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.

The causal effect of iron status on risk of anxiety disorders: A two-sample Mendelian randomization study.

OBJECTIVES: Observational studies had investigated the association of iron metabolism with anxiety disorders. The conclusions were inconsistent and not available to reveal the causal or reverse-causal association due to the confounding. In this study we estimated the potential causal effect of iron homeostasis markers on anxiety disorders using two-sample Mendelian randomization (MR) analysis. METHODS: Summary data of single nucleotide polymorphisms (SNPs) associated with four iron-related biomarkers were extracted from a recent report about analysis of three genome-wide association study (GWAS), the sample size of which ranged from 131471 to 246139 individuals. The corresponding data for anxiety disorders were from Finngen database (20992 cases and 197800 controls). The analyses were mainly based on inverse variance weighted (IVW) method. In addition, the heterogeneity and pleiotropy of the results were assessed by Cochran's Q test and MR-Egger regression. RESULTS: Basing on IVW method, genetically predicted serum iron level, ferritin and transferrin had negative effects on anxiety disorders. The odd ratios (OR) of anxiety disorders per 1 standard deviation (SD) unit increment in iron status biomarkers were 0.922 (95% confidence interval (CI) 0.862-0.986; p = 0.018) for serum iron level, 0.873 (95% CI 0.790-0.964; p = 0.008) for log-transformed ferritin and 0.917 (95% CI 0.867-0.969; p = 0.002) for transferrin saturation. But no statical significance was found in the association of 1 SD unit increased total iron-binding capacity (TIBC) with anxiety disorders (OR 1.080; 95% CI 0.988-1.180; p = 0.091). The analyses were supported by pleiotropy test which suggested no pleiotropic bias. CONCLUSION: Our results indicated that genetically determined iron status biomarkers causally linked to the risk of anxiety disorders, providing valuable insights into the genetic research and clinical intervention of anxiety disorders.

Reducedhumoral response against variants of concern in childhood solid cancer patients compared to adult patients and healthy children after SARS-CoV-2 vaccination.

Introduction: Although there is extended research on the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in adult cancer patients (ACP), the immunogenicity to the variants of concern (VOCs) in childhood cancer patients (CCP) and safety profiles are now little known. Methods: A prospective, multi-center cohort study was performed by recruiting children with a solid cancer diagnosis and childhood healthy control (CHC) to receive standard two-dose SARS-CoV-2 vaccines. An independent ACP group was included to match CCP in treatment history. Humoral response to six variants was performed and adverse events were followed up 3 months after vaccination. Responses to variants were compared with ACP and CHC by means of propensity score-matched (PSM) analysis. Results: The analysis included 111 CCP (27.2%, median age of 8, quartile 5.5-15 years), 134 CHC (32.8%), and 163 ACP (40.0%), for a total 408 patients. Pathology included carcinoma, neural tumors, sarcoma, and germ cell tumors. Median chemotherapy time was 7 (quartile, 5-11) months. In PSM sample pairs, the humoral response of CCP against variants was significantly decreased, and serology titers (281.8 ± 315.5 U/ml) were reduced, as compared to ACP (p< 0.01 for the rate of neutralization rate against each variant) and CHC (p< 0.01 for the rate of neutralization against each variant) groups. Chemotherapy time and age (Pearson r ≥ 0.8 for all variants) were associated with the humoral response against VOCs of the CHC group. In the CCP group, less than grade II adverse events were observed, including 32 patients with local reactions, and 29 patients had systemic adverse events, including fever (n = 9), rash (n = 20), headache (n = 3), fatigue (n = 11), and myalgia (n = 15). All reactions were well-managed medically. Conclusions: The humoral response against VOCs after the CoronaVac vaccination in CCP was moderately impaired although the vaccine was safe. Age and chemotherapy time seem to be the primary reason for poor response and low serology levels.

Cognitive adverse events in patients with lung cancer treated with checkpoint inhibitor monotherapy: a propensity score-matched analysis.

