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Myeloid-derived suppressor cells (MDSCs) regulate T cell immunity, and this population is a new therapeutic target for immune regulation. A previous study showed that transforming growth factor-β (TGF-β) is involved in controlling MDSC differentiation and immunoregulatory function in vivo. However, the direct effect of TGF-β on MDSCs with various cytokines has not previously been tested. Thus, we examined the effect of various cytokine combinations with TGF-β on MDSCs derived from bone marrow cells. The data show that different cytokine combinations affect the differentiation and immunosuppressive functions of MDSCs in different ways. In the presence of TGF-β, interleukin-6 (IL-6) was the most potent enhancer of MDSC function, whereas granulocyte colony-stimulating factors (G-CSF) was the most potent in the absence of TGF-β. In addition, IL-4 maintained MDSCs in an immature state with an increased expression of arginase 1 (Arg1). However, regardless of the cytokine combinations, TGF-β increased expansion of the monocytic MDSC (Mo-MDSC) population, expression of immunosuppressive molecules by MDSCs, and the ability of MDSCs to suppress CD4+ T cell proliferation. Thus, although different cytokine combinations affected the MDSCs in different ways, TGF-β directly affects monocytic-MDSCs (Mo-MDSCs) expansion and MDSCs functions.

Acute kidney injury (AKI) is a common reactive oxygen species (ROS)-related renal disease that causes numerous deaths annually, yet only supportive treatment is currently available in the clinics. Development of antioxidants with high accumulation rates in kidneys is highly desired to help prevent AKI. Here we report molybdenum-based polyoxometalate (POM) nanoclusters with preferential renal uptake as novel nano-antioxidants for kidney protection. These POM nanoclusters, with a readily variable valence state of molybdenum ions, possess the capability to scavenge detrimental ROS. Our results demonstrate that POM nanoclusters can efficiently alleviate clinical symptoms in mice subjected to AKI, as verified by dynamic PET imaging with 68 Ga-EDTA, serum tests, kidney tissue staining, and biomarkers detection in the kidneys. The protective effect of POM nanoclusters against AKI in living animals suggests exploring their use for the treatment of AKI patients, as well as patients with other ROS-related diseases. There are currently no effective therapies available for acute kidney injury (AKI). Here the authors generate molybdenum-based polyoxometalate nanoclusters and show that these have preferential renal uptake and can ameliorate AKI pathology in mice by scavenging reactive oxygen species.

The tightly structured neural retina has a unique vascular network comprised of three interconnected plexuses in the inner retina (and choroid for outer retina), which provide oxygen and nutrients to neurons to maintain normal function. Clinical and experimental evidence suggests that neuronal metabolic needs control both normal retinal vascular development and pathological aberrant vascular growth. Particularly, photoreceptors, with the highest density of mitochondria in the body, regulate retinal vascular development by modulating angiogenic and inflammatory factors. Photoreceptor metabolic dysfunction, oxidative stress, and inflammation may cause adaptive but ultimately pathological retinal vascular responses, leading to blindness. Here we focus on the factors involved in neurovascular interactions, which are potential therapeutic targets to decrease energy demand and/or to increase energy production for neovascular retinal disorders.

Hodgkin lymphoma and non-Hodgkin lymphoma are common malignancies in children and are now highly treatable. Imaging plays a major role in diagnosis, staging and response using conventional CT and MRI and metabolic imaging with positron emission tomography (PET)/CT and PET/MRI. Cross-sectional imaging has replaced staging laparotomy and splenectomy by demonstrating abdominal nodal groups and organ involvement. [F-18]2-fluoro-2-deoxyglucose (FDG) PET provides information on bone marrow involvement, and MRI elucidates details of cortical bone and confirmation of bone marrow involvement. The staging system for Hodgkin lymphoma is the Ann Arbor system with Cotswald modifications and is based on imaging, whereas the non-Hodgkin staging system is the St. Jude Classification by Murphy or the more recent revised International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS). Because all pediatric lymphomas are metabolically FDG-avid and identify all nodal, solid organ, cortical bone and bone marrow disease, staging evaluations require FDG PET as PET/CT or PET/MRI in both Hodgkin and non-Hodgkin lymphoma. Both diseases have in common issues of airway compromise at presentation demonstrated by imaging. Differences exist in that Hodgkin lymphoma has several independent poor prognostic factors seen by imaging such as large mediastinal adenopathy, Stage IV disease, systemic symptoms, pleural effusion and pericardial effusion. Non-Hodgkin lymphoma includes more organ involvement such as renal, ovary, central nervous system and skin. Early or interim PET-negative scans are a reliable indicator of improved clinical outcome and optimize risk-adapted therapy and patient management; imaging may not, however, predict who will relapse. A recent multicenter trial has concluded that it is usually sufficient for pediatric lymphoma at staging and interim assessment to evaluate children with PET imaging from skull base to mid-thigh. Various systems of assessment of presence of disease or response are used, including the Deauville visual scale, where avidity is compared to liver; Lugano, which includes size change as part of response; or quantitative PET, which uses standardized uptake values to define more accurate response. Newer methods of immunotherapy can produce challenges in FDG PET evaluation because of inflammatory changes that may not represent disease.

Purpose Prostate-specific membrane antigen (PSMA) is a recognized target for imaging prostate cancer. Here we present initial safety, biodistribution, and radiation dosimetry results with [ 18 F]DCFPyL, a second-generation fluorine-18-labeled small-molecule PSMA inhibitor, in patients with prostate cancer. Procedures Biodistribution was evaluated using sequential positron-emission tomography (PET) scans in nine patients with prostate cancer. Time-activity curves from the most avid tumor foci were determined. The radiation dose to selected organs was estimated using OLINDA/EXM. Results No major radiotracer-specific adverse events were observed. Physiologic accumulation was observed in known sites of PSMA expression. Accumulation in putative sites of prostate cancer was observed (SUV max up to >100, and tumor-to-blood ratios up to >50). The effective radiation dose from [ 18 F]DCFPyL was 0.0139 mGy/MBq or 5 mGy (0.5 rem) from an injected dose of 370 MBq (10 mCi). Conclusions [ 18 F]DCFPyL is safe with biodistribution as expected, and its accumulation is high in presumed primary and metastatic foci. The radiation dose from [ 18 F]DCFPyL is similar to that from other PET radiotracers.

Prostate specific membrane antigen (PSMA)-based radiotracers have shown promise for prostate cancer assessment. Evaluation of quantitative variability and establishment of reference standards are important for optimal clinical and research utility. This work evaluates the variability of PSMA-based [ 18 F]DCFPyL (PyL) PET quantitative reference standards. Consecutive eligible patients with biochemically recurrent prostate cancer were recruited for study participation from August 2016-October 2017. After PyL tracer injection, whole body PET/CT (wbPET/CT) was obtained with subsequent whole body PET/MR (wbPET/MR). Two readers independently created regions of interest (ROIs) including a 40% standardized uptake value (SUV) threshold ROI of the whole right parotid gland and separate spherical ROIs in the superior, mid, and inferior gland. Additional liver (right lobe) and blood pool spherical ROIs were defined. Bland-Altman analysis, including limits of agreement (LOA), as well as interquartile range (IQR) and coefficient of variance (CoV) was used. Twelve patients with prostate cancer were recruited (mean age, 61.8 yrs; range 54–72 years). One patient did not have wbPET/MR and was excluded. There was minimal inter-reader SUV mean variability (bias±LOA) for blood pool (-0.13±0.42; 0.01±0.41), liver (-0.55±0.82; -0.22±1.3), or whole parotid gland (-0.05±0.31; 0.08±0.24) for wbPET/CT and wbPET/MR, respectively. Greater inter-reader variability for the 1-cm parotid gland ROIs was present, for both wbPET/CT and wbPET/MR. Comparing wbPET/CT to the subsequently acquired wbPET/MR, blood pool had a slight decrease in SUV mean . The liver as well as parotid gland showed a slight increase in activity although the absolute bias only ranged from 0.45–1.28. The magnitude of inter-subject variability was higher for the parotid gland regardless of modality or reader. In conclusion, liver, blood pool, and whole parotid gland quantitation show promise as reliable reference normal organs for clinical/research PET applications. Variability with 1-cm parotid ROIs may limit its use.

Purpose Total metabolic tumor volume (TMTV) segmentation has significant value enabling quantitative imaging biomarkers for lymphoma management. In this work, we tackle the challenging task of automated tumor delineation in lymphoma from PET/CT scans using a cascaded approach. Methods Our study included 1418 2-[ 18 F]FDG PET/CT scans from four different centers. The dataset was divided into 900 scans for development/validation/testing phases and 518 for multi-center external testing. The former consisted of 450 lymphoma, lung cancer, and melanoma scans, along with 450 negative scans, while the latter consisted of lymphoma patients from different centers with diffuse large B cell, primary mediastinal large B cell, and classic Hodgkin lymphoma cases. Our approach involves resampling PET/CT images into different voxel sizes in the first step, followed by training multi-resolution 3D U-Nets on each resampled dataset using a fivefold cross-validation scheme. The models trained on different data splits were ensemble. After applying soft voting to the predicted masks, in the second step, we input the probability-averaged predictions, along with the input imaging data, into another 3D U-Net. Models were trained with semi-supervised loss. We additionally considered the effectiveness of using test time augmentation (TTA) to improve the segmentation performance after training. In addition to quantitative analysis including Dice score (DSC) and TMTV comparisons, the qualitative evaluation was also conducted by nuclear medicine physicians. Results Our cascaded soft-voting guided approach resulted in performance with an average DSC of 0.68 ± 0.12 for the internal test data from developmental dataset, and an average DSC of 0.66 ± 0.18 on the multi-site external data ( n  = 518), significantly outperforming ( p  < 0.001) state-of-the-art (SOTA) approaches including nnU-Net and SWIN UNETR. While TTA yielded enhanced performance gains for some of the comparator methods, its impact on our cascaded approach was found to be negligible (DSC: 0.66 ± 0.16). Our approach reliably quantified TMTV, with a correlation of 0.89 with the ground truth ( p  < 0.001). Furthermore, in terms of visual assessment, concordance between quantitative evaluations and clinician feedback was observed in the majority of cases. The average relative error (ARE) and the absolute error (AE) in TMTV prediction on external multi-centric dataset were ARE = 0.43 ± 0.54 and AE = 157.32 ± 378.12 (mL) for all the external test data ( n  = 518), and ARE = 0.30 ± 0.22 and AE = 82.05 ± 99.78 (mL) when the 10% outliers ( n  = 53) were excluded. Conclusion TMTV-Net demonstrates strong performance and generalizability in TMTV segmentation across multi-site external datasets, encompassing various lymphoma subtypes. A negligible reduction of 2% in overall performance during testing on external data highlights robust model generalizability across different centers and cancer types, likely attributable to its training with resampled inputs. Our model is publicly available, allowing easy multi-site evaluation and generalizability analysis on datasets from different institutions.

Objective Molecular imaging with positron emission tomography (PET) provides a powerful means of identifying and characterizing cancerous processes, as well as providing a quantitative framework within which response to therapy can be ascertained. Unfortunately, the most commonly used PET radiotracer, 18 F-fluorodeoxyglucose (FDG), has not demonstrated a definitive role in determining response to therapy in metastatic renal cell carcinoma (RCC). As a result, new radiotracers able to reliably image RCC could be of tremendous value for this purpose. Methods Five patients with known metastatic RCC were imaged with the low-molecular weight radiotracer 18 F-DCFPyL, an inhibitor of the prostate-specific membrane antigen at 60 min post injection. 18 F-DCFPyL PET/CT and conventional images (either contrast-enhanced computed tomography or magnetic resonance imaging) were centrally reviewed for suspected sites of disease. Results In all five patients imaged, sites of putative metastatic disease were readily identifiable by abnormal 18 F-DCFPyL uptake, with overall more lesions detected than on conventional imaging. These PET-detected sites included lymph nodes, pancreatic parenchymal lesions, lung parenchymal lesions, a brain parenchymal lesion, and other soft tissue sites. 18 F-DCFPyL uptake ranged from subtle to intense with maximum standardized uptake values (SUV max ) for the identified lesions of 1.6–19.3. Based upon this small patient series, limited pathology and imaging follow-up of these patients suggests a higher sensitivity for 18 F-DCFPyL compared to conventional imaging in the detection of metastatic RCC (94.7 versus 78.9 %). Conclusions PSMA expression in the tumor neovasculature of RCC has been previously established and is believed to provide the basis for the imaging findings presented here. PSMA-based PET/CT with radiotracers such as 18 F-DCFPyL may allow more accurate staging of patients with RCC and conceivably the ability to predict and follow therapy in patients treated with agents targeting the neovasculature.

The light‐sensitive photoreceptors in the retina are extremely metabolically demanding and have the highest density of mitochondria of any cell in the body. Both physiological and pathological retinal vascular growth and regression are controlled by photoreceptor energy demands. It is critical to understand the energy demands of photoreceptors and fuel sources supplying them to understand neurovascular diseases. Retinas are very rich in lipids, which are continuously recycled as lipid‐rich photoreceptor outer segments are shed and reformed and dietary intake of lipids modulates retinal lipid composition. Lipids (as well as glucose) are fuel substrates for photoreceptor mitochondria. Dyslipidemia contributes to the development and progression of retinal dysfunction in many eye diseases. Here, we review photoreceptor energy demands with a focus on lipid metabolism in retinal neurovascular disorders. Graphical Abstract In the growing field of lipid metabolism in retinopathies, this review provides insights on the possible implication of lipid metabolism, energy demands and fuel source in the retina, but also systemic dyslipidemia on neovascular retinopathy.

Purpose Current standard of care conventional imaging modalities (CIM) such as X-ray computed tomography (CT) and bone scan can be limited for detection of metastatic prostate cancer and therefore improved imaging methods are an unmet clinical need. We evaluated the utility of a novel second-generation low molecular weight radiofluorinated prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) radiotracer, [ 18 F]DCFPyL, in patients with metastatic prostate cancer. Procedures Nine patients with suspected prostate cancer recurrence, eight with CIM evidence of metastatic prostate cancer and one with biochemical recurrence, were imaged with [ 18 F]DCFPyL PET/CT. Eight of the patients had contemporaneous CIM for comparison. A lesion-by-lesion comparison of the detection of suspected sites of metastatic prostate cancer was carried out between PET and CIM. Statistical analysis for estimated proportions of inter-modality agreement for detection of metastatic disease was calculated accounting for intra-patient correlation using general estimating equation (GEE) intercept-only regression models. Results One hundred thirty-nine sites of PET positive [ 18 F]DCFPyL uptake (138 definite, 1 equivocal) for metastatic disease were detected in the eight patients with available comparison CIM. By contrast, only 45 lesions were identified on CIM (30 definite, 15 equivocal). When lesions were negative or equivocal on CIM, it was estimated that a large portion of these lesions or 0.72 (95 % confidence interval (CI) 0.55–0.84) would be positive on [ 18 F]DCFPyL PET. Conversely, of those lesions negative or equivocal on [ 18 F]DCFPyL PET, it was estimated that only a very small proportion or 0.03 (95 % CI 0.01–0.07) would be positive on CIM. Delayed 2-h-post-injection time point PET yielded higher tumor radiotracer uptake and higher tumor-to-background ratios than an earlier 1-h-post-injection time point. Conclusions A novel PSMA-targeted PET radiotracer, [ 18 F]DCFPyL, was able to a large number of suspected sites of prostate cancer, many of which were occult or equivocal by CIM. This study provides strong preliminary evidence for the use of this second-generation PSMA-targeted PET radiotracer for detection of metastatic prostate cancer and lends further support for the importance of PSMA-targeted PET imaging in prostate cancer.