Cerebral 18F-FDG PET/CT Metabolism as Diagnostic Signature for Central Nervous System Toxicity After Immune Checkpoint Blockade Cancer Treatment.

Our aim was to investigate probable biomarkers specific to immune-related central nervous system toxicity (CNST) in cancer patients treated with immune checkpoint inhibitors (ICI) by analysis of 18F-FDG PET/CT images. Methods: Cancer patients receiving ICI treatment were enrolled in a multicenter observational study that analyzed regional metabolic changes before and during CNST onset from January 2020 to February 2022. In 1:1 propensity score-matched pairs, the regional SUVmean of each bilateral brain lobe of CNST patients (CNST+) was compared with that of patients who had central nervous system infections (CNSIs) and patients without CNST or CNSI (CNST-). In a validation cohort, patients were recruited from February 2022 to July 2023 and followed up for 24 wk after the start of ICI. Early changes in regional SUVmean at 5-6 wk after therapy initiation were evaluated for ability to predict later CNST onset. Results: Of 6,395 ICI-treated patients, 2,387 underwent prognostic 18F-FDG PET/CT and 125 of the scanned patients had CNST (median time from ICI treatment to onset, 9 wk; quartile range, 2-23 wk). Regional 18F-FDG PET/CT SUVmean changes were higher in CNST+ than in CNST- patients (117 patient pairs) but were lower than in CNSI patients (50 pairs). Differentiating analysis reached an area under the curve (AUC) of 0.83 (95% CI, 0.78-0.88) for CNST+ versus CNST- and of 0.80 (95% CI, 0.72-0.89) for CNST+ versus CNSI. Changes in SUVmean were also higher before CNST onset than for CNST- (60 pairs; AUC, 0.74; 95% CI, 0.66-0.83). In a validation cohort of 2,878 patients, preonset changes in SUVmean reached an AUC of 0.86 (95% CI, 0.79-0.94) in predicting later CNST incidence. Conclusion: Brain regional hypermetabolism could be detected during and before CNST clinical onset. CNST may be a distinct pathologic entity versus brain infections defined by 18F-FDG PET/CT brain scans. Regional SUV differences may be translated into early diagnostic tools based on moderate differentiating accuracy in our study.

Adropin attenuates pancreatitis­associated lung injury through PPARγ phosphorylation­related macrophage polarization.

Acute pancreatitis (AP)­associated lung injury (ALI) is a critical complication of AP. Adropin is a regulatory protein of immune metabolism. The present study aimed to explore the immunomodulatory effects of adropin on AP­ALI. For this purpose, serum samples of patients with AP were collected and the expression levels of serum adropin were detected using ELISA. Animal models of AP and adropin knockout (Adro­KO) were constructed, and adropin expression in serum and lung tissues was investigated. The levels of fibrosis and apoptosis were evaluated using hematoxylin and eosin staining, Masson's staining and immunohistochemistry of in lung tissue. M1/M2 type macrophages in the lungs were detected using immunofluorescence staining, western blot analysis and reverse transcription­quantitative PCR. As shown by the results, adropin expression was decreased in AP. In the Adro­KO + L­arginine (L­Arg) group, macrophage infiltration, fibrosis and apoptosis were increased. The expression of peroxisome proliferator­ activated receptor γ (PPARγ) was downregulated, and the macrophages exhibited a trend towards M1 polarization in the Adro­KO + L­Arg group. Adropin exogenous supplement attenuated the levels of fibrosis and apoptosis in the model of AP. Adropin exogenous supplement also increased PPARγ expression by the regulation of the phosphorylation levels, which was associated with M2 macrophage polarization. On the whole, the findings of the present study suggest that adropin promotes the M2 polarization of lung macrophages and reduces the severity of AP­ALI by regulating the function of PPARγ through the regulation of its phosphorylation level.

Multi-omics Analysis Reveals the Crucial Mediators of DJB in the Treatment of Type 2 Diabetes.

PURPOSE: Duodenal-jejunal bypass (DJB) has a definite hypoglycemic effect; however, the intrinsic mechanisms remain unclear. The purpose of this study was to determine whether DJB may cause changes in the gut microbiota and metabolite of portal venous blood and to explore the effects of DJB on blood glucose metabolism. METHODS: T2DM was induced in rats with a high-fat diet and a low dose of streptozotocin, which were randomly divided into two groups: Sham operation and DJB. RESULTS: DJB significantly improved several diabetic parameters. 16S rRNA analyses showed that the compositions of the gut microbiota were significantly different between the two groups. The results of metabolomics showed that DJB could significantly regulate the metabolites, among which diaminopimelic acid and isovaleric acid had a significant down-regulation in the DJB group. Transcriptomic analysis showed that DJB can regulate the expression of hepatic genes related to abnormal glucose metabolism, such as Ltc4s, Alox15, Ggt1, Gpat3, and Cyp2c24. Correlation analyses showed that diaminopimelic acid was positively associated with Allobaculum, Serratia, and Turicibacter. There was a significant correlation between diaminopimelic acid and Gpat3, and its Spearman correlation coefficient was the highest among metabolite-DEG pairs (ρ=0.97). DISCUSSIONS: These results suggest an important cue of the relation between the diaminopimelic acid, Gpat3, and gut microbiome in the mechanism by which DJB can improve glucose metabolism.

Immune disguise: the mechanisms of Neu5Gc inducing autoimmune and transplant rejection.

Organ (stem cell) transplantation is the most effective treatment for advanced organ failure. Neu5Gc (N-hydroxyacetylneuraminic acid) is a pathogenic non-human sialic acid, which is very similar to the molecular structure of Neu5Ac (N-acetylneuraminic acid) in human body. Neu5Gc has the function of "immune disguise", which is the main obstacle to transplantation. Gene knockout such as cytidine monophosphate-N-acetylneuraminidase (CMAH) reduces donor antigenicity, making xenotransplantation from fiction to reality. Exploring the immune disguise event in this emerging field has become a hot topic in the research of transplantation immune tolerance mechanism.

Use of the Advanced Lung Cancer Inflammation Index as a Prognostic Indicator for Patients With Cholangiocarcinoma.

BACKGROUND: This study aimed to assess the clinical utility of the advanced lung cancer inflammation index (ALI) as a prognostic indicator for patients with cholangiocarcinoma (CCA) and construct a prognostic nomogram based on ALI. METHODS: A total of 97 CCA patients who received radical resection were included. The optimal cut-off point for ALI was identified by X-tile analysis. COX regression analysis were used to identify risk factors of overall survival (OS) and disease-free survival (DFS). A predictive nomogram for DFS was constructed. RESULTS: The optimal cut-off value for preoperative ALI was 31.8. 35 (36.1%) patients were categorized into the low-ALI group and 62 (63.9%) patients into the high-ALI group. Low ALI was independently associated with hypoproteinemia and lower body mass index (BMI) (all P < 0.05). COX regression analysis revealed that preoperative ALI level (HR = 0.974, P = 0.037) and pathological TNM stage (HR = 7.331, P < 0.001) were independently correlated with OS for patients with CCA, and preoperative ALI level (HR = 0.978, P = 0.042) and pathological T stage (HR = 1.473, P = 0.035) remained to be independent prognostic factors for DFS in CCA patients. Using time-dependent ROC analysis, we found that ALI was better at predicting prognosis than other parameters, such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and prognostic nutritional index (PNI) in terms of OS and DFS. A nomogram predicting DFS was built (C-index: 0.73 95%CI: 0.67-0.79). CONCLUSIONS: ALI may be useful for prognosis assessment for patients with CCA.

Methylation of CALCA and CALCB in Pancreatic Ductal Adenocarcinoma.

Calcitonin gene-related peptide (CGRP) plays a diverse and intricate role in chronic low-grade inflammation and is closely related to specific cancers. It includes two subtypes, CALCA (αCGRP) and CALCB (ßCGRP), of which αCGRP expression accounts for more than 90%. Here, we show that methylation of CALCA and CALCB in pancreatic ductal adenocarcinoma was significantly higher than that in paracancer. Western blot and immunohistochemistry showed that CGRP, p-AKT, and p-CREB in the tumor tissues were lower than those in the paracarcinoma tissues. In vivo, the expressions of p-AKT and p-CREB in the pancreatic tissues of CALCA-KO rats were also lower than those of wild type. Methylation of CALCA and CALCB is increased in pancreatic adenocarcinoma, and under that condition, p-AKT and p-CREB levels were decreased.

DDIT4 Novel Mutations in Pancreatic Cancer.

Pancreatic cancer is one of the most common malignancies worldwide. This study is aimed at searching the possible genetic mutations and the value of novel gene mutation in the DNA damage-inducible transcript 4 (DDIT4) and signaling pathway in pancreatic cancer. Polymerase chain reaction (PCR) was performed to amplify the DNA sequences of DDIT4 from patients with pancreatic ductal adenocarcinoma. In addition, we used IHC to detect the expression level of DDIT4 in patients with pancreatic cancer in different types of gene mutation. Double-labeled immunofluorescence was employed to explore the expression levels of DDIT4/LC3 and their potential correlation. Our work indicated the two novel stable gene mutations in DDIT4 mRNA 3'-untranslated region (m.990 U>A and m.1246 C>U). Thirteen samples were found to have mutation in the DDIT4 3'-untranslated regions (UTR). To further verify the influence of gene mutation on protein expression, we performed immunohistochemistry on different gene mutation types, and we found a correlation between DDIT4 expression and gene mutation, which is accompanied by nuclear staining deepening. In order to further discuss the clinical value of DDIT4 gene mutation, immunofluorescence suggested that the expression of DDIT4 colocated with LC3; thus, we speculated that DDIT4 mutation may be involved in autophagy in pancreatic cancer cell. In this study, we found mutation in the 3'-UTR region of DDIT4, which may be associated with DDIT4 expression and tumor autophagy in pancreatic cancer tissues.

A review of the mechanism of DDIT4 serve as a mitochondrial related protein in tumor regulation.

DDIT4 is a mitochondrial and tumor-related protein involved in anti-tumor therapy resistance, proliferation, and invasion, etc. Its expression level increases under the stress such as chemotherapy, hypoxia, and DNA damage. A number of clinical studies have confirmed that DDIT4 can change the behavior of tumor cells and the prognosis of patients with cancer. However, the role of DDIT4 in promoting or suppressing cancer is still inconclusive. This article summarized the four characteristics of DDIT4 including a mitochondria-related protein, interactions with various protein molecules, immune and metabolic cell related proteins and participator in the oxygen sensing pathway, which may be related to the progress of cancer.

PRSS1 genotype is associated with prognosis in patients with pancreatic ductal adenocarcinoma.

The prognostic value of the genotype of the PRSS1 gene in patients with pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. The aim of the present study was to evaluate the association between the PRSS1 genotype and clinicopathological characteristics of patients with PDAC, as well as to explore the prognostic significance of the PRSS1 genotype in patients with PDAC. A total of 124 patients with PDAC patients were included in the current study and the PRSS1 genotype of the enrolled patients was determined by the polymerase chain reaction. Associations between the PRSS1 genotype and clinicopathological characteristics were subsequently analyzed using the Chi-square test. The impact of the PRSS1 genotype on patient prognosis was assessed using the Kaplan-Meier method, and predictive factors of overall survival (OS) time were analyzed by Cox regression. A total of 56 patients with PDAC (45.16%) had the T/C PRSS1 genotype, which was associated with large tumor sizes (P=0.027) and higher tumor node metastasis (TNM) stages (P=0.041). Following a median follow-up of 19 months, the T/C genotype of PRSS1 genotype was associated with a shorter OS time (P=0.037) compared with the C/C or T/T PRSS1 genotypes. Univariate and multivariate analyses revealed that PRSS1 genotype was identified to be an independent prognostic factor for the OS time of patients with PDAC. The results obtained in the current study suggested that the PRSS1 genotype, as well as factors such as the serum level of carbohydrate antigen 19-9 and the TNM stage, may act as independent prognostic factors for the OS time of patients with PDAC.