Background: Cancer-related cognitive decline is a serious problem in long-term survival but no pivotal study has investigated whether checkpoint inhibitors (ICI) may be associated with cognitive adverse events. Methods: This propensity score-matched analysis recruited non-small cell lung cancer (NSCLC) patients prescribed with or without ICI monotherapy from three Chinese tertiary hospitals. Patients were excluded from study who developed brain metastasis or had disorders severely affecting cognitive abilities. Primary outcomes were changes in neuropsychological battery test (NBT) at baseline, 6- and 12-month sessions, and any NBT score changes that exceeded 3∗SD of baseline scores would be marked as objective cognitive adverse events (CoAE). Secondary endpoint was the 20-item Perceived Cognitive Impairment (PCI) sub-scale score change in Functional Assessment of Cancer Therapy-Cognitive Function questionnaire, administered at baseline, 3-, 6-, 9-, 12-, and 15-month follow-up session. Per-protocol ICI and control arms were matched with propensity scores that incorporated baseline variables to compare both NBT and PCI assessment results. Patients participating in PCI assessments were analysed in intention-to-treat analysis. Kaplan-Meier survival curves with log-rank tests were adopted to analyse incidence of perceived cognitive decline events (PCDE). Findings: Between March 12, 2020, and March 28, 2021, 908 participants were enrolled. Compared to control, 3 of 4 subtest of NBT scores in ICI arm showed significant cognitive decline in 6- and 12-month sessions, in which Trail Making Test score change (13.56 ± 11.73) reached threshold of cognitive deficit diagnosis in the 12-month session. In 1:1 matched 292 pairs from 908 patients, PCI score changes in ICI arms were -4.26 ± 8.54 (3rd month), -4.72 ± 11.83 (6th month), -6.16 ± 15.41 (9th month), -6.07 ± 15.71 (12th month), and -7.96 ± 13.97 (15th month). The scores were significantly lower than control arm in 3-, 6-, and 12-session follow-up. The result was validated after adjusting quality of life scores and in intention-to-treat analysis. Mean PCI change exceeded 1/2 SD of baseline PCI score (5.81) in 9-, 12-, and 15-month sessions in ICI arm, but not in control arm. PCDE incidence/prevalence was significantly higher in ICI arm (incidence 26.4% vs. 5.1%, and prevalence 16.2% vs. 1.7%). Immune-related adverse events related to incidence of PCDE after adjusting for baseline variables. Interpretation: ICI monotherapy seemed to relate to higher cognitive decline represented by score changes and incidence/prevalence rates. The decline deteriorated as treatment progressed, and immune-related adverse events seemed to be associated with higher cognitive adverse events incidence in the ICI treatment. Funding: The Fellowship of China Postdoctoral Science Foundation and National Natural Science Foundation of China Youth Science Fund Project.

Thyroid function and associated mood changes after COVID-19 vaccines in patients with Hashimoto thyroiditis.

Context: Severe acute respiratory syndrome-coronavirus 2 (COVID-19) vaccines may incur changes in thyroid functions followed by mood changes, and patients with Hashimoto thyroiditis (HT) were suggested to bear a higher risk. Objectives: We primarily aim to find whether COVID-19 vaccination could induce potential subsequent thyroid function and mood changes. The secondary aim was to find inflammatory biomarkers associated with risk. Methods: The retrospective, multi-center study recruited patients with HT receiving COVID-19-inactivated vaccines. C-reactive proteins (CRPs), thyroid-stimulating hormones (TSHs), and mood changes were studied before and after vaccination during a follow-up of a 6-month period. Independent association was investigated between incidence of mood state, thyroid functions, and inflammatory markers. Propensity score-matched comparisons between the vaccine and control groups were carried out to investigate the difference. Results: Final analysis included 2,765 patients with HT in the vaccine group and 1,288 patients in the control group. In the matched analysis, TSH increase and mood change incidence were both significantly higher in the vaccine group (11.9% versus 6.1% for TSH increase and 12.7% versus 8.4% for mood change incidence). An increase in CRP was associated with mood change (p< 0.01 by the Kaplan-Meier method) and severity (r = 0.75) after vaccination. Baseline CRP, TSH, and antibodies of thyroid peroxidase (anti-TPO) were found to predict incidence of mood changes. Conclusion: COVID-19 vaccination seemed to induce increased levels and incidence of TSH surge followed by mood changes in patients with HT. Higher levels of pre-vaccine serum TSH, CRP, and anti-TPO values were associated with higher incidence in the early post-vaccine phase.

A Descriptive Study of Total Serum Homocysteine Status in Adult Henan Province, China.

