Comparison of Tumor Non-specific and PD-L1 Specific Imaging by Near-Infrared Fluorescence/Cerenkov Luminescence Dual-Modality In-situ Imaging.

Background: Labeled antibodies are excellent imaging agents in oncology to non-invasively visualize cancer-related antigens expression levels. However, tumor tracer uptake (TTU) of specific antibodies in-vivo may be inferior to non-specific IgG in some cases. Objectives: To explore factors affecting labeled antibody visualization by PD-L1 specific and non-specific imaging of nude mouse tumors. Methods: TTU was observed in RKO model on Cerenkov luminescence (CL) and near-infrared fluorescence (NIRF) imaging of radionuclide 131I or NIRF dyes labeled Atezolizumab and IgG. A mixture of NIRF dyes labeled Atezolizumab and 131I-labeled IgG was injected, and TTU was observed in the RKO and HCT8 model by NIRF/CL dual-modality in-situ imaging. TTU were observed by 131I-labeled Atezolizumab and IgG in-vitro distribution. Results: Labeled IgG concentrated more in tumors than Atezolizumab. NIRF/CL imaging in 24 to 168 h showed that TTU gradually decreased over time, which decreased more slowly on CL imaging compared to NIRF imaging. The distribution data in-vitro showed that TTU of 131I-labeled IgG was higher than that of 131I-labeled Atezolizumab at any time point. Conclusion: Non-specific IgG may not be suitable as a control for Atezolizumab in comparing tumor PD-L1 expression in nude mice via labeled antibody optical imaging under certain circumstances.

Accumulation and ecological risk assessment of diazinon in surface sediments of Baiyangdian lake and its potential impact on probiotics and pathogens.

Diazinon is an organophosphorus pesticide widely used in agriculture and household pest control, and its use also poses several environmental and health hazards. In this study, we investigated the spatial and temporal distribution of diazinon in Baiyangdian, evaluated its potential ecological risk and toxicity to aquatic organisms based on RQ (Risk quotient) and TU (Toxic unit) analysis, and assessed the potential effects of diazinon accumulation on probiotics and pathogens based on statistical analysis of high-throughput sequencing data. The results showed that diazinon in Baiyangdian posed a low to moderate chronic risk to sediment-dwelling organisms and a low toxicity effect on aquatic invertebrates, which was mainly concentrated in October and human-intensive areas. Meanwhile, increases in sediment electrical conductivity (EC), amorphous iron oxides content and phenol oxidase activity favored diazinon accumulation in sediments, whereas the opposite was the case for sediment organic carbon, ß-1,4-glucosidase, phosphatase, catalase and pH, suggesting that environmental indicators play a key role in the behavior and distribution of diazinon. In addition, diazinon in heavily contaminated areas seem to inhibit the rare probiotics (Bifidobacterium adolescentis and Serratia sp.), while promoted dominant pathogens (e.g., Burkholderia cenocepacia), which can lead to increased disease risk to humans and ecosystems, disruption of ecological balance and potential health problems. However, probiotic Streptomyces xiamenensis resist to diazinon would be a potential degrader for diazinon remove. In conclusion, this study unveiled the effects of diazinon pollution on wetland ecosystems, emphasizing ecological impacts and potential health concerns. In addition, the discovery of diazinon resistant probiotics provided new insights into wetland ecological restoration.

Distribution of organophosphorus pesticides and its potential connection with probiotics in sediments of a shallow freshwater lake.

