Structural changes in the retina and serum HMGB1 levels are associated with decreased cognitive function in patients with Parkinson's disease.

BACKGROUND: Cognitive impairment is a serious nonmotor symptom in patients with Parkinson's disease (PD). Currently, there are few studies investigating the relationship of serum markers and retinal structural changes with cognitive function in PD. OBJECTIVE: To investigate the relationship between retinal structural changes, serum high mobility group box-1 (HMGB1) levels and cognitive function and motor symptoms in PD patients. METHODS: Eighty-nine participants, including 47 PD patients and 42 healthy subjects, were enrolled. PD patients were divided into Parkinson's disease with normal cognitive (PD-NC), Parkinson's disease with mild cognitive impairment (PD-MCI), and Parkinson's disease with dementia (PDD) groups. The motor and nonmotor symptoms of PD patients were evaluated with clinical scale. Serum HMGB1 levels were detected by enzyme-linked immunosorbent assay (ELISA), and ganglion cell-inner plexiform layer complex (GCIPL) thickness changes in the macula were quantitatively analyzed by swept source optical coherence tomography (SS-OCT) in all patients. RESULTS: Compared with the control group, the macular GCIPL (t = -2.308, P = 0.023) was thinner and serum HMGB1 (z = -2.285, P = 0.022) was increased in PD patients. Macular GCIPL thickness in patients with PD-MCI and PDD were significantly lower than that in PD-NC patients, but there were no significant difference between the PD-MCI and PDD groups. Serum HMGB1 levels in patients with PD-MCI and PDD were significantly higher than those in PD-NC patients, and serum HMGB1 levels in PDD patients were higher than those in PD-MCI patients. Correlation analysis showed that serum HMGB1 levels in PD patients were positively correlated with disease duration, HY stage, UPDRS-I score, UPDRS-III score, and UPDRS total score and negatively correlated with MOCA score. Macular GCIPL thickness was negatively correlated with HY stage and positively correlated with MOCA score, and macular GCIPL thickness was negatively correlated with serum HMGB1 level. Logistic regression analysis showed that elevated serum HMGB1 level, thinner macular GCIPL thickness, and higher HY stage were independent risk factors for Parkinson's disease with cognitive impairment (PD-CI). The areas under the receiver operating characteristic curve (AUC) for the serum HMGB1 level and macular GCIPL thickness-based diagnosis of PD-MCI, PDD and PD-CI based on in patients with PD were 0.786 and 0.825, 0.915 and 0.856, 0.852 and 0.841, respectively. The AUC for the diagnosis of PD-MCI, PDD and PD-CI with serum HMGB1 level and GCIPL thickness combined were 0.869, 0.967 and 0.916, respectively. CONCLUSION: The macular GCIPL thickness and serum HMGB1 level are potential markers of cognitive impairment in PD patients, and their combination can significantly improve the accuracy of the diagnosis of cognitive impairment in PD.

Clinical findings of hyperechoic substantia nigra in patients with Parkinson's disease.

This study aims to analyse hyperechoic substantia nigra (HSN) characteristics and the correlation of HSN with clinical features and blood biomarkers in patients with Parkinson's disease (PD). Transcranial sonography (TCS) evaluations of the substantia nigra (SN) were performed in 40 healthy controls and 71 patients with PD, including patients with SN hyperechogenicity (SN+) and those with normal SN echogenicity (SN-). Evaluation of motor and non-motor symptoms was assessed by a series of rating scales. The uricase method was used to determine serum uric acid (UA) levels, and enzyme-linked immunosorbent assay (ELISA) was used to measure plasma interleukin (IL)-1ß levels. TCS showed 92.50% specificity and 61.97% sensitivity in differentiating PD patients from controls. The area of SN+ contralateral to the side of initial motor symptoms (SNcontra) was larger than that ipsilateral to the side of initial motor symptoms (SNipsi). The PDSN+ group had lower Argentine Hyposmia Rating Scale (AHRS) scores and UA levels than the PDSN- group. Binary logistic regression analysis revealed that AHRS scores and UA levels could be independent predictors for HSN. The larger SN echogenic area (SNL) sizes positively correlated with plasma IL-1ß levels in PD patients with SN+. The present study provides further evidence of the potential of SN echogenicity as an imaging biomarker for PD diagnosis. PD patients with HSN have more severe non-motor symptoms of hyposmia. HSN in PD patients is related to the mechanism of abnormal iron metabolism and microglial activation.

Increased plasma lipocalin-2 levels are associated with nonmotor symptoms and neuroimaging features in patients with Parkinson's disease.

Lipocalin-2 (LCN2) is essential for the regulation of neuroinflammation and cellular uptake of iron. This study aimed to evaluate plasma LCN2 levels and explore their correlation with clinical and neuroimaging features in Parkinson's disease (PD) patients. Enzyme-linked immunosorbent assay (ELISA) was used to measure plasma LCN2 levels in 120 subjects. Evaluation of motor symptoms and nonmotor symptoms in PD patients was assessed by the associated scales. Voxel-based morphometry (VBM) was used to evaluate brain volume alterations, and quantitative susceptibility mapping (QSM) was used to quantitatively analyze brain iron deposition in 46 PD patients. Plasma LCN2 levels were significantly higher in PD patients than those in healthy controls. LCN2 levels were negatively correlated with Montreal Cognitive Assessment (MoCA) scores, total brain gray matter volume (GMV), and GMV/total intracranial volume (TIV) ratio, but positively correlated with Hamilton Anxiety Rating Scale (HAMD) scores and mean QSM values of the bilateral substantial nigra (SN). Receiver operating characteristic (ROC) curves confirmed that plasma LCN2 levels had good predictive accuracy for PD. The results suggest that plasma LCN2 levels have potential as a biomarker for the diagnosis of PD. LCN2 may be a therapeutic target for neuroinflammation and brain iron deposition.

Diagnostic value of plasma SIRT1 levels and whole-brain gray matter volume in Parkinson's disease patients with cognitive impairment.

OBJECTIVE: This study was designed to investigate the diagnostic value of plasma SIRT1 levels and whole-brain gray matter (GM) volume in Parkinson's disease (PD) patients with cognitive impairment. METHODS: Automated enzymatic analysis was performed to measure plasma SIRT1 levels in 80 healthy controls and 77 PD patients. Motor symptoms and nonmotor symptoms in PD patients were assessed using the corresponding scales. A Siemens MAGNETOM Prisma 3 T MRI scanner was used to acquire images in 35 of 77 PD patients. RESULTS: Plasma SIRT1 levels in PD patients were lower than those in healthy controls. Plasma SIRT1 levels were negatively correlated with the age, Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) scores, anxiety, depression, excessive daytime sleepiness (EDS), quality of life, and especially cognitive impairment. Thus, it showed that plasma SIRT1 levels were relevant to visuospatial/executive function, memory, and language. Receiver-operating characteristic (ROC) analysis confirmed that plasma SIRT1 levels had good diagnostic accuracy for PD with anxiety and EDS. Furthermore, plasma SIRT1 levels had a significant positive correlation with GM volume in the whole brain, and ROC analysis confirmed that plasma SIRT1 levels and the total GM volume had good diagnostic accuracy for PD with cognitive impairment. CONCLUSIONS: This study showed that plasma SIRT1 levels were correlated with the nonmotor symptoms of anxiety, depression, EDS, and especially cognitive impairment as well as the total GM volume. Furthermore, the combination of plasma SIRT1 levels and the total GM volume had good diagnostic accuracy for PD with cognitive impairment.

STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging.

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT). Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.

NAD+ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition.

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.

Predictors of dopamine dysregulation syndrome in patients with early Parkinson's disease.

BACKGROUND: Dopamine dysregulation syndrome (DDS) is a complication of Parkinson's disease (PD) that seriously affects the quality of life of PD patients. Currently, the risk factors for DDS are poorly known, and it is critical to identify them in the early stages of PD. OBJECTIVE: To explore the incidence of and risk factors for DDS in patients with early PD. METHODS: A retrospective cohort study was conducted on the general data, clinical features, and imaging data of patients with early PD in the PPMI database. Multivariate Cox regression analysis was performed to analyze the risk factors for the development of DDS in patients with early PD, and Kaplan‒Meier curves examined the frequency and predictors of incident DDS symptoms. RESULTS: At baseline, 2.2% (n = 6) of patients with early PD developed DDS, and the cumulative incidence rates of DDS during the 5-year follow-up period were 2.8%, 6.4%, 10.8%, 15.5%, and 18.7%, respectively. In the multivariate Cox regression model controlling for age, sex, and drug use, hypersexuality (HR = 3.088; 95% CI: 1.416~6.732; P = 0.005), compulsive eating (HR = 3.299; 95% CI: 1.665~6.534; P = 0.001), compulsive shopping (HR = 3.899; 95% CI: 1.769~8.593; P = 0.001), anxiety (HR = 4.018; 95% CI: 2.136~7.599; P < 0.01), and lower Hoehn-Yahr (H-Y) stage (HR = 0.278; 95% CI: 0.152~0.509; P < 0.01) were independent risk factors for DDS in patients with early PD. PD patients with DDS had lower DAT uptake values than those patients without DDS. CONCLUSION: Early PD patients with hypersexuality, compulsive eating, compulsive shopping, anxiety, and lower H-Y stage were at increased risk for DDS. The occurrence of DDS may be related to the decrease in the average DAT uptake of the caudate and putamen.

Determination of Afatinib in Human Plasma by 2-Dimensional Liquid Chromatography.

INTRODUCTION: A simple, sensitive, rapid, and practical 2-dimensional liquid chromatography (2D-LC) method was developed and validated for the quantification of a 500-µL afatinib sample extracted from human plasma. METHODS: The plasma samples were pretreated with acetonitrile for protein precipitation. The mobile phase consisted of a first-dimensional mobile phase (acetonitrile, methanol, and 25 mmol/L ammonium phosphate in a ratio of 25:25:50, V/V/V) and a second-dimensional mobile phase (acetonitrile and 10 mmol/L ammonium phosphate in a ratio of 25:75, V/V). The average recovery of the plasma samples was stable and reproducible (98.56%-100.02%). RESULTS: The analyte was sufficiently stable for handling and analysis. The calibration curve was linear, ranging from 10.93 to 277.25 ng/mL with regression equation y = 804.60 x - 4,169.87 (R2 = 0.999). The relative standard deviations for accuracy and precision studies were within ±2.30% and <3.41%, respectively (intra- and interday). Finally, the validated method was successfully employed to determine the drug levels in plasma from the patients treated with afatinib. In clinical assessment, the patients with gastric cancer were orally administered with 30 or 40 mg per day of afatinib, which resulted in large plasma concentrations, ranging from 5.52 to 45.16 ng/mL. CONCLUSION: The results indicated that this method was useful for the therapeutic drug monitoring of afatinib and suitable for the assessment of the risks and benefits of chemotherapy in patients with non-small cell lung cancer.

Identification of dissociation factors in pancreatic Cancer using a mass spectrometry-based proteomic approach.

BACKGROUD: Pancreatic cancer is a highly malignant tumor of the digestive system. This secretome of pancreatic cancer is key to its progression and metastasis. But different methods of protein extraction affect the final results. In other words, the real secretion of proteins in cancer cells has been changed. Based on mass spectrometry, we analyze the secretome from the serum-containing and serum-free medium, using different protein pretreatment methods. This study aims to identify dissociation factors in pancreatic cancer. METHODS: In this study, pancreatic cancer cells were cultured in serum-containing or serum-free medium, and the corresponding supernatants were extracted as samples. Subsequently, the above samples were separated by size exclusion chromatography (SEC), and peptide segments were identified by LC-MS/MS. The final results were identified via the hamster secreted protein database and a public database. RESULTS: Although the number of identified proteins in the serum-free medium group was high, the real secretion of proteins in pancreatic cancer cells was changed. There were six significant secreted proteins in the serum-containing medium group. Survival analysis via the TCGA database suggested that patients with higher expression levels of YWHAG showed a worse overall survival rate than those with lower YWHAG expression. CONCLUSIONS: Our study demonstrated the results in the serum-containing medium group were more similar to the real secretome of pancreatic cancer cells. YWHAG could be used as a prognostic indicator for pancreatic cancer.

Remote Ischemic Post-Conditioning may Improve Post-Stroke Cognitive Impairment: A Pilot Single Center Randomized Controlled Trial.

BACKGROUND AND PURPOSE: We aimed to demonstrate the tolerability and feasibility and the effect of remote ischemic post-conditioning on cognitive functioning in patients with post-stroke cognitive impairment. METHODS: This was a single-center, randomized, outcome-blinded, placebo-controlled trial, randomized 1:1 to receive 4 cycles of remote ischemic post-conditioning or a sham procedure for 7 days. The primary outcome measure was tolerability and feasibility of remote ischemic post-conditioning. Secondary outcomes to measure the neurological function with national institute of health stroke scale and the cognitive impairment with Montreal Cognitive Assessment scale and Alzheimer's disease assessment scale-cognitive (at baseline, 90 days, 180 days). RESULTS: 48 patients (24 RIPC and 24 Control) were recruited. remote ischemic post-conditioning was well tolerated with 90 out of 96 cycles completed in full. 4 patients experienced vascular events in the control group: 3 cerebrovascular and 1 cardiovascular event versus only 2 cerebrovascular events in the RIPC group. We showed the similar result in the neurological function with national institute of health stroke scale score with no statistically significant differences between RIPC and control group at baseline (P = 0.796) and 90 days (P = 0.401) and 180 days (P = 0.695). But compare with baseline, it was significantly difference in the control and RIPC group at 90 days (P < 0.05) and 180 days (P < 0.05). The comparison of Montreal Cognitive Assessment scale between two groups both showed that P > 0.05 at baseline which was no statistical difference, but P < 0.05 at 90 days and 180 days which were significant statistical difference. The comparison of Alzheimer's disease assessment scale-cognitive between two groups showed that P > 0.05 at baseline (P = 0.955) and 90 days (P = 0.138) was no statistical difference, but P = 0.005<0.05 at 180 days was significant statistical difference. CONCLUSIONS: The remote ischemic post-conditioning for post-stroke cognitive impairment was well tolerated, safe and feasible. The remote ischemic post-conditioning may improve neurological and cognitive outcomes in patients with post-stroke cognitive impairment. A larger trial is warranted. (Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: ChiCTR1800015231.).

Upper Limb Ischemic Postconditioning as Adjunct Therapy in Acute Stroke Patients: A Randomized Pilot.

OBJECTIVE: This study aims to observe the clinical effect of upper limb ischemic postconditioning (LIPostC) as an adjunct to treatment with acute stroke patients, possibly due to increased cerebral perfusion. METHODS: We perform a randomized blinded placebo controlled trial in nonthrombolysis patients with acute ischemic stroke, within 72hours of ictus, divided into the LIPostC group and control group. The LIPostC group is induced by 4 cycles of intermittent repeated limb ischemia: alternating 5 minutes inflation (20mm Hg above systolic blood pressure) and 5 minutes deflation performed manually using a standard upper arm blood pressure cuff in the nonparetic arm. The control group receives a sham procedure (cuff inflation to 30mm Hg). Patients underwent the intervention from the time of enrollment to Day 14. Comparison of National Institutes of Health Stroke Scale (NIHSS) score, cerebral infarction volume, relative Perfusion weighted imaging (PWI) parameters (regional relative cerebral blood flow, regional relative mean transit time; preintervention [day 0], day 14, day 90), modified Rankin Scale (mRS; the preintervention score [day 0], the curative ratio at day 90 [we define 0-1 score as close to recovery or full recovery]). RESULTS: Sixty eligible patients with acute stroke (29 LIPostC and 31 control) are recruited age 65years (SD 12.22), blood pressure 156/74mm Hg (SD 14/10), and NIHSS score 5.98 (SD 3.35), mRS score 2.25 (SD .79). Only 1 in the LIPostC group is intolerant the first cycle to give up. All patients tolerate the sham procedure. Two patients experience recurrent stroke versus none in the LIPostC group. Day 90, compared with the control group, there is a significant decrease the NIHSS score, regional relative mean transit time (P < .05) and increase the curative ratio of mRS, regional relative cerebral blood flow(P < .05) in the LIPostC group, which infarct volume decreased by 31.3% (P < .05). CONCLUSIONS: LIPostC after acute stroke is well tolerated and appears safe and feasible. LIPostC may improve neurological outcome, and protective mechanisms may be increased cerebral blood flow to improve cerebral perfusion. A larger trial is warranted.

Risk factors of central lymph node metastasis in cN0 papillary thyroid carcinoma: a study of 529 patients.

BACKGROUND: Lymph node metastasis in papillary thyroid carcinoma (PTC) is common; however, the need for prophylactic central lymph node dissection (CLND) in PTC is still controversial. The objective of this study was to investigate the risk factors of central lymph node metastasis (CLNM) in clinically lymph node-negative (cN0) PTC patients. MATERIAL AND METHODS: A total of 529 cN0 PTC patients who underwent lobectomy plus isthmusectomy or total thyroidectomy with unilateral or bilateral CLND between 2010 and 2012 were enrolled in this study. Clinicopathologic risk factors for CLNM were studied using univariate and multivariate analysis. RESULTS: CLNM was found in 238 (45.0%) cases. In univariate analysis, male sex, age <45 years, tumor size >2 cm, tumor located in the middle/lower third of lobe, and multifocality were significantly associated with CLNM (P<0.05); extrathyroid extension, Hashimoto's thyroiditis, and TSH value were not associated with CLNM. In multivariate analysis, tumor size >2 cm, age <45 years, multifocality, and tumor located in the middle/lower third of the lobe were independent predictors for CLNM. CONCLUSIONS: Prophylactic CLND should be considered in cN0 PTC patients with the following risk factors: tumor size >2 cm, age <45 years, multifocality, or tumor located in the middle/lower third of the lobe. However, further long-term follow-up studies and multicenter research are needed to better understand these risk factors and the significance of prophylactic CLND.

Artificial intelligence to predict T4 stage of pancreatic ductal adenocarcinoma using CT imaging.

BACKGROUND: The accurate assessment of T4 stage of pancreatic ductal adenocarcinoma (PDAC) has consistently presented a considerable difficulty for radiologists. This study aimed to develop and validate an automated artificial intelligence (AI) pipeline for the prediction of T4 stage of PDAC using contrast-enhanced CT imaging. METHODS: The data were obtained retrospectively from consecutive patients with surgically resected and pathologically proved PDAC at two institutions between July 2017 and June 2022. Initially, a deep learning (DL) model was developed to segment PDAC. Subsequently, radiomics features were extracted from the automatically segmented region of interest (ROI), which encompassed both the tumor region and a 3 mm surrounding area, to construct a predictive model for determining T4 stage of PDAC. The assessment of the models' performance involved the calculation of the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. RESULTS: The study encompassed a cohort of 509 PDAC patients, with a median age of 62 years (interquartile range: 55-67). The proportion of patients in T4 stage within the model was 16.9%. The model achieved an AUC of 0.849 (95% CI: 0.753-0.940), a sensitivity of 0.875, and a specificity of 0.728 in predicting T4 stage of PDAC. The performance of the model was determined to be comparable to that of two experienced abdominal radiologists (AUCs: 0.849 vs. 0.834 and 0.857). CONCLUSION: The automated AI pipeline utilizing tumor and peritumor-related radiomics features demonstrated comparable performance to that of senior abdominal radiologists in predicting T4 stage of PDAC.

A comparison of computed tomography imaging with histopathology in the sensitivity and correlation of evaluating coronary arterial calcification.

Background: The sensitivity and correlation of coronary computed tomography angiography (CTA) as compared with histopathology are unknown in evaluating coronary arterial calcification. In this study, we retrospectively evaluated qualitatively and quantitatively the sensitivity and correlation of coronary CTA compared with histopathology in assessing coronary arterial calcification. Methods: This study was conducted on 12 randomly selected cadavers aged over 40 years at the time of death, and 53 segments of coronary arteries from these 12 cadavers were obtained from the Human Anatomy Laboratory of Tianjin Medical University. The artery segments were scanned using contrasted-enhanced dual-source computed tomography (DSCT) with an axial slice thickness of 0.6 mm. Coronary artery calcification in a coronary segment was defined as the presence of 1 or more voxels with a CT density >130 Hounsfield units. According to the arc of calcification in the cross section of the coronary artery wall, calcified plaques were divided into three categories: mild, moderate, and severe calcification. The coronary artery stenosis caused by calcified plaque was observed and calculated with multiplanar reconstruction (MPR), maximum density projection, volume rendering (VR), and cross-sectional reconstruction. After CT enhancement scanning, the coronary artery specimens were cut into 4-mm long segments and embedded in paraffin for pathological staining. Pathological classification and coronary artery stenosis measured with pathological analysis were used as comparison criteria. Results: Histopathology detected 69 Vb-type plaques, while DSCT detected 57 calcified plaques. The sensitivity of CT for detecting mild, moderate, and severe calcified plaques were 88.3% [95% confidence interval (CI): 74.1-95.6%], 100% (95% CI: 69.8-100%), and 100% (95% CI: 73.2-100%), respectively. DSCT had a significant (P<0.001) correlation with histopathology in quantifying coronary artery stenosis caused by mild, moderate, and severe calcified plaques (R2=0.9278, R2=0.9158, R2=0.7923, respectively). Compared with histopathology, DSCT overestimated coronary artery stenosis caused by mild, moderate, and severe calcified plaques (3.2%±2.0%, 4.9%±4.7%, and 14.7%±8.2%, respectively; P<0.05). Conclusions: DSCT contrast enhancement scanning can detect and characterize coronary artery calcification with a good correlation with histopathologic quantification of coronary artery stenosis caused by different types of calcified plaques, even though coronary CTA may overestimate the stenosis.

Associations of blood UCH-L1 and NfL levels with cognitive dysfunction in Parkinson's disease patients.

OBJECTIVE: Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and Neurofilament light chain (NfL) are associated with Lewy body formation, Lewy bodies are the main pathological feature of Parkinson's disease (PD). The relationship between UCH-L1 and PD cognition remains unclear, and NfL is an important marker of cognitive impairment. The aim of this study is to investigate the relationship among serum UCH-L1 levels, plasma NfL levels and cognitive dysfunction in PD patients. RESULTS: There were significant differences in UCH-L1 and NfL levels among PD patients with normal cognitive function (PD-CN), PD patients with mild cognitive impairment (PD-MCI), and PD-dementia patients (PDD) (P < 0.001; P < 0.001). The PDD group had lower levels of UCH-L1 (Z = 6.721, P < 0.001; Z = 7.577, P < 0.001) and higher levels of NfL (Z = -3.626, P = 0.001; Z = -2.616P = 0.027) than the PD-NC and PD-MCI groups. Serum UCH-L1 levels were positively correlated with MMSE scores, MoCA scores, and its subitems in PD patients (P < 0.001), and plasma NfL levels were negatively correlated with MMSE scores, MoCA scores, and its items (P < 0.01) (except for "abstract"). CONCLUSION: Decreased UCH-L1 levels and elevated NfL levels in the blood are associated with cognitive dysfunction in PD; thus, these proteins are potential biomarkers for the diagnosis of cognitive dysfunction in PD patients.

MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell-intrinsic Amplification of Type I IFN Signaling.

PURPOSE: Stimulator of interferon genes (STING) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest, and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor cell-intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity. EXPERIMENTAL DESIGN: We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo. RESULTS: We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce type I IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB activation. CONCLUSIONS: Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.

18F-FDG PET Visualizes Systemic STING Agonist-Induced Lymphocyte Activation in Preclinical Models.

Stimulator of interferon genes (STING) is a mediator of immune recognition of cytosolic DNA, which plays important roles in cancer, cytotoxic therapies, and infections with certain pathogens. Although pharmacologic STING activation stimulates potent antitumor immune responses in animal models, clinically applicable pharmacodynamic biomarkers that inform of the magnitude, duration, and location of immune activation elicited by systemic STING agonists are yet to be described. We investigated whether systemic STING activation induces metabolic alterations in immune cells that can be visualized by PET imaging. Methods: C57BL/6 mice were treated with systemic STING agonists and imaged with 18F-FDG PET after 24 h. Splenocytes were harvested 6 h after STING agonist administration and analyzed by single-cell RNA sequencing and flow cytometry. 18F-FDG uptake in total splenocytes and immunomagnetically enriched splenic B and T lymphocytes from STING agonist-treated mice was measured by γ-counting. In mice bearing prostate or pancreas cancer tumors, the effects of STING agonist treatment on 18F-FDG uptake, T-lymphocyte activation marker levels, and tumor growth were evaluated. Results: Systemic delivery of structurally distinct STING agonists in mice significantly increased 18F-FDG uptake in the spleen. The average spleen SUVmax in control mice was 1.90 (range, 1.56-2.34), compared with 4.55 (range, 3.35-6.20) in STING agonist-treated mice (P < 0.0001). Single-cell transcriptional and flow cytometry analyses of immune cells from systemic STING agonist-treated mice revealed enrichment of a glycolytic transcriptional signature in both T and B lymphocytes that correlated with the induction of immune cell activation markers. In tumor-bearing mice, STING agonist administration significantly delayed tumor growth and increased 18F-FDG uptake in secondary lymphoid organs. Conclusion: These findings reveal hitherto unknown functional links between STING signaling and immunometabolism and suggest that 18F-FDG PET may provide a widely applicable approach toward measuring the pharmacodynamic effects of systemic STING agonists at a whole-body level and guiding their clinical development.

[Effects of Angelicae Sinensis Radix on cAMP/Epac signaling pathway in the treatment of chronically infected cough mice with Yin deficiency syndrome].

OBJECTIVE: To investigate the effects of Angelicae Sinensis Radix (ASR) on cyclic adenosine monophosphate (cAMP) /exchange protein activated by cAMP (Epac) signaling pathway in the treatment of chronically infected cough mice with Yin deficiency syndrome. METHODS: Mice were randomly divided into blank control group, model control group, positive control group and ASR group (n=8). The chronic cough mouse model of hyperreactive and infected airway with Yin deficiency syndrome was established with fumigation (once a day, 30 days in total), lipopolysaccharide nasal drip (every 3 days 10 µl, 10 times in total), intragastric administration of thyroid gland (120 mg/kg, once a day, a total of 15 days) and inhalation of ammonia (3 min / time × 10 times). On the basis of observing eating and drinking water, body weight and autonomic activities, the effects of ASR on metabolic level, autonomous activities, antitussive effect, cell factor in bronchoalveolar lavage fluid (BALF) brain tissue 5-HT and lung tissue related active factors(SP, PGP9.5, cAMP, Epac1) were detected. RESULTS: ASR could significantly restrain cough, alleviate the pathological changes of bronchioles, reduce the contents of IL-4, IL-13, TNF-α in BALF and the levels of SP, PGP9.5, cAMP and Epac1 in lung tissues, increase the content of 5-HT in brain tissue (P＜0.05, 0.01). CONCLUSION: ASR has some effects on restraining cough and one of its mechanisms is to down-regulate cAMP/Epac signaling pathway, to alleviate airway neurogenic inflammation and reduce sensitivity of cough neural pathway.

Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells.

We determine that type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors; however, actionable vulnerabilities associated with IFN signaling have not been systematically defined. Integration of a phosphoproteomic analysis and a chemical genomics synergy screen reveals that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) in PDAC cells and sensitizes them to ATR inhibitors. IFN triggers cell-cycle arrest in S-phase, which is accompanied by nucleotide pool insufficiency and nucleoside efflux. In combination with IFN, ATR inhibitors induce lethal DNA damage and downregulate nucleotide biosynthesis. ATR inhibition limits the growth of PDAC tumors in which IFN signaling is driven by stimulator of interferon genes (STING). These results identify a cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors.

Effect of flame retardants on mechanical and thermal properties of bio-based polyurethane rigid foams.

A soy oil-based polyol (HSBP) was synthesized from epoxidized soy oil through a ring-opening reaction with distilled water. A phosphorus-containing flame retardant (DOPO-HSBP) was synthesized through the reaction of 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) and HSBP. A nitrogen-containing flame retardant (T-D) was prepared by the reaction of diethanolamine with glycol diglycidyl ether. The structures of HSBP, DOPO-HSBP, and T-D were characterized by Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (1H NMR). The flame-retardant rigid polyurethane foam (PPUFs and NPUFs) was prepared successfully by mixing HSBP, DOPO-HSBP, and T-D. The effects of DOPO-HSBP content on the mechanical, thermal, and flame-retardant properties of PPUFs and NPUFs were investigated by tensile tests, thermogravimetric analyses (TGA), limiting oxygen index (LOI), and UL-94 vertical burning level. The morphology of PPUFs and NPUFs was studied via scanning electron microscopy (SEM). With the increase in the percentage of DOPO-HSBP added, the flame retardant property of rigid polyurethane foam (RPUF) was greatly improved. When the phosphorus-containing flame retardant DOPO-HSBP was added to 50% of the RPUF with the nitrogen-containing flame retardant T-D, the LOI value of the foam increased from 18.3 to 25.5, and the UL-94 result was classified as "V-0" with almost no effect on the mechanical properties of the RPUF. The results showed that the phosphorus and nitrogen synergistic flame retardants of DOPO-HSBP and T-D can endow excellent flame retardant properties to RPUF without affecting its mechanical properties.