BACKGROUND: Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease. Total serum homocysteine (tHcy) status varies greatly with ethnicity and gender. Here, we studied the tHcy status by investigating concentration of tHcy and calculating prevalence of HHcy according to different age groups and genders. METHODS: This is a cross-sectional study of 10,258 participants (7,248 males and 3,010 females) above 19 years old from Henan Province, northern China. tHcy levels were determined enzymatically. HHcy was defined as a tHcy level higher than 15 µmol/L. RESULTS: In the whole population, the median value of tHcy was 13.56 (11.50, 16.50) µmol/L, and the HHcy prevalence was 34.61%. Males had much higher tHcy levels than females: 14.51 (12.58, 17.71) µmol/L vs. 11.23 (9.75, 12.97) µmol/L, p < 0.001. Also, males had much higher HHcy prevalence than females (44.33% vs. 11.20%, p < 0.001, OR = 6.33, 95% CI: 5.59 - 7.14). HHcy prevalence and tHcy levels increased greatly for both genders above 60 years old. CONCLUSIONS: Our results demonstrated that prevalence of HHcy is very high in northern China. Implementation of tHcy-lowering strategies is needed.

The Changes in Coagulation Test Results in Subjects with Varying Levels of Thyroid Stimulating Hormone.

BACKGROUND: The aim is to investigate the changes in coagulation test results in subjects with varying serum levels of thyroid stimulating hormone. METHODS: We performed a one-year retrospective analysis to retrieve combined results of activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (Fib), D-dimer, free thyroxine (fT4), tri-iodothyronine (fT3), and thyroid stimulating hormone (TSH) from inpatients who were referred by general practitioners for routine blood testing. Cumulative results were retrieved for 2,794 such inpatients. RESULTS: Patients with a TSH level < 0.34 µIU/mL had higher PT values (10.43 ± 1.02 vs. 10.27 ± 0.91) and Fib values (3.00 ± 0.92 vs. 2.7 ± 0.56) compared with patients with 0.34 µIU/mL < TSH < 5.6 µIU/mL. Conversely, the PT values (10.01 ± 0.95 vs. 10.27 ± 0.91) were lower and APTT (33.70 ± 4.17 vs. 32.56 ± 4.12) values higher in patients with TSH > 5.6 µIU/mL compared to patients with 0.34 µIU/mL < TSH < 5.6 µIU/mL. CONCLUSIONS: There are changes in coagulation test results in subjects with varying levels of thyroid stimulating hormone.

Shortened Activated Partial Thromboplastin Time and Increased Superoxide Dismutase Levels Are Associated with Type 2 Diabetes Mellitus.

BACKGROUND: To determine differences in levels of coagulation and superoxide dismutase in normal controls and type 2 diabetes mellitus patients with different stages of glucose control. METHODS: Type 2 diabetes mellitus patients were divided into two groups according to their fasting blood glucose (GM1 and GM2) and HbA1c levels (BM1 and BM2). Blood clotting times and levels of serum superoxide dismutase were compared among the three groups. A receiver operating characteristic (ROC) curve was generated to evaluate predictors and determine their sensitivities and specificities. A Pearson correlation analysis was performed on the type 2 diabetes mellitus patients using standard methods to evaluate the association of serum levels of superoxide dismutase and coagulation parameters with certain disease risk factors. A multiple linear stepwise regression analysis was also performed. RESULTS: There is a significant difference in levels of superoxide dismutase (SOD) and activated partial thromboplastin time (APTT) between normal controls and type 2 diabetes patients with varying glucose tolerance statuses (P<0.001). The difference between GM1 and GM2 with respect to APTT was also statistically significant (P=0.048). The area under the ROC for APTT and SOD was 0.705 and 0.707, respectively. An inverse and highly significant correlation was found between APTT and fasting plasma glucose (r =-0.177, P=0.024), and the serum level of SOD was negatively correlated with age (r=-0.309, P<0.001), D-Dimer (r=-0.253, P=0.001) and APTT (r=-0.2, P=0.007). CONCLUSIONS: Shorter APTT and increased SOD levels might be useful hemostatic markers in patients with type 2 diabetes mellitus.

Role of exosomes in pancreatic cancer.

Pancreatic cancer is one of the most lethal malignancies. Exosomes, which are released by multiple cell types, such as cancer cells, contain functional biomolecules (including proteins, nucleic acids and lipids) that can be horizontally delivered to recipient cells. Exosomes act as the most prominent mediator of intercellular communication and can regulate, instruct and re-educate their surrounding microenvironment and target specific organs. The present review performed an extensive search of multiple databases from 2005 to April 23 2017, for eligible literature relating to exosomes and their role in pancreatic cancer. With a focus on the latest findings for pancreatic cancer exosomes, their role in tumorigenesis was summarized, as well as their aggressive behaviors and their contribution to immunosuppression and therapy resistance in pancreatic cancer. In addition, the potential function of exosomes as novel diagnostic biomarkers is briefly discussