CSF AOPPs levels were significantly elevated. Levels of CSF AOPPs in aSAH patients on days 1-3, 4-6, and 7-9 were independently associated with poor prognosis at the 90-day follow-up, and the optimal area under the curve (AUC) values for CSF AOPPs levels were found on days 1-3. CONCLUSIONS: AOPPs may serve as the potential biomarker to assess the severity of EBI and prognosis in patients with aSAH.
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Edema Encefálico , Lesiones Encefálicas , Hidrocefalia , Hemorragia Subaracnoidea , Productos Avanzados de Oxidación de Proteínas , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/etiología , Interleucina-6 , Pronóstico , Estudios Prospectivos , Hemorragia Subaracnoidea/diagnóstico , Hemorragia Subaracnoidea/terapiaRESUMEN
Rictor is an essential component that directly activates the mammalian target of rapamycin (mTOR) activity, which contributes to the intrinsic axon growth capacity of adult sensory neurons after injury. However, whether its action also applies to regeneration after spinal cord injury (SCI) remains unknown. In this study, rats were given spinal cord contusion at the T9-10 level to establish the SCI model and were subsequently treated with intraspinal cord injection of a Rictor overexpression lentiviral vector to locally upregulate the Rictor expression in the injured spinal cord. Thereafter, we investigated the therapeutic effects of Rictor overexpression in the injured spinal cords of SCI rats. Rictor overexpression not only significantly attenuated the acute inflammatory response and cell death after SCI but also markedly increased the shift in macrophages around the lesion from the M1 to M2 phenotype compared to those of the control lentiviral vector injection-treated group. Furthermore, Rictor overexpression dramatically increased neurogenesis in the lesion epicenter, subsequently promoting the tissue repair and functional recovery in SCI rats. Interestingly, the mechanism underlying the beneficial effects of Rictor overexpression on SCI may be associated with the Rictor overexpression playing a role in the anti-inflammatory response and driving macrophage polarization toward the M2 phenotype, which benefits resident neuronal and oligodendrocyte survival. Our findings demonstrate that Rictor is an effective target that affects the generation of molecules that inhibit spinal cord regeneration. In conclusion, localized Rictor overexpression represents a promising potential strategy for the repair of SCI.
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Proteína Asociada al mTOR Insensible a la Rapamicina/fisiología , Traumatismos de la Médula Espinal/terapia , Animales , Apoptosis , Supervivencia Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Macrófagos/clasificación , Macrófagos/metabolismo , Macrófagos/patología , Neuronas Motoras/patología , Neuronas Motoras/fisiología , Plasticidad Neuronal , Oligodendroglía/patología , Oligodendroglía/fisiología , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Recuperación de la Función/genética , Recuperación de la Función/fisiología , Remielinización , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatología , Regulación hacia ArribaRESUMEN
OBJECTIVE: To compare the neurological recovery between patients with adequate and inadequate immediate spinal cord expansion after sufficient decompression in degenerative cervical myelopathy (DCM). METHODS: Twenty-seven patients subjected to French-door laminoplasty underwent the guidance of intraoperative ultrasound (IOUS) and were prospectively included. The modified Japanese Orthopedic Association (mJOA) score was evaluated before surgery and at 12 months postoperatively. The maximum spinal cord compression (MSCC) after sufficient decompression was calculated on the IOUS image; patients were divided into adequate (MSCC ≥ 0.95) and inadequate (MSCC < 0.95) expansion groups according to the MSCC. The mJOA score, spinal cord hyperechogenicity, age at surgery, symptom duration, occupational rate of the spinal canal, and the minimum anteroposterior diameter of the spinal cord between the two groups were compared. RESULTS: Initially, 2 cases showed residual compression on IOUS; after further decompression, all patients acquired sufficient decompression. All patients achieved improvements in mJOA scores with an average recovery rate of 68.6 ± 20.3%. The recovery rate of the mJOA score of the inadequate expansion group was significantly inferior to that of the adequate expansion group (59.2 ± 21.7% versus 76.2 ± 16.2%, p = 0.028). The spinal cord hyperechogenicity was more common in the inadequate expansion group, while the spinal cord anteroposterior diameter of the inadequate expansion group was significantly smaller than that of the adequate expansion group. CONCLUSIONS: The application of IOUS in French-door laminoplasty could help to confirm sufficient decompression for the treatment of DCM. Inadequate spinal cord expansion after sufficient decompression had the high possibility of predicting less satisfactory neurological recovery of DCM. KEY POINTS: ⢠The intraoperative ultrasound revealed that not all degenerative cervical myelopathy patients acquired adequate spinal cord expansion after sufficient decompression. ⢠Patients who failed to acquire adequate spinal cord expansion commonly combined with spinal cord hyperechogenicity and trended to achieve less satisfactory neurological recovery after surgical decompression. ⢠Inadequate spinal cord expansion after sufficient decompression had the high possibility of predicting less satisfactory neurological recovery of patients with degenerative cervical myelopathy.