Despite the serious health threats due to wide use of organophosphorus pesticides (OPPs) have been experimentally claimed to be remediated by probiotic microorganisms in various food and organism models, the interactions between OPPs and probiotics in the natural wetland ecosystem was rarely investigated. This study delves into the spatial and temporal distribution, contamination levels of OPPs in the Baiyangdian region, the diversity of probiotic communities in varying environmental contexts, and the potential connection with OPPs on these probiotics. In typical shallow lake wetland ecosystem-Baiyangdian lake in north China, eight OPPs were identified in the lake sediments, even though their detection rates were generally low. Malathion exhibited the highest average content among these pesticides (9.51 ng/g), followed by fenitrothion (6.70 ng/g). Conversely, chlorpyrifos had the lowest detection rate at only 2.14%. The region near Nanliu Zhuang (F10), significantly influenced by human activities, displayed the highest concentration of total OPPs (136.82 ng/g). A total of 145 probiotic species spanning 78 genera were identified in Baiyangdian sediments. Our analysis underscores the relations of environmental factors such as phosphatase activity, pH, and electrical conductivity (EC) with probiotic community. Notably, several high-abundance probiotics including Pseudomonas chlororaphis, Clostridium sp., Lactobacillus fermentum, and Pseudomonas putida, etc., which were reported to exhibit significant potential for the degradation of OPPs, showed strongly correlations with OPPs in the Baiyangdian lake sediments. The outcomes of this research offer valuable insights into the spatiotemporal dynamics of OPPs in natural large lake wetland and the probability of their in-situ residue bioremediation through the phosphatase pathway mediated by probiotic such as Lactic acid bacteria in soils/sediments contaminated with OPPs.

Pathogen profile of Baiyangdian Lake sediments using metagenomic analysis and their correlation with environmental factors.

Increasing concerns about public health and safety after covid-19 have raised pathogen studies, especially in aquatic environments. However, the extent to how different location and human activities affect geographic occurrence and distribution of pathogens in response to agricultural pollution, boat tourism disturbances and municipal wastewater inflow in a degraded lake remains unclear. Since the surrounding residents depend on the lake for their livelihood, understanding the pathogens reserved in lake sediment and the regulation possibility by environmental factors are challenges with far-reaching significance. Results showed that 187 pathogens were concurrently shared by the nine sediment samples, with Salmonella enterica and Pseudomonas aeruginosa being the most abundant. The similar composition of the pathogens suggests that lake sediment may act as reservoirs of generalist pathogens which may pose infection risk to a wide range of host species. Of the four virulence factors (VFs) types analyzed, offensive VFs were dominant (>46 % on average) in all samples, with dominant subtypes including adherence, secretion systems and toxins. Notably, the lake sediments under the impact of agricultural use (g1) showed significantly higher diversity and abundance of pathogen species and VFs than those under the impact of boat tourism (g2) and/or municipal wastewater inflow with reed marshes filtration (g3). From the co-occurrence networks, pathogens and pesticides, aggregate fractions, EC, pH, phosphatase have strong correlations. Strong positive correlations between pathogens and diazinon in g1 and ppDDT in g2 and g3 suggest higher pesticide-pathogen co-exposure risk. These findings highlight the need to explore pathogen - environmental factor interaction mechanisms in the human-impacted water environments where the control of pathogen invasion by environmental factors may accessible.

Performance of Rod-Shaped Ce Metal-Organic Frameworks for Defluoridation.

The performance of a Ce(III)-4,4',4″-((1,3,5-triazine-2,4,6-triyl) tris (azanediyl)) tribenzoic acid-organic framework (Ce-H3TATAB-MOFs) for capturing excess fluoride in aqueous solutions and its subsequent defluoridation was investigated in depth. The optimal sorption capacity was obtained with a metal/organic ligand molar ratio of 1:1. The morphological characteristics, crystalline shape, functional groups, and pore structure of the material were analyzed via SEM, XRD, FTIR, XPS, and N2 adsorption-desorption experiments, and the thermodynamics, kinetics, and adsorption mechanism were elucidated. The influence of pH and co-existing ions for defluoridation performance were also sought. The results show that Ce-H3TATAB-MOFs is a mesoporous material with good crystallinity, and that quasi-second kinetic and Langmuir models can describe the sorption kinetics and thermodynamics well, demonstrating that the entire sorption process is a monolayer-governed chemisorption. The Langmuir maximum sorption capacity was 129.7 mg g-1 at 318 K (pH = 4). The adsorption mechanism involves ligand exchange, electrostatic interaction, and surface complexation. The best removal effect was reached at pH 4, and a removal effectiveness of 76.57% was obtained under strongly alkaline conditions (pH 10), indicating that the adsorbent has a wide range of applications. Ionic interference experiments showed that the presence of PO43- and H2PO4- in water have an inhibitory effect on defluoridation, whereas SO42-, Cl-, CO32-, and NO3- are conducive to the adsorption of fluoride due to the ionic effect.

