Pre-therapy PET-based voxel-wise dosimetry prediction by characterizing intra-organ heterogeneity in PSMA-directed radiopharmaceutical theranostics.

BACKGROUND AND OBJECTIVE: Treatment planning through the diagnostic dimension of theranostics provides insights into predicting the absorbed dose of RPT, with the potential to individualize radiation doses for enhancing treatment efficacy. However, existing studies focusing on dose prediction from diagnostic data often rely on organ-level estimations, overlooking intra-organ variations. This study aims to characterize the intra-organ theranostic heterogeneity and utilize artificial intelligence techniques to localize them, i.e. to predict voxel-wise absorbed dose map based on pre-therapy PET. METHODS: 23 patients with metastatic castration-resistant prostate cancer treated with [177Lu]Lu-PSMA I&T RPT were retrospectively included. 48 treatment cycles with pre-treatment PET imaging and at least 3 post-therapeutic SPECT/CT imaging were selected. The distribution of PET tracer and RPT dose was compared for kidney, liver and spleen, characterizing intra-organ heterogeneity differences. Pharmacokinetic simulations were performed to enhance the understanding of the correlation. Two strategies were explored for pre-therapy voxel-wise dosimetry prediction: (1) organ-dose guided direct projection; (2) deep learning (DL)-based distribution prediction. Physical metrics, dose volume histogram (DVH) analysis, and identity plots were applied to investigate the predicted absorbed dose map. RESULTS: Inconsistent intra-organ patterns emerged between PET imaging and dose map, with moderate correlations existing in the kidney (r = 0.77), liver (r = 0.5), and spleen (r = 0.58) (P < 0.025). Simulation results indicated the intra-organ pharmacokinetic heterogeneity might explain this inconsistency. The DL-based method achieved a lower average voxel-wise normalized root mean squared error of 0.79 ± 0.27%, regarding to ground-truth dose map, outperforming the organ-dose guided projection (1.11 ± 0.57%) (P < 0.05). DVH analysis demonstrated good prediction accuracy (R2 = 0.92 for kidney). The DL model improved the mean slope of fitting lines in identity plots (199% for liver), when compared to the theoretical optimal results of the organ-dose approach. CONCLUSION: Our results demonstrated the intra-organ heterogeneity of pharmacokinetics may complicate pre-therapy dosimetry prediction. DL has the potential to bridge this gap for pre-therapy prediction of voxel-wise heterogeneous dose map.

Effects of high-quality protein supplementation on cardiovascular risk factors in individuals with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Uncertainties still existed about the effect of high-quality protein supplementation on cardiovascular disease (CVD) risk factors, although high-quality proteins such as soy and milk proteins have proposed to be beneficial for cardiometabolic health. METHODS: A systematic search in PubMed, Web of Science, Cochrane Library, Scopus, and Embase was conducted to quantify the impact of high-quality protein on CVD risk factors. RESULTS: 63 RCTs on 4 types of high-quality protein including soy protein, milk protein, whey, and casein were evaluated. Soy protein supplementation decreased systolic blood pressure (SBP, -1.42 [-2.68, -0.17] mmHg), total cholesterol (TC, -0.18 [-0.30, -0.07] mmol/L), and low-density lipoprotein cholesterol (LDL-C, -0.16 [-0.27, -0.05] mmol/L). Milk protein supplementation decreased SBP (-2.30 [-3.45, -1.15] mmHg) and total cholesterol (-0.27 [-0.51, -0.03] mmol/L). Whey supplementation decreased SBP (-2.20 [-3.89, -0.51] mmHg), diastolic blood pressure (DBP, -1.07 [-1.98, -0.16] mmHg), triglycerides (-0.10 [-0.17, -0.03] mmol/L), TC (-0.18 [-0.35, -0.01] mmol/L), LDL-C (-0.09 [-0.16, -0.01] mmol/L) and fasting blood insulin (FBI, -2.02 [-3.75, -0.29] pmol/L). Casein supplementation decreased SBP (-4.10 [-8.05, -0.14] mmHg). In the pooled analysis of four high-quality proteins, differential effects were seen in individuals with different health status. In hypertensive individuals, high-quality proteins decreased both SBP (-2.69 [-3.50, -1.87] mmHg) and DBP (-1.34 [-2.09, -0.60] mmHg). In overweight/obese individuals, high-quality proteins improved SBP (-1.40 [-2.22, -0.59] mmHg), DBP (-2.59 [-3.20, -1.98] mmHg), triglycerides (-0.09 [-0.15, -0.02] mmol/L), TC (-0.14 [-0.22, -0.05] mmol/L), LDL-C (-0.12 [-0.16, -0.07] mmol/L), and HDL-C levels (0.02 [0.01, 0.04] mmol/L). According to the benefits on CVD risks factors, whey ranked top for improving cardiometabolic health in hypertensive or overweight/obese individuals. CONCLUSION: Our study supports a beneficial role of high-quality protein supplementation to reduce CVD risk factors. Further studies are still warranted to investigate the effects of different high-quality proteins on CVD risks in individuals with cardiometabolic disorders.

