Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2).

Parkinson's disease (PD) is one of the most highly debilitating neurodegenerative disorders, which affects millions of people worldwide, and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved in the pathogenesis of PD. Developing a potent LRRK2 positron emission tomography (PET) tracer would allow for in vivo visualization of LRRK2 distribution and expression in PD patients. In this work, we present the facile synthesis of two potent and selective LRRK2 radioligands [11C]3 ([11C]PF-06447475) and [18F]4 ([18F]PF-06455943). Both radioligands exhibited favorable brain uptake and specific bindings in rodent autoradiography and PET imaging studies. More importantly, [18F]4 demonstrated significantly higher brain uptake in the transgenic LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models. This work may serve as a roadmap for the future design of potent LRRK2 PET tracers.

Development and validation of a diagnostic nomogram model for predicting monoclonal gammopathy of renal significance.

In patients with kidney disease, the presence of monoclonal gammopathy necessitates the exploration of potential causal relationships. Therefore, in this study, we aimed to address this concern by developing a nomogram model for the early diagnosis of monoclonal gammopathy of renal significance (MGRS). Univariate and multivariate logistic regression analyses were employed to identify risk factors for MGRS. Verification and evaluation of the nomogram model's differentiation, calibration, and clinical value were conducted using the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis. The study encompassed 347 patients who underwent kidney biopsy, among whom 116 patients (33.4%) were diagnosed with MGRS and 231 (66.6%) with monoclonal gammopathy of undetermined significance. Monoclonal Ig-related amyloidosis (n = 86) and membranous nephropathy (n = 86) was the most common renal pathological type in each group. Notably, older age, abnormal serum-free light chain ratio, and the absence of microscopic hematuria were identified as independent prognostic factors for MGRS. The areas under the ROC curves for the training and verification sets were 0.848 and 0.880, respectively. In conclusion, the nomogram model demonstrated high accuracy and clinical applicability for diagnosing MGRS, potentially serving as a valuable tool for noninvasive early MGRS diagnosis.

Nanoclay-Modified Hyaluronic Acid Microspheres for Bone Induction by Sustained rhBMP-2 Delivery.

Microspheres (MSs) are ideal candidates as biological scaffolds loading with growth factors or cells for bone tissue engineering to repair irregular alveolar bone defects by minimally invasive injection. However, the high initial burst release of growth factor and low cell attachment limit the application of microspheres. The modification of microspheres often needs expensive experiments facility or complex chemical reactions, which is difficult to achieve and may bring other problems. In this study, a sol-grade nanoclay, laponite XLS is used to modify the surface of MSs to enhance its affinity to either positively or negatively charged proteins and cells without changing the interior structure of the MSs. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used as a representation of growth factor to check the osteoinduction ability of laponite XLS-modified MSs. By modification, the protein sustained release, cell loading, and osteoinduction ability of MSs are improved. Modified by 1% laponite XLS, the MSs can not only promote osteogenic differentiation of MC3T3-E1 cells by themselves, but also enhance the effect of the rhBMP-2 below the effective dose. Collectively, the study provides an easy and viable method to modify the biological behavior of microspheres for bone tissue regeneration.

An Iterative Method of Modeling Pump-Treat-Inject System with "Partial Treatment".

Pump-and-treat technologies are widely used in groundwater remediation and site cleanup. Such technologies involve pumping contaminated groundwater to the surface for treatment. Following treatment, the water is often reinjected back into the aquifer (referred to as pump-treat-inject or PTI) for potential reuse. The treatment system is often designed to remove dissolved-phase contaminants in groundwater such that water meets applicable cleanup standards (herein referred to as "full treatment"). However, in some cases, the treatment system may not effectively reduce the dissolved-phase concentrations (herein referred to as "partial treatment") for some of the contaminants present in groundwater. Modeling PTI under partial treatment conditions is challenging because contaminant concentrations in injected water depend on the pumped water concentrations and the system treatment efficiency. Essentially, the injected water concentration (a transport model input) is unknown prior to transport simulation. This study presents a novel iterative approach to modeling PTI under partial treatment scenarios, where the injected water concentration is linked to the modeled pumped water concentration. The method was developed for a complicated three-dimensional (3D) flow and transport modeling study conducted for a confidential remediation site where PTI with partial treatment was applied. However, due to the complexity of the 3D model and the confidential information of the site, a simple two-dimensional (2D) numerical model is presented to demonstrate the iterative method. The 2D model test runs and the 3D model application in a remediation site showed that the iterative simulation results quickly converged to a viable final solution.

Diagnostic value of α1-MG and URBP in early diabetic renal impairment.

Aims/Introduction: Diabetic kidney disease (DKD) is defined as diabetes with impaired renal function, elevated urinary albumin excretion, or both. DKD is one of the most common microvascular complications of diabetes and plays an important role in the cause of end-stage renal disease (ESRD). About 5% of people with type 2 diabetes (T2DM) already have kidney damage at the time they are diagnosed, but other triggers of renal insufficiency, such as obesity, hyperlipidemia, glomerular atherosclerosis are often present, making it difficult to define "diabetic kidney disease" or "diabetic nephropathy" precisely in epidemiology or clinical practice. Therefore, the aim of this study is to identify diabetic patients with CKD at an early stage, and evaluate the value of tubular injury markers including α1-microglobulin (α1-MG), ß2-microglobulin (ß2-MG), N-acetyl-beta-D-glucosaminidase (NAG) and Urinary retinol binding protein (URBP) in the development of diabetes to DKD. Materials and methods: We recruited a total of 182 hospitalized patients with T2DM in the First Affiliated Hospital of Zhengzhou University from February 2018 to April 2023. We collected basic clinical characteristics and laboratory biochemical parameters of the patients. Based on their levels of urinary albumin creatinine ratio (UACR) and glomerular filtration rate (GFR), patients were divided into DM group (UACR≤30 mg/g and eGFR≥90 mL/min/1.73 m2, n = 63) and DKD group (UACR>30 mg/g or eGFR<90 mL/min/1.73 m2, n = 119) excluding other causes of chronic kidney disease. We further developed diagnostic models to improve the ability to predict the risk of developing DKD by screening potential risk factors using univariate and multivariate logistic regression analysis. Calibration plots and curve analysis were used to validate the model and clinical usefulness. Next, we screened patients with relatively normal estimated glomerular filtration rate (eGFR) (≥90 mL/min/1.73 m2) to investigate whether tubular injury markers could accurately predict the risk of DKD in patients with normal renal function. We defined the rate of GFR decline as a prognostic indicator of renal function in patients and collected the information of the re-hospitalized DKD patients to determine whether the relevant indicators had an impact on the renal prognosis. Results: The patients with DKD had higher levels of tubular injury markers than patients with DM. URBP, α1-MG, eGFR were statistically different in both univariate and multivariate logistic regression analyses and displayed great predictive power after modeling with an area under curve of 0.987. The calibration curve showed medium agreement. Decision curve showed it would add more net benefits for clinical decision. After adjusting eGFR and serum creatinine (Scr), URBP was demonstrated to be associated with early renal function impairment. Conclusion: Tubular injury markers play an important role in early diabetic renal function impairment.

Development of Novel 11C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging.

Orexin 2 receptors (OX2R) represent a vital subtype of orexin receptors intricately involved in the regulation of wakefulness, arousal, and sleep-wake cycles. Despite their importance, there are currently no positron emission tomography (PET) tracers available for imaging the OX2R in vivo. Herein, we report [11C]1 ([11C]OX2-2201) and [11C]2 ([11C]OX2-2202) as novel PET ligands. Both compounds 1 (Ki = 3.6 nM) and 2 (Ki = 2.2 nM) have excellent binding affinity activities toward OX2R and target selectivity (OX2/OX1 > 600 folds). In vitro autoradiography in the rat brain suggested good to excellent in vitro binding specificity for [11C]1 and [11C]2. PET imaging in rat brains indicated that the low brain uptake of [11C]2 may be due to P-glycoprotein and/or breast cancer resistance protein efflux interaction and/or low passive permeability. Continuous effort in medicinal chemistry optimization is necessary to improve the brain permeability of this scaffold.

FG-4592 relieves diabetic kidney disease severity by influencing metabolic profiles via gut microbiota reconstruction in both human and mouse models.

Objective: Diabetic kidney disease (DKD) is one of the most prevalent complications of diabetes mellitus (DM) and is highly associated with devastating outcomes. Hypoxia-inducible factor (HIF), the main transcription factor that regulates cellular responses to hypoxia, plays an important role in regulating erythropoietin (EPO) synthesis. FG-4592 is the HIF stabilizer that is widely used in patients with renal anemia. We investigated the effect of FG-4592 on DKD phenotypes and the pharmacologic mechanism from the perspective of gut microbiota and systemic metabolism. Design: We collected the clinical data of 73 participants, including 40 DKD patients with combined renal anemia treated with FG-4592, and 33 clinical index-matched DKD patients without FG-4592 treatment from The First Affiliated Hospital of Zhengzhou University at the beginning and after a 3-6-month follow-up period. We established DKD mouse models treated by FG-4592 and performed fecal microbiota transplantation from FG-4592-treated DKD mice to investigate the effects of FG-4592 on DKD and to understand this mechanism from a microbial perspective. Untargeted metabolome-microbiome combined analysis was implemented to globally delineate the mechanism of FG-4592 from both microbial and metabolomic aspects. Result: DKD phenotypes significantly improved after 3-6 months of FG-4592 treatment in DKD patients combined with renal anemia, including a decreased level of systolic blood pressure, serum creatinine, and increased estimated glomerular infiltration rate. Such effects were also achieved in the DKD mouse model treated with FG-4592 and can be also induced by FG-4592-influenced gut microbiota. Untargeted plasma metabolomics-gut microbiota analysis showed that FG-4592 dramatically altered both the microbial and metabolic profiles of DKD mice and relieved DKD phenotypes via upregulating beneficial gut microbiota-associated metabolites. Conclusion: FG-4592 can globally relieve the symptoms of DKD patients combined with renal anemia. In the animal experiment, FG-4592 can reconstruct the intestinal microbial profiles of DKD to further upregulate the production of gut-associated beneficial metabolites, subsequently improving DKD phenotypes.

Biomimetic hypoxia-triggered RNAi nanomedicine for synergistically mediating chemo/radiotherapy of glioblastoma.

Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein, to improve the therapeutic effect of RNAi on GBM, a cancer cell membrane (CCM)-disguised hypoxia-triggered RNAi nanomedicine was developed for short interfering RNA (siRNA) delivery to sensitize cells to chemotherapy and radiotherapy. Our synthesized CCM-disguised RNAi nanomedicine showed prolonged blood circulation, high BBB transcytosis and specific accumulation in GBM sites via homotypic recognition. Disruption and effective anti-GBM agents were triggered in the hypoxic region, leading to efficient tumor suppression by using phosphoglycerate kinase 1 (PGK1) silencing to enhance paclitaxel-induced chemotherapy and sensitize hypoxic GBM cells to ionizing radiation. In summary, a biomimetic intelligent RNAi nanomedicine has been developed for siRNA delivery to synergistically mediate a combined chemo/radiotherapy that presents immune-free and hypoxia-triggered properties with high survival rates for orthotopic GBM treatment.

The Glutaminase-1 Inhibitor [11C-carbony]BPTES: Synthesis and Positron Emission Tomography Study in Mice.

Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a selective inhibitor of glutaminase-1 (GLS1), consequently inhibiting glutaminolysis. BPTES is known for its potent antitumor activity and plays a significant role in senescent cell removal. In this study, we synthesized [11C-carbonyl]BPTES ([11C]BPTES) as a positron emission tomography (PET) probe for the first time and assessed its biodistribution in mice using PET. [11C]BPTES was synthesized by the reaction of an amine precursor () with [11C-carbonyl]phenylacetyl acid anhydride ([11C]2), which was prepared from [11C]CO2 and benzyl magnesium chloride, followed by in situ treatment with isobutyl chloroformate. The decay-corrected isolated radiochemical yield of [11C]BPTES was 9.5% (based on [11C]CO2) during a synthesis time of 40 min. A PET study with [11C]BPTES showed high uptake levels of radioactivity in the liver, kidney, and small intestine of mice.

Automated radiosynthesis and in vivo evaluation of 18F-labeled analog of the photosensitizer ADPM06 for planning photodynamic therapy.

BACKGROUND: A family of BF2-chelated tetraaryl-azadipyrromethenes was developed as non-porphyrin photosensitizers for photodynamic therapy. Among the developed photosensitizers, ADPM06 exhibited excellent photochemical and photophysical properties. Molecular imaging is a useful tool for photodynamic therapy planning and monitoring. Radiolabeled photosensitizers can efficiently address photosensitizer biodistribution, providing helpful information for photodynamic therapy planning. To evaluate the biodistribution of ADPM06 and predict its pharmacokinetics on photodynamic therapy with light irradiation immediately after administration, we synthesized [18F]ADPM06 and evaluated its in vivo properties. RESULTS: [18F]ADPM06 was automatically synthesized by Lewis acid-assisted isotopic 18F-19F exchange using ADPM06 and tin (IV) chloride at room temperature for 10 min. Radiolabeling was carried out using 0.4 µmol of ADPM06 and 200 µmol of tin (IV) chloride. The radiosynthesis time was approximately 60 min, and the radiochemical purity was > 95% at the end of the synthesis. The decay-corrected radiochemical yield from [18F]F- at the start of synthesis was 13 ± 2.7% (n = 5). In the biodistribution study of male ddY mice, radioactivity levels in the heart, lungs, liver, pancreas, spleen, kidney, small intestine, muscle, and brain gradually decreased over 120 min after the initial uptake. The mean radioactivity level in the thighbone was the highest among all organs investigated and increased for 120 min after injection. Upon co-injection with ADPM06, the radioactivity levels in the blood and brain significantly increased, whereas those in the heart, lung, liver, pancreas, kidney, small intestine, muscle, and thighbone of male ddY mice were not affected. In the metabolite analysis of the plasma at 30 min post-injection in female BALB/c-nu/nu mice, the percentage of radioactivity corresponding to [18F]ADPM06 was 76.3 ± 1.6% (n = 3). In a positron emission tomography study using MDA-MB-231-HTB-26 tumor-bearing mice (female BALB/c-nu/nu), radioactivity accumulated in the bone at a relatively high level and in the tumor at a moderate level for 60 min after injection. CONCLUSIONS: We synthesized [18F]ADPM06 using an automated 18F-labeling synthesizer and evaluated the initial uptake and pharmacokinetics of ADPM06 using biodistribution of [18F]ADPM06 in mice to guide photodynamic therapy with light irradiation.

Linear Peptide-Based PET Tracers for Imaging PD-L1 in Tumors.

Programmed cell death receptor 1 (PD-1) and its ligand PD-L1 are particularly interesting immune checkpoint proteins for human cancer treatment. Positron emission tomography (PET) imaging allows for the dynamic monitoring of PD-L1 status during tumor progression, thus informing patients' response index. Herein, we report the synthesis of two linear peptide-based radiotracers, [64Cu]/[68Ga]HKP2201 and [64Cu]/[68Ga]HKP2202, and validate their utility for PD-L1 visualization in preclinical models. The precursor peptide HKP2201 was derived from a linear peptide ligand, CLP002, which was previously identified by phage display and showed nanomolar affinity toward PD-L1. Appropriate modification of CLP002 via PEGylation and DOTA conjugation yielded HKP2201. The dimerization of HKP2201 generated HKP2202. The 64Cu and 68Ga radiolabeling of both precursors was studied and optimized. PD-L1 expression in mouse melanoma cell line B16F10, mouse colon cancer cell line MC38, and their allografts were assayed by immunofluorescence and immunohistochemistry staining. Cellular uptake and binding assays were conducted in both cell lines. PET imaging and ex vivo biodistribution studies were employed in tumor mouse models bearing B16F10 and MC38 allografts. [64Cu]/[68Ga]HKP2201 and [64Cu]/[68Ga]HKP2202 were obtained with satisfactory radiocharacteristics. They all showed lower liver accumulation compared to [64Cu]/[68Ga]WL12. B16F10 and MC38 cells and their tumor allografts sections were verified to express PD-L1. These tracers demonstrated a concentration-dependent cell affinity and a comparable half-maximal effect concentration (EC50) with radiolabeled WL12. Competitive binding and blocking studies demonstrated the specific target of these tracers to PD-L1. PET imaging and ex vivo biodistribution studies revealed notable tumor uptake in tumor-bearing mice and rapid clearance from blood and major organs. Importantly, [64Cu]/[68Ga]HKP2202 showed higher tumor uptake compared to [64Cu]/[68Ga]HKP2201. Of note, [64Cu] labeled tracers showed longer retention in tumors than [68Ga] labeled traces, indicating advantages in the long-term tracking of PD-L1 dynamics. In comparison, [68Ga]HKP2201 and [68Ga]HKP2202 showed lower liver accumulation, enabling its great potential in the fast detection of both primary and metastatic tumors, including hepatic carcinoma. [64Cu]/[68Ga]HKP2201 and [64Cu]/[68Ga]HKP2202 are promising PET tracers for visualizing PD-L1 status. Notably, their combination would cooperate in rapid diagnosis and subsequent treatment guidance. Future assessment of the radiotracers in patients is needed to fully evaluate their clinical value.

Combination of the gut microbiota and clinical indicators as a potential index for differentiating idiopathic membranous nephropathy and minimal change disease.

Objectives: Membranous nephropathy (MN) and minimal change disease (MCD) are two common types of nephrotic syndrome that have similar clinical presentations but require different treatment strategies. Currently, the definitive diagnosis for these conditions relies on invasive renal biopsy, which can be limited in clinical practice.Methods: In this study, we aimed to differentiate idiopathic MN (IMN) from MCD using clinical data and gut microbiota. We collected clinical data and stool samples from 115 healthy individuals, 115 IMN, and 45 MCD at the onset of disease and performed 16S rRNA sequencing. Through machine learning methods including random forest, logistic regression, and support vector machine, a classifier to differentiate IMN from MCD was constructed.Results: Baseline clinical data comparing the IMN and MCD groups showed that the MCD had higher levels of hemoglobin, uric acid, cystatin C, ß2-microglobulin, α1-microglobulin, total cholesterol, and low-density lipoprotein and lower levels of albumin and CD4+ T-cell counts. The gut microbiota of the two groups differed at all levels of the phylum and genus. Differential gut microbiota may disturb the integrity of the intestinal wall and lead to the passage of inflammatory mediators through the intestinal barrier, causing kidney injury. We constructed a noninvasive classifier with a discrimination efficacy of 0.939 that combined the clinical data and gut microbiota information to identify IMN and MCD.Conclusions: The classifier of the gut microbiota combined with clinical indicators has achieved good performance in identifying IMN and MCD, which provides a new approach for the noninvasive discrimination of different pathological types of kidney disease.

A 211At-labelled mGluR1 inhibitor induces cancer senescence to elicit long-lasting anti-tumor efficacy.

Metabotropic glutamate receptor 1 (mGluR1), a key mediator of glutamatergic signaling, is frequently overexpressed in tumor cells and is an attractive drug target for most cancers. Here, we present a targeted radiopharmaceutical therapy strategy that antagonistically recognizes mGluR1 and eradicates mGluR1+ human tumors by harnessing a small-molecule alpha (α)-emitting radiopharmaceutical, 211At-AITM. A single dose of 211At-AITM (2.96 MBq) in mGluR1+ cancers exhibits long-lasting in vivo antitumor efficacy across seven subtypes of four of the most common tumors, namely, breast cancer, pancreatic cancer, melanoma, and colon cancers, with little toxicity. Moreover, complete regression of mGluR1+ breast cancer and pancreatic cancer is observed in approximate 50% of tumor-bearing mice. Mechanistically, the functions of 211At-AITM are uncovered in downregulating mGluR1 oncoprotein and inducing senescence of tumor cells with a reprogrammed senescence-associated secretory phenotype. Our findings suggest α-radiopharmaceutical therapy with 211At-AITM can be a useful strategy for mGluR1+ pan-cancers, regardless of their tissue of origin.

The relationship between Ki-67 expression and imaging signs and pathological features in GISTs.

Introduction: To investigate the correlations between the Ki-67 index and plain-scan computerized tomography (CT) signs and pathological features of gastrointestinal stromal tumor (GIST) tissue. Materials and methods: Data from 186 patients with GIST diagnosed by pathology and immunohistochemistry (IHC) in Peking University First Hospital from May 2016 to May 2022 were analyzed. The patients were divided into two groups: Ki-67 ≤5% and >5%. Correlation analysis, univariate and multivariate Logistic regression analysis were used to explore the correlations between CT signs, pathological features, and Ki-67 expression. Results: Univariate indicators correlated with the Ki-67 index were mitotic count, pathological grade, tumor hemorrhage, tumor necrosis, tumor size, and tumor density. Multivariate Logistic regression indicated that the mitotic count [odds ratio (OR) 10.222, 95% confidence interval (CI) 4.312-31.039], pathological grade (OR 2.139, 95% CI 1.397-3.350), and tumor size (OR 1.096, 95% CI 1.020-1.190) were independently associated with the Ki-67 expression level. The concordance indexes (C-index) for the pathological features and CT signs models were 0.876 (95% CI 0.822-0.929) and 0.697 (95% CI 0.620-0.774), respectively, with positive predictive values of 93.62% and 58.11% and negative predictive values of 81.29% and 75.89%, respectively. After internal verification by the Bootstrap method, the fitting degree of the pathological features model was found to be better than that of the CT signs model. Conclusion: Mitotic count, pathological risk grading, and tumor size are independent risk factors correlating with high Ki-67 index. These results indicate that the Ki-67 index reflects tumor malignancy and can predict recurrence and metastasis of GIST.

Evaluation and improvement of CuI-mediated 11 C-cyanation.

CuI-mediated 11 C-cyanation was evaluated by synthesizing [11 C]perampanel ([11 C]5) as a model compound and compared with previous reports. To a DMF solution with 5'-(2-bromophenyl)-1'-phenyl-[2,3'-bipyridin]-6'(1'H)-one (4) and CuI, [11 C]NH4 CN in a stream of ammonia/nitrogen (5:95, v/v) gas was bubbled. Subsequently, the reaction mixture was heated at 180°C for 5 min. After HPLC purification, [11 C]5 was obtained in 7.2 ± 1.0% (n = 4) non-decay corrected radiochemical yield with >99% radiochemical purity and a molar activity of 98 ± 28 GBq/µmol. In vivo evaluations of [11 C]5 were performed using small animals. PET scans to check the kinetics of [11 C]5 in the whole body of mice suggested that [11 C]5 spreads rapidly into the brain, heart, and lungs and then accumulates in the small intestine. To evaluate the performance of CuI-mediated 11 C-cyanation reaction, bromobenzene (6a) was selected as the model compound; however, it failed. Therefore, optimization of the reaction conditions has been performed, and consequently, the addition of K2 CO3 and prolonging the reaction time improved the radiochemical yield about double. With this improved method, CuI-mediated 11 C-cyanation of various (hetero)aromatic bromides was performed to exhibit the tolerance of most functional groups and to provide 11 C-cyanated products in good to moderate radiochemical yields.

Small-animal PET study for noninvasive quantification of transmembrane AMPA receptor regulatory protein γ-8 (TARP γ-8) in the brain.

Transmembrane AMPA receptor regulatory protein γ-8 (TARP γ-8) mediates various AMPA receptor functions. Recently, [11C]TARP-2105 was developed as a PET ligand for TARP γ-8 imaging. We performed a full kinetic analysis of [11C]TARP-2105 using PET with [11C]TARP-2105 for the first time. The distribution volume (VT), which is a macro parameter consisting of the K1-k4 rate constants in the two-tissue compartment model analysis, exhibited the following rank order: hippocampus (1.4 ± 0.3) > amygdala (1.0 ± 0.2) > frontal cortex (0.9 ± 0.2) > striatum (0.8 ± 0.2) ≫ cerebellum (0.5 ± 0.1) ≈ thalamus (0.5 ± 0.1) > pons (0.4 ± 0.1 mL/cm3). These heterogenous VT values corresponded with the order of biological distribution of TARP γ-8 in the brain. To validate the reference tissue model, the binding potential (BPND) of [11C]TARP-2105 for TARP γ-8 was estimated using general methods (SRTM, MRTM0, Logan reference model, and ratio method). These BPNDs based on reference models indicated excellent correlation (R2 > 0.9) to the indirect BPNDs based on 2TCM with moderate reproducibility (%variability ≈ 10). PET with [11C]TARP-2105 enabled noninvasive BPND estimation and visual mapping of TARP γ-8 in the living rat brain.

Neuropathology-Independent Association Between APOE Genotype and Cognitive Decline Rate in the Normal Aging-Early Alzheimer Continuum.

Background and Objectives: We previously found that the APOE genotype affects the rate of cognitive decline in mild-to-moderate Alzheimer disease (AD) dementia independently of its effects on AD neuropathologic changes (ADNC) and copathologies. In this study, we tested the hypothesis that the APOE alleles differentially affect the rate of cognitive decline at the normal aging-early AD continuum and that this association is independent of their effects on classical ADNC and copathologies. Methods: We analyzed APOE associations with the cognitive trajectories (Clinical Dementia Rating scale Sum of Boxes [CDR-SOB] and Mini-Mental State Examination [MMSE]) of more than 1,000 individuals from a national clinicopathologic sample who had either no, mild (sparse neuritic plaques and the Braak neurofibrillary tangle [NFT] stage I/II), or intermediate (moderate neuritic plaques and the Braak NFT stage III/IV) ADNC levels at autopsy via 2 latent classes reverse-time longitudinal modeling. Results: Carrying the APOEε4 allele was associated with a faster rate of cognitive decline by both CDR-SOB and MMSE relative to APOEε3 homozygotes. This association remained statistically significant after adjusting for ADNC severity, comorbid pathologies, and the effects of ADNC on the slope of cognitive decline. Our modeling strategy identified 2 latent classes in which APOEε4 carriers declined faster than APOEε3 homozygotes, with latent class 1 members representing slow decliners (CDR-SOB: 76.7% of individuals, 0.195 vs 0.146 points/y in APOEε4 vs APOEε3/ε3; MMSE: 88.6% of individuals, -0.303 vs -0.153 points/y in APOEε4 vs APOEε3/ε3), whereas latent class 2 members were fast decliners (CDR-SOB: 23.3% of participants, 1.536 vs 1.487 points/y in APOEε4 vs APOEε3/ε3; MMSE: 11.4% of participants, -2.538 vs -2.387 points/y in APOEε4 vs APOEε3/ε3). Compared with slow decliners, fast decliners were more likely to carry the APOEε4 allele, younger at initial visit and death, more impaired at initial and last visits, and more likely to have intermediate (vs none or mild) ADNC levels, as well as concurrent Lewy bodies and hippocampal sclerosis at autopsy. Discussion: In a large national sample selected to represent the normal aging-early AD continuum, the APOEε4 allele is associated with a modest but statistically significant acceleration of the cognitive decline rate even after controlling for its effects on ADNC and comorbid pathologies.

Characterization and diagnostic value of the gut microbial composition in patients with minimal change disease.

Background: Minimal change disease (MCD) is one of the most common causes of primary nephrotic syndrome with high morbidity. This study aimed to explore the typical alterations of gut microbiota in MCD and establish a non-invasive classifier using key gut microbiome. We also aimed to evaluate the therapeutic efficiency of gut microbiota intervention in MCD through animal experiments. Methods: A total of 222 stool samples were collected from MCD patients and healthy controls at the First Affiliated Hospital of Zhengzhou University and Shandong Provincial Hospital for 16S rRNA sequencing. Optimum operational taxonomic units (OTUs) were obtained for constructing a diagnostic model. MCD rat models were established using doxorubicin hydrochloride for exploring the therapeutic efficiency of gut microbial intervention through fecal microbiota transplantation (FMT). Results: The α-diversity of gut microbiota decreased in MCD patients when compared with healthy controls. The relative abundance of bacterial species also changed significantly. We constructed a diagnostic model based on eight optimal OTUs and it achieved efficiency of 97.81% in discovery cohort. The high efficiency of diagnostic model was also validated in the patients with different disease states and cross-regional cohorts. The treatment partially recovered the gut microbial dysbiosis in patients with MCD. In animal experiments, likewise, the gut microbiota changed sharply in MCD rats. However, gut microbial interventions did not reduce urinary protein or pathological kidney damage. Conclusion: Gut Microbiota shifts sharply in both patients and rats with MCD. Typical microbial changes can be used as biomarkers for MCD diagnosis. The gut microbiota compositions in patients with MCD tended to normalize after treatment. However, the intervention of gut microbiota seems to have no therapeutic effect on MCD.

Development and validation of diagnostic models for immunoglobulin A nephropathy based on gut microbes.

Background: Immunoglobulin A nephropathy (IgAN) is a highly prevalent glomerular disease. The diagnosis potential of the gut microbiome in IgAN has not been fully evaluated. Gut microbiota, serum metabolites, and clinical phenotype help to further deepen the understanding of IgAN. Patients and methods: Cohort studies were conducted in healthy controls (HC), patients of IgA nephropathy (IgAN) and non-IgA nephropathy (n_IgAN). We used 16S rRNA to measure bacterial flora and non-targeted analysis methods to measure metabolomics; we then compared the differences in the gut microbiota between each group. The random forest method was used to explore the non-invasive diagnostic value of the gut microbiome in IgAN. We also compared serum metabolites and analyzed their correlation with the gut microbiome. Results: The richness and diversity of gut microbiota were significantly different among IgAN, n_IgAN and HC patients. Using a random approach, we constructed the diagnosis model and analysed the differentiation between IgAN and n_IgAN based on gut microbiota. The area under the receiver operating characteristic curve for the diagnosis was 0.9899. The metabolic analysis showed that IgAN patients had significant metabolic differences compared with HCs. In IgAN, catechol, l-tryptophan, (1H-Indol-3-yl)-N-methylmethanamine, and pimelic acid were found to be enriched. In the correlation analysis, l-tryptophan, blood urea nitrogen and Eubacterium coprostanoligenes were positively correlated with each other. Conclusion: Our study demonstrated changes in the gut microbiota and established models for the non-invasive diagnosis of IgAN from HC and n_IgAN. We further demonstrated a close correlation between the gut flora, metabolites, and clinical phenotypes of IgAN. These findings provide further directions and clues in the study of the mechanism of IgAN.

Renal insufficiency predicts worse prognosis in newly diagnosed IgD multiple myeloma patients.

Objective: IgD multiple myeloma (MM) is a rare type of MM, accounting for about 1%-2% of all MMs. IgD MM always causes kidney damage and even leads to renal failure, which is the most common complication. This study aimed to explore the risk factors of renal damage and prognosis of IgD MM patients. Design: From March 2018 to November 2021, 85 patients with IgD MM diagnosed for the first time at the First Affiliated Hospital of Zhengzhou University were included in this study. We collected information on clinical features and laboratory examinations. Patients were divided into the renal impairment (RI) (47/85) and non-renal impairment (no-RI) (38/85) groups. Binary logistic regression was used to explore risk factors of renal damage. The Chi-square test was used to analyze the difference in chemotherapy effect between the two groups. We also analyzed whether early dialysis was beneficial to acute renal failure (RF) in IgD MM patients. Finally, Kaplan-Meier was used to compare the survival of the two groups. Results: In IgD MM, 55.3% of patients had renal damage as a complication, of which up to 59.6% presented with acute renal failure as the first manifestation. Serum ß2-microglobulin (ß2-MG) was an independent risk factor for renal damage in IgD MM (p = 0.002), but cytogenetic analysis suggested that it had no effect on patients' renal damage. There was also no significant difference in the effect of chemotherapy between the two groups (p = 0.255). In patients with acute renal failure, there was no significant difference between dialysis and no dialysis groups in the proportion of patients with improved renal function after treatment. The median overall survival (OS) of the RI group was significantly shorter than that of the no-RI group (p = 0.042). In the RI group, the median OS was 29 months, and in the no-RI group, the median OS was > 40 months. Conclusion: Elevated serum ß2-MG is an independent risk factor for renal damage. Compared with the no-RI group, patients in the RI group had poorer prognosis and shorter median OS. For patients with acute renal failure as the first manifestation, the treatment of primary disease is more meaningful than dialysis.