Ecological risk assessment of glyphosate and its possible effect on bacterial community in surface sediments of a typical shallow Lake, northern China.

Glyphosate is a widely used herbicide worldwide and its prevalent presence in aquatic ecosystems poses a threat to living organisms. This study evaluated potential ecological risk of glyphosate to sediment-dwelling organisms and assessed the probable effect of glyphosate on structure and predicated function of sediment-attached bacterial communities from a large shallow lake in northern China based on 16S rRNA high-throughput sequencing. Results suggested that glyphosate showed a medium to high concentration (up to 8.63 mg/kg) and chronic risk to sediment-dwelling organisms (10% samples exhibiting medium to high risk quotient), especially in sites nearby farmland and residential areas in August. Bacterial community identification based on 16S rRNA sequence indicated some species of dominant phylum Proteobacteria and Campilobacterota (e.g., Steroidobacteraceae, Thiobacillus, Gallionellaceae, Sulfurimonadaceae) were stimulated while some species of dominant phylum Actinobacteriota, Acidobacteriota and Firmicutes (e.g., Nocardioidaceae, Microtrichales, Vicinamibacteraceae, Paenisporosarcina) were inhibited by glyphosate accumulation. The stimulating species were related to sulfur-oxidizing, sulfate-, iron-, or nitrate-reducing bacteria; The inhibiting species were related to plant bacterial endophytes, polyphosphate-accumulating organisms (PAOs) and denitrifers. Correspondingly, promoted bacterial metabolic functions of "sulfite respiration", "nitrogen respiration", "aromatic compound degradation" and "nitrification" but suppressed "cellulolysis", "manganese oxidation", "anoxygenic photoautotrophy S oxidizing" and "nitrate denitrification" were predicated on functional annotation of prokaryotic taxa. Although these results could only partly suggest the impacts of glyphosate on the bacterial communities due to the lack of actual results from control experiments, the identified Steroidobacteraceae could be thought as a bioindicator in the future mechanism study for the ecological effect and bioremediation of glyphosate. This work intends to arise the concern about the depletion of biodiversity and bacterial metabolic functions with contribution of glyphosate in part in eutrophic lakes.

Radioimmunotherapy study of 131I-labeled Atezolizumab in preclinical models of colorectal cancer.

BACKGROUND: Programmed cell death 1 ligand 1(PD-L1) is overexpressed in many tumors. The radionuclide-labeled anti-PD-L1 monoclonal antibody can be used for imaging and therapy of PD-L1 overexpressing cancer. Here, we described 131I-labeled Atezolizumab (131I-Atezolizumab, targeting PD-L1) as a therapeutic agent for colorectal cancer with PD-L1 overexpression. METHODS: 131I-Atezolizumab was prepared by the Iodogen method. The expression levels of PD-L1 in different human colorectal cells were determined by flow cytometry, western blot and cell binding assay. The immunoreactivity of 131I-Atezolizumab to PD-L1 high-expressing cells was determined by immunoreactive fraction. The killing abilities of different concentrations of 131I-Atezolizumab on cells with high and low expression of PD-L1 were detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Cerenkov luminescence imaging (CLI) and radioimmunotherapy (RIT) of 131I-Atezolizumab were performed on two human colorectal cancer models. The distribution and tumor targeting of 131I-Atezolizumab were evaluated by imaging. Tumor volume and survival time were used as indicators to evaluate the anti-tumor effect of 131I-Atezolizumab. RESULTS: The expression level of PD-L1 in vitro determined by the cell binding assay was related to the data of flow cytometry and western blot. 131I-Atezolizumab can specifically bind to PD-L1 high-expressing cells in vitro to reflect the expression level of PD-L1. Immunoreactive fraction of PD-L1 high-expressing RKO cells with 131I-Atezolizumab was 52.2%. The killing ability of 131I-Atezolizumab on PD-L1 high-expressing cells was higher than that of low-expressing cells. CLI proved that the specific uptake level of tumors depends on the expression level of PD-L1. Effect of 131I-Atezolizumab RIT showed an activity-dependent tumor suppressor effect on RKO tumor-bearing mice with high PD-L1 expression. 131I-Atezolizumab (37 MBq) can improve the median survival time of mice (34 days), compared to untreated mice (27 days) (P = 0.027). Although a single activity(37 MBq) of 131I-Atezolizumab also inhibited the tumors of HCT8 tumor-bearing mice with low PD-L1 expression (P < 0.05), it could not prolong the survival of mice(P = 0.29). CONCLUSION: 131I-Atezolizumab can be used as a CLI agent for screening PD-L1 expression levels. It may be used as a radioimmunotherapy drug target for PD- L1 overexpressing tumors.

Application of Convolutional Neural Network in Motor Bearing Fault Diagnosis.

In the field of mechanical and electrical equipment, the motor rolling bearing is a workpiece that is extremely prone to damage and failure. However, the traditional fault diagnosis methods cannot keep up with the development pace of the times because they need complex manual pretreatment or the support of specific expert experience and knowledge. As a rising star, the data-driven fault diagnosis methods are increasingly favored by scholars and experts at home and abroad. The convolutional neural network has been widely used because of its powerful feature extraction ability for all kinds of complex information and its outstanding research results in image processing, target tracking, target diagnosis, time-frequency analysis, and other scenes. Therefore, this paper introduces a convolutional neural network and applies it to motor-bearing fault diagnosis. Aiming at the shortcomings of fault signal and convolutional neural network, a large-scale maximum pooling strategy is proposed and optimized by wavelet transform to improve the fault diagnosis efficiency of motor bearing under high-voltage operation. Compared with other machine learning algorithms, the convolution neural network fault diagnosis model constructed in this paper not only has high accuracy (up to 0.9871) and low error (only 0.032) but also is simple to use. It provides a new way for motor bearing fault diagnosis and has very important economic and social value.

MicroRNA-483-5p accentuates cisplatin-induced acute kidney injury by targeting GPX3.

The ability of cisplatin (cis-diamminedichloroplatinum II) toxicity to induce acute kidney injury (AKI) has attracted attention and concern for a long time, but the molecular mechanism of action for cisplatin is not clear. MicroRNA-483 is involved in several diseases, such as tumorigenesis and osteoarthritis, but its renal target and potential role in AKI are unknown. In this study, we explored the pathogenic role and underlying mechanism of miR-483-5p in cisplatin-induced AKI, using transgenic mice, clinical specimen, and in vitro cell line. We found that miR-483-5p was significantly upregulated by cisplatin in a cisplatin-induced mouse model, in serum samples of patients who received cisplatin therapy, and in NRK-52E cells. Overexpression of miR-483-5p in mouse kidneys by stereotactic renal injection of lentiviruses mediated miR-483-5p or generation of conditional miR-483-overexpressing transgenic mice accentuated cisplatin-induced AKI by increasing oxidative stress, promoting apoptosis, and inhibiting autophagy of tubular cells. Furthermore, our results revealed miR-483-5p directly targeted to GPX3, overexpression of which rescued cisplatin-induced AKI by inhibiting oxidative stress and apoptosis of tubular cells, but not by regulating autophagy. Collectively, miR-483-5p is upregulated by cisplatin and exacerbates cisplatin-induced AKI via negative regulation of GPX3 and contributing oxidative stress and tubular cell apoptosis. These findings reveal a pathogenic role for miR-483-5p in cisplatin-induced AKI and suggest a novel target for the diagnosis and treatment of AKI.

Metagenomics reveals biogeochemical processes carried out by sediment microbial communities in a shallow eutrophic freshwater lake.

Introduction: As the largest shallow freshwater lake in the North China Plain, Baiyangdian lake is essential for maintaining ecosystem functioning in this highly populated region. Sediments are considered to record the impacts of human activities. Methods: The abundance, diversity and metabolic pathways of microbial communities in sediments were studied by metagenomic approach to reveal patterns and mechanism of C, N, P and S cycling under the threat of lake eutrophication. Results: Many genera, with plural genes encoding key enzymes involved in genes, belonging to Proteobacteria and Actinobacteria which were the most main phylum in bacterial community of Baiyangdian sediment were involved in C, N, S, P cycling processes, such as Nocardioides (Actinobacteria), Thiobacillus, Nitrosomonas, Rhodoplanes and Sulfuricaulis (Proteobacteria).For instance, the abundance of Nocardioides were positively correlated to TN, EC, SOC and N/P ratio in pathways of phytase, regulation of phosphate starvation, dissimilatory sulfate reduction and oxidation, assimilatory sulfate reduction, assimilatory nitrate reduction and reductive tricarboxylic acid (rTCA) cycle. Many key genes in C, N, P, S cycling were closely related to the reductive citrate cycle. A complete while weaker sulfur cycle between SO4 2- and HS- might occur in Baiyangdian lake sediments compared to C fixation and N cycling. In addition, dissimilatory nitrate reduction to ammonia was determined to co-occur with denitrification. Methanogenesis was the main pathway of methane metabolism and the reductive citrate cycle was accounted for the highest proportion of C fixation processes. The abundance of pathways of assimilatory nitrate reduction, denitrification and dissimilatory nitrate reduction of nitrogen cycling in sediments with higher TN content was higher than those with lower TN content. Besides, Nocardioides with plural genes encoding key enzymes involved in nasAB and nirBD gene were involved in these pathways. Discussion: Nocardioides involved in the processes of assimilatory nitrate reduction, denitrification and dissimilatory nitrate reduction of nitrogen cycling may have important effects on nitrogen transformation.

3.0 T MRI IVIM-DWI for predicting the efficacy of neoadjuvant chemoradiation for locally advanced rectal cancer.

PURPOSE: The purpose of this study was to determine the diagnostic performance of intravoxel incoherent motion (IVIM) on assessing response to neoadjuvant chemoradiation (nCRT) in patients with Locally Advanced Rectal Cancer (LARC). METHODS: 50 patients with rectal cancer who underwent magnetic resonance (MR) imaging before and after nCRT, the values of pre-nCRT and post-nCRT IVIM-DWI parameters apparent diffusion coefficient (ADC), diffusion coefficient (D), false diffusion coefficient (D*), and perfusion fraction (f), together with the percentage changes (∆% parametric value) induced by nCRT were calculated. According to the patient's response to nCRT, the patients were divided into pathological complete response (pCR) and non-pCR groups, Good Response (GR) group and Poor Response (PR) group, and the above values were compared between different groups. Univariate and multiple logistic regression analysis were done to investigate the relation between different parameters and patient nCRT. Draw ROC curve according to sensitivity and specificity, and compare its diagnostic efficacy. RESULTS: There were no significant differences in the baseline data of 50 patients. After nCRT, the ADC and D values for LARC increased significantly (all p < 0.05). The pCR group (n = 9) had higher preD*, pref, postD*, ∆%ADC and ∆%D values than the non-pCR group (n = 41) (all p < 0.05). The GR group (n = 17) exhibited higher post D, ∆%ADC and ∆%D values than the PR group (n = 33) (all p < 0.05). From the results of Logistic regression analysis found that ∆%ADC and ∆%D were significantly correlated with patients' response to nCRT. Based on ROC analysis, ∆%D had a higher area under the curve value than ∆%ADC (p = 0.009) in discriminating the pCR from non-pCR groups. CONCLUSIONS: IVIM-DWI technology may be helpful in identifying the pCR and GR patients to nCRT for LARC.

Stronger network connectivity with lower diversity of soil fungal community was presented in coastal marshes after sixteen years of freshwater restoration.

Freshwater input for salt marsh restoration in the Yellow River Delta induced Phragmites australis expansion and thus may cause shifts of soil fungi from halophilic to desalination-adapted species for increased litter decomposition. In this study, soil fungal communities of restored and natural salt marshes were determined to reveal further details of shift in soil fungal community and its probable prediction for salt marsh restoration. Our results showed a stronger network within Ascomycota (e.g. Sordariales, Aspergillus, Hypocreales and Cladosporium herbarum) in restored marshes, but with a lower diversity of halophilic taxa (e.g. Chytridiomycota and Nematoda) in comparison with natural salt marshes. Contrarily, the occurrence of Chytridiomycota, Ichthyosporea and Discicristoidea in the soil fungal networks of the natural salt marsh emphasized the importance of salt tolerant species at the land-sea transition zone. The Sordariales was dominant and had a strong correlation with other fungal species and aggregate associated soil organic carbon (SOC), which probably contributed to SOC accumulation in restored marshes. But the reduced halophilic species specific to salt marsh elucidated that the formation of monospecific stands of P. australis along with the freshwater input induced desalination to the saline habitats changed the native patterns of vegetation and soil organisms. As the buffer between terrestrial and marine systems, a single habitat type such as dense monocultures of P. australis must be avoided and diverse saltmarsh habitats across a salinity gradient should be reserved. In this way, the diversity and specificity of coastal halophytes and related microorganisms could be maintained and thus might confer benefits in balancing various functions of the salt marsh ecosystem and preserving the system's elasticity and resistance to stress.

Cerenkov luminescence imaging is an effective preclinical tool for assessing colorectal cancer PD-L1 levels in vivo.

BACKGROUND: Preclinical and clinical studies have demonstrated that immunotherapy has effectively delayed tumor progression, and the clinical outcomes of anti-PD-1/PD-L1 therapy were related to PD-L1 expression level in the tumors. A 131I-labeled anti-PD-L1 monoclonal antibody tracer, 131I-PD-L1-Mab, was developed to study the target ability of noninvasive Cerenkov luminescence imaging in colorectal cancer xenograft mice. METHOD: Anti-PD-L1 monoclonal antibody labeled with 131I (131I-PD-L1-Mab), and in vitro binding assays were used to evaluate the affinity of 131I-PD-L1-Mab to PD-L1 and their binding level to different colorectal cancer cells, and compared with flow cytometry, Western blot analysis, and immunofluorescence staining. The clinical application value of 131I-PD-L1-Mab was evaluated through biodistribution and Cerenkov luminescence imaging, and different tumor-bearing models expressing PD-L1 were evaluated. RESULTS: 131I-PD-L1-Mab showed high affinity to PD-L1, and the equilibrium dissociation constant was 1.069 × 10-9 M. The competitive inhibition assay further confirmed the specific binding ability of 131I-PD-L1-Mab. In four different tumor-bearing models with different PD-L1 expression, the biodistribution and Cerenkov luminescence imaging showed that the RKO tumors demonstrated the highest uptake of the tracer 131I-PD-L1-Mab, with a maximum uptake of 1.613 ± 0.738% IA/g at 48 h. CONCLUSIONS: There is a great potential for 131I-PD-L1-Mab noninvasive Cerenkov luminescence imaging to assess the status of tumor PD-L1 expression and select patients for anti-PD-L1 targeted therapy.

[Expression of kinesin KIF3A in the kidney of mice with unilateral ureteral obstruction].

OBJECTIVE: To investigate the expression of KIF3A in mice with unilateral ureteral obstruction (UUO) and TGF-ß1-induced NRK-52E cells and the role of KIF3A in renal tubular epithelial cell transdifferentiation. METHODS: Thirty-six C57BL/6J mice were randomly divided into the sham group (n=18) and UUO group (n=18). Six mice in each group were sacrificed at 7, 14 and 21days after the operation. The degree of renal tubulointerstitial fibrosis of the mice was observed by HE staining, Masson trichrome staining and Sirius red staining. The expression and distribution of KIF3A in the kidney of the mice was detected using RT-PCR, Western blotting and immunohistochemistry. Western blotting was used to detect the expression of KIF3A, E-cadherin and α-SMA proteins in the renal tissue of the mice. The expressions of KIF3A, E-cadherin, α-SMA, Wnt4 and ß-catenin proteins in NRK-52E cells with TGF-ß1-induced transdifferentiation were detected by Western blotting. RESULTS: Compared with the sham-operated mice, the mice with UUO showed worsened renal interstitial fibrosis with the increase of obstruction time, indicating successful modeling. The expressions of KIF3A mRNA and protein increased progressively and reached the peaked level at 21 days after UUO. The expression of α-SMA protein was significantly increased while E-cadherin protein expression was significantly reduced after UUO. The transdifferentiated NRK-52E cells showed significantly increased expressions of KIF3A (P < 0.001), Wnt4 (P < 0.05) and ß-catenin proteins (P < 0.0001). CONCLUSIONS: KIF3A may participate in the development of renal fibrosis through epithelial-mesenchymal transition mediated by wnt/ß-catenin signaling pathway.

Retrospective analysis of the prognostic value of PD-L1 expression and 18F-FDG PET/CT metabolic parameters in colorectal cancer.

Background: It has been rarely reported whether 18F-fluorodeoxyglucose (18F-FDG) uptake in colorectal cancer cells is associated with the expression of PD-L1. We performed a clinical pathology study to evaluate PD-L1 expression in patients undergoing surgical resection of colorectal cancer with preoperative 18F-FDG PET/CT imaging, with the aim of predicting the response of CRC patients to immune checkpoint inhibitors. Material and Methods: A retrospective analysis of patients with CRC who underwent FDG-PET imaging before surgery was performed to measure the parameters of FDG-PET imaging: the maximum standardized uptake value (SUVmax), the metabolic tumor volume (MTV), and the total lesion glycolysis (TLG) were evaluated to determine whether each parameter was associated with clinical pathology. Tumor specimens were subjected to PD-L1 staining by immunohistochemistry. Analysis of whether there is a correlation between PD-L1 expression and 18F-FDG uptake parameters in CRC. Results: PD-L1 expression level was significantly correlated with SUVmax, MTV3.0 and TLG3.0. Multivariate analysis showed that PD-L1 and TLG3.0 were independent predictors of poor DFS in patients with CRC (P=0.009; P=0.016), PD-L1 expression is closely related to the patient's lesion (TLG3.0) (P<0.01). Conclusion: The results of this study indicate that there was a significant correlation between PD-L1 expression and TLG3.0 which suggested that FDG-PET could serve as a noninvasive tool to assess the tumor microenvironment and as a predictor of PD-L1 inhibitor activity to determine the optimal therapeutic strategy for CRC. High PD-L1 expression levels and high TLG3.0 are independent risk factors for DFS differences in CRC patients.

LDL-C plays a causal role on T2DM: a Mendelian randomization analysis.

Diabetic dyslipidemia is a common condition in patients with Type 2 diabetes mellitus (T2DM). However, with the increasing application of statins which mainly decrease low-density lipoprotein cholesterol (LDL-C) levels, clinical trials and meta-analysis showed a clearly increase of the incidence of new-onset DMs, partly due to genetic factors. To determine whether a causal relationship exists between LDL-C and T2DM, we conducted a two-sample Mendelian Randomization (MR) analysis using genetic variations as instrumental variables (IVs). Initially, 29 SNPs significantly related to LDL-C (P≤ 5.0×10-8) were selected as based on results from the study of Henry et al, which processed loci data influencing lipids identified by the Global Lipids Genetics Consortium (GLGC) from 188,577 individuals of European ancestry. While 6 SNPs related to T2DM (P value < 5×10-2) were deleted, with the remaining 23 SNPs without LD eventually being deemed as IVs. The combined effect of all these 23 SNPs on T2DM, as generated with use of the penalized robust inverse-variance weighted (IVW) method (Beta value 0.24, 95%CI 0.087~0.393, P-value=0.002) demonstrated that elevated LDL-C levels significantly increased the risk of T2DM. The relationship between LDL-C and Type 1 diabetes mellitus (T1DM) with this analysis producing negative pooled results (Beta value -0.202, 95%CI -2.888~2.484, P-value=0.883).

Evaluation of [18F]FDG/[18F]FLT/[18F]FMISO-based micro-positron emission tomography in detection of liver metastasis in human colorectal cancer.

INTRODUCTION: Positron emission tomography (PET) is extensively used in clinical oncology for tumor detection. This study aimed to explore the application of the radiotracers [18F]fluorodeoxyglucose ([18F]FDG), 3'-deoxy-3'- [18F]fluorothymidine ([18F]FLT), and [18F]fluoromisonidazole ([18F]FMISO) in the diagnosis and monitoring of hepatic metastasis in human colorectal cancer (CRC). METHODS: A mouse model of human CRC with hepatic metastasis was established by intrasplenic implantation of human CRC cell lines LoVo or HCT8. Metastatic potential of these two cell lines was evaluated by wound healing assay in vitro and survival analysis. Uptake of radiotracers between LoVo and HCT8 cells and uptake of radiotracers in the resulting mouse tumor models were examined by in vivo and in vitro experiments. Uptake of each radiotracer in hepatic metastatic lesions was quantified and expressed as standard uptake value (SUV). Protein expression of multiple tumor biomarkers was determined in metastatic lesions. The correlation between tracer uptake and tumor marker expression was evaluated using linear regression. RESULTS: LoVo cells exhibited a stronger metastatic potential and a higher radiotracer uptake ability than HCT8 cells, as evidenced by significantly greater wound closure percentage, shorter survival, higher incidence of liver metastases, and higher cellular radiotracer levels in LoVo cells or LoVo cell-xenografted mice. SUV values of [18F]FLT and [18F]FMISO, but not [18F]FDG, in LoVo cell-derived metastatic lesions were significantly greater than those in HCT8 lesions. Mechanistically, the expression of MACC1, HIF-1α, and GLUT-1(metastasis associated in colon cancer 1, MACC1; hypoxia-inducible factor 1-alpha, HIF-1α; and glucose transporter 1, GLUT-1, respectively) in LoVo cell-derived metastatic lesions was more effectively induced than in HCT8-derived ones. A linear regression analysis demonstrated significant positive correlations between [18F]FLT/[18F]FMISO uptake and tumor biomarker expression in metastatic tissues. CONCLUSIONS: [18F]FLT and [18F]FMISO-based PET imaging may serve as a promising method for early detection and monitoring of hepatic metastasis in patients with CRC.

18F-fluoromisonidazole positron emission tomography may be applicable in the evaluation of colorectal cancer liver metastasis.

BACKGROUND: Positron emission tomography (PET) imaging is a non-invasive functional imaging method used to reflect tumor spatial information, and to provide biological characteristics of tumor progression. The aim of this study was to focus on the application of 18F-fluoromisonidazole (FMISO) PET quantitative parameter of maximum standardized uptake value (SUVmax) ratio to detect the liver metastatic potential of human colorectal cancer (CRC) in mice. METHODS: Colorectal liver metastases (CRLM) xenograft models were established by injecting tumor cells (LoVo, HT29 and HCT116) into spleen of mice, tumor-bearing xenograft models were established by subcutaneously injecting tumor cells in the right left flank of mice. Wound healing assays were performed to examine the ability of cell migration in vitro. 18F-FMISO uptake in CRC cell lines was measured by cellular uptake assay. 18F-FMISO-based micro-PET imaging of CRLM and tumor-bearing mice was performed and quantified by tumor-to-liver SUVmax ratio. The correlation between the 18F-FMISO SUVmax ratio, liver metastases number, hypoxia-induced factor 1α (HIF-1α) and serum starvation-induced glucose transporter 1 (GLUT-1) was evaluated using Pearson correlation analysis. RESULTS: Compared with HT29 and HCT116, LoVo-CRLM mice had significantly higher liver metastases ratio and shorter median survival time. LoVo cells exhibited stronger migration capacity and higher radiotracer uptake compared with HT29 and HCT116 in in vitro. Moreover, 18F-FMISO SUVmax ratio was significantly higher in both LoVo-CRLM model and LoVo-bearing tumor model compared to models established using HT29 and HCT116. In addition, Pearson correlation analysis revealed a significant correlation between 18F-FMISO SUVmax ratio of CRLM mice and number of liver metastases larger than 0.5 cm, as well as between 18F-FMISO SUVmax ratio and HIF-1α or GLUT-1 expression in tumor-bearing tissues. CONCLUSIONS: 18F-FMISO parameter of SUVmax ratio may provide useful tumor biological information in mice with CRLM, thus allowing for better prediction of CRLM and yielding useful radioactive markers for predicting liver metastasis potential in CRC.