Evolutionary Dynamics Optimal Research-Oriented Tumor Immunity Architecture.

The article is devoted to evolutionary dynamics optimal control-oriented tumor immune differential game system. First, the mathematical model covering immune cells and tumor cells considering the effects of chemotherapy drugs and immune agents. Second, the bounded optimal control problem covering is transformed into solving Hamilton-Jacobi-Bellman (HJB) equation considering the actual constraints and infinite-horizon performance index based on minimizing the amount of medication administered. Finally, approximate optimal control strategy is acquired through iterative-dual heuristic dynamic programming (I-DHP) algorithm avoiding dimensional disaster effectively and providing optimal treatment scheme for clinical applications.

Higher Adherence to the AMED, DASH, and CHFP Dietary Patterns Is Associated with Better Cognition among Chinese Middle-Aged and Elderly Adults.

The available evidence regarding the association between adherence to the Alternate Mediterranean Diet (AMED) and Dietary Approaches to Stop Hypertension (DASH) dietary patterns and cognitive performance exhibits inconsistency, and its applicability within the Asian population remains uncertain. The association between adherence to the Chinese Food Pagoda (CHFP) and cognitive function is also unknown. In this study, we aimed to assess the association between adherence to the AMED, DASH, and CHFP different dietary patterns and cognitive function. The study included 3353 Chinese adults aged 55 years and over from the China Health and Nutrition Survey (CHNS) in 2006. A 24 h dietary recall over three consecutive days was used to collect dietary information. Dietary patterns included AMED, DASH, and CHFP. A subset of items from the Telephone Interview for Cognitive Status-Modified was used for cognitive screening. Poor cognitive performance was defined as a global cognitive function score < 7. Binary logistic regression was used to estimate the association between adherence to the three different dietary patterns and cognitive function. Binary logistic regression analysis showed that there is a negative association between higher adherence to the AMED, DASH, and CHFP and poorer cognitive performance (AMED: OR = 0.594, 95% CI = 0.458-0.771, p < 0.001; DASH: OR = 0.652, 95% CI = 0.504-0.843, p = 0.001; CHFP: OR = 0.599, 95% CI = 0.417-0.861, p = 0.006). There was a significant interaction between each of the three dietary patterns and residential regions (AMED: p for interaction = 0.045; DASH: p for interaction = 0.003; CHFP: p for interaction < 0.001). Higher adherence to the AMED, DASH, and CHFP dietary patterns was inversely associated with poor cognition in Chinese middle-aged and elderly adults, particularly among urban residents.

Accumulation of formaldehyde causes motor deficits in an in vivo model of hindlimb unloading.