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Compresión de la Médula Espinal , Enfermedades de la Médula Espinal , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/cirugía , Descompresión Quirúrgica , Humanos , Compresión de la Médula Espinal/diagnóstico por imagen , Compresión de la Médula Espinal/cirugía , Enfermedades de la Médula Espinal/diagnóstico por imagen , Enfermedades de la Médula Espinal/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: To study the correlation of neurological function in degenerative cervical myelopathy (DCM) patients with quantitative assessment of spinal cord compression and impairment by intraoperative ultrasound imaging (IOUSI). METHODS: Twenty-three patients who underwent French-Door laminoplasty for multilevel DCM were followed for 6 months. Modified Japanese Orthopaedic Association (mJOA) score and cervical MRI were assessed before surgery and at postoperative 6 months. IOUS, used to guide decompression, were recorded. The anteroposterior diameter (APD) and the gray values of the IOUSI hyperechogenicity of the midsagittal IOUSI at the narrowest level and at the lesion-free level, and the APD and traverse diameter at the traverse maximum compression level of IOUSI were measured. Maximum spinal cord compression (MSCC), compression rate (CR), and IOUSI gray value ratio (Rgray) were calculated. The appearance of preoperative T2W MRI increased signal intensity (ISI), and the signal change rate (SCR) on postoperative T2W MRI of 9 patients were also measured and calculated, and compared with that of IOUSI hyperechogenicity. RESULTS: Average mJOA score increased significantly from 11.57 ± 2.67 before surgery to 15.39 ± 1.50 at 6 months after surgery, with an average recovery rate (RR) of 71.11 ± 22.81%. The difference between the appearance of preoperative T2W MRI ISI and IOUSI hyperechogenicity was not significant. Spearman correlation analysis found that the IOUSI Rgray were negatively correlated with the RR of mJOA score with a coefficient of - 0.77, and the IOUSI Rgray was not correlated with the postoperative MRI SCR. CONCLUSIONS: In DCM patients, the gray values of IOUSI can be measured accurately. The IOUSI Rgray correlated with postoperative neurological recovery significantly.
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Vértebras Cervicales/cirugía , Laminoplastia/métodos , Enfermedades de la Médula Espinal/diagnóstico , Enfermedades de la Médula Espinal/cirugía , Ultrasonografía , Anciano , Vértebras Cervicales/diagnóstico por imagen , Descompresión Quirúrgica/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de la Médula Espinal/patología , Cirugía Asistida por Computador , Resultado del TratamientoRESUMEN
N-18 F-labeled amino acids are important substitutes for new positron emission tomography (PET) imaging tracers complementing the deficiency of 18 F-fluorodeoxyglucose (18 F-FDG). In this work, two novel N-6-18 F-alkyl amino acid imaging agents, 18 F-FHex-α-l-Glu and 18 F-FHex-ß-Glu, were designed and synthesized as potential probes for PET imaging of tumors. 18 F-FHex-α-l-Glu was synthesized using the precursor 6 from 18 F-F- with the yield of 16 ± 4% (n = 5, uncorrected) within about 50 minutes. The specific activity was 14.5 GBq/µmol, and the radiochemical purity was more than 95%. 18 F-FHex-ß-Glu was synthesized using the precursor 12 based on 18 F-F- with the yield of 11 ± 3% (n = 3, uncorrected) in about 60 minutes. The specific activity was 9.1 GBq/µmol, and the radiochemical purity was more than 95%.
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Radioisótopos de Flúor/química , Ácido Glutámico/química , Tomografía de Emisión de Positrones , Línea Celular Tumoral , Humanos , Marcaje Isotópico , RadioquímicaRESUMEN
OBJECTIVE: To evaluate the preclinical value of 18F-fluoropropionic acid (18F-FPA) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) for imaging HCCs. METHODS: The 18F-FPA and 18F-FDG uptake patterns in 3 HCC cell lines (Hep3B, HepG2, and SK-Hep1) were assessed in vitro and in vivo. The 18F-FPA uptake mechanism was investigated using inhibition experiments with orlistat and 5-tetradecyloxy-2-furoic acid. The 18F-FPA PET imaging was performed in different tumor animal models and compared with 18F-FDG. We also evaluated the expressions of glucose transporter-1 (GLUT1), fatty acid synthase (FASN), and matrix metalloproteinase-2 (MMP2) in these cell lines. RESULTS: In vitro experiments showed that the radiotracer uptake patterns were complementary in the HCC cell lines. Orlistat and 5-tetradecyloxy-2-furoic acid decreased the uptake of 18F-FPA. The tumor-to-liver ratio of 18F-FPA was superior to that of 18F-FDG in the SK-Hep1 and HepG2 tumors ( P < .05). However, in the Hep3B tumors, the tumor-to-liver normalized uptake of 18F-FDG was higher than 18F-FPA ( P < .01). FASN was highly expressed in cell lines with high 18F-FPA uptake, whereas GLUT1 was highly expressed in cell lines with high 18F-FDG uptake. The 18F-FPA uptake correlated with FASN ( r = 0.89, P = .014) and MMP2 ( r = 0.77, P = .002) expressions. CONCLUSIONS: PET imaging with 18F-FPA combined with 18F-FDG can be an alternative for detecting HCC.