During duration spaceflight, or after their return to earth, astronauts have often suffered from gait instability and cerebellar ataxia. Here, we use a mouse model of hindlimb unloading (HU) to explore a mechanism of how reduced hindlimb burden may contribute to motor deficits. The results showed that these mice which have experienced HU for 2 weeks exhibit a rapid accumulation of formaldehyde in the gastrocnemius muscle and fastigial nucleus of cerebellum. The activation of semicarbazide-sensitive amine oxidase and sarcosine dehydrogenase induced by HU-stress contributed to formaldehyde generation and loss of the abilities to maintain balance and coordinate motor activities. Further, knockout of formaldehyde dehydrogenase (FDH-/-) in mice caused formaldehyde accumulation in the muscle and cerebellum that was associated with motor deficits. Remarkably, formaldehyde injection into the gastrocnemius muscle led to gait instability; especially, microinfusion of formaldehyde into the fastigial nucleus directly induced the same symptoms as HU-induced acute ataxia. Hence, excessive formaldehyde damages motor functions of the muscle and cerebellum.

Aberrant expression of miR-214 is associated with obesity-induced insulin resistance as a biomarker and therapeutic.

BACKGROUND: Insulin resistance (IR) in obesity is associated with the occurrence of metabolic and cardiovascular diseases. Dipepidyl peptidase 4 (DPP4) plays a pivotal role during the development of IR, and was found to be a target gene of microRNA-214 (miR-214) in our study. This study sought to assess the expression and clinical value of miR-214 in obese patients with IR, and investigate its therapeutic potential in obese rats and adipocytes with IR. METHODS: Serum expression of miR-214 in obese patients with or without IR was estimated by quantitative real-time-PCR. A receiver operating characteristic curve was plotted to evaluate the diagnostic value of miR-214 in the patients. Obesity-induced IR animal and cell models were constructed, and the therapeutic ability of miR-214 was explored. RESULTS: Serum expression of miR-214 was decreased in obese patients compared with the healthy controls, and the lowest expression was observed in the cases with IR. Downregulation of miR-214 was significantly correlated with the serum DPP4 levels and HOMA-IR of the patients upon IR conditions, and was demonstrated to perform diagnostic accuracy for distinguishing obese patients with IR from those without IR. In obesity-associated IR animal and cell models, the downregulation of miR-214 was also been detected. According to the measurement of glucose and insulin tolerance and glucose uptake abilities, we found that the overexpression of miR-214 could be used to alleviate IR in the IR models, especially when collaboratively used with DPP4 inhibitor vildagliptin. CONCLUSION: All data revealed that miR-214, as a regulator of DPP4, is decreased in obese patients with IR and may serve as a diagnostic biomarker. The upregulation of miR-214 could improve IR in obese rats and adipocytes, indicating that miR-214 has the therapeutic potential for obesity and IR.

Dysregulation of DPP4 Is Associated with the AMPK/JAK2/STAT3 Pathway in Adipocytes Under Insulin Resistance Status and Liraglutide Intervention.

PURPOSE: Dipeptidyl peptidase 4 (DPP4) is one of the newly identified adipokines, which acts as paracrine in adipose tissue and as endocrine hormones in the liver, muscles and central nervous system. Expression of DPP4 was significantly upregulated in obese patients upon insulin resistance (IR) conditions, but the mechanism underlying the dysregulation of DPP4 remains unclear. This study aimed to investigate the DPP4 expression in adipose tissue and adipocytes under IR conditions or with liraglutide intervention, and explore the potential molecular mechanisms. METHODS: Obesity-associated IR animal and cell models were, respectively, constructed by using high-fat diet and palmitic acid (PA) stimulation. Expression of DPP4 in adipose tissues and adipocytes was estimated by quantitative real-time RT-PCR and Western-blot. Effects of the AMPK/JAK2/STAT3 pathway on DPP4 were examined by regulating the activity of AMPK and the JAK2/STAT signaling. The therapeutic efficacy of liraglutide in the IR models was evaluated, and its regulatory effects on DPP4 expression and the underlying molecular mechanisms were explored. RESULTS: The expression of DPP4 was markedly upregulated in both the animal and cell IR models. In the adipocyte, DPP4 expression was found to be suppressed by the activation of AMPK, and this inhibition effect was mediated by the JAK2/STAT3 signaling. Moreover, liraglutide could alleviate the obesity-induced IR, and led to the downregulation of DPP4 in IR animal and cell models. Liraglutide intervention resulted in the activation of AMPK and deactivation of the JAK2/STAT3 signaling in the adipocytes. CONCLUSION: Taken together, the expression of DPP4 is upregulated in adipose tissues and adipocytes upon IR conditions, but is reduced after liraglutide intervention. The dysregulation of DPP4 in the adipocytes may be performed by the AMPK/JAK2/STAT3 pathway.

Association of IL-16 gene polymorphisms with the risk of developing type 2 diabetes mellitus in the Chinese Han population.

Objective: The aim of the present study was to explore the genetic association of single nucleotide polymorphisms (SNPs) in interleukin-16 (IL-16) gene with type 2 diabetes mellitus (T2DM) susceptibility in a Chinese Han population.Methods: In total, 133 T2DM patients and 127 healthy controls matched by age and gender were recruited in the case-control study. IL-16 gene rs4778889 and rs11556218 polymorphisms were genotyped in the two groups via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Differences in genotype and allele distributions between groups were compared by the χ2 test. All the comparisons were adjusted for age, gender, and body mass index (BMI) by logistic regression. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the association strength between IL-16 gene polymorphism and T2DM risk.Results: The TG genotype and G allele frequencies of rs11556218 increased remarkably in the case group than that in controls (45.86 vs 33.86%; 29.70 vs 20.87%), and the differences reached a significant level (P<0.05). After adjusting for age, gender, and BMI, the differences still reached a significant level (P<0.05). Rs11556218 TG genotype carriers had a 1.769-fold increased risk of developing T2DM (OR = 1.769, 95% CI = 1.045-2.994), and G allele was also associated with an increased risk of T2DM (OR = 1.639, 95% CI = 1.087-2.471). IL-16 rs4778889 polymorphism showed no significant association with T2DM risk.Conclusion:IL-16 gene rs11556218 polymorphism was significantly associated with T2DM susceptibility in the Chinese Han population, while rs4778889 was not.

Mast Cell and M1 Macrophage Infiltration and Local Pro-Inflammatory Factors Were Attenuated with Incretin-Based Therapies in Obesity-Related Glomerulopathy.

BACKGROUND: The global increase of obesity parallels the obesity-related glomerulopathy (ORG) epidemic. Dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 receptor agonists were well recognized to attenuate renal injury independent of glucose control in diabetic nephropathy. There are limited studies focusing on their effects on ORG. We explored the effects of incretin-based therapies on early ORG and the inflammatory responses involved mainly concentrated on mast cell (MC) and macrophage (M) infiltration and local pro-inflammatory factors. METHODS: ORG rat models were induced by high-fat diet and then divided into ORG vehicle, vildagliptin (3 mg/kg/day, qd) and liraglutide (200 µg/kg, bid) treated groups. After 8 weeks of treatments, albuminuria, glomerular histology, renal inflammatory cell infiltration, and pro-inflammatory factors were analyzed. RESULTS: Early ORG model was demonstrated by albuminuria, glomerulomegaly, foot process fusion, and mesangial and endothelial mild proliferation. Incretin-based therapies limited body weight gain and improved insulin sensitivity. ORG was alleviated, manifested by decreased average glomerular area, attenuated mesangial and endothelial cell proliferation, and revived cell-to-cell propagation of podocytes, which contributed to reduced albuminuria. Compared with ORG vehicle, MC and M1 macrophage (pro-inflammatory) infiltration and M1/M2 ratio were significantly decreased; M2 macrophage (anti-inflammatory) was not significantly increased after incretin-based treatments. Tumor necrosis factor-α (TNF-α) and IL-6 in renal cortex were significantly downregulated, while transforming growth factor-ß1 (TGF-ß1) remained unchanged. CONCLUSIONS: Incretin-based treatments could alleviate high-fat diet-induced ORG partly through the systemic insulin sensitivity improvement and the attenuated local inflammation, mainly by the decrease of MC and M1 macrophage infiltration and reduction of TNF-α and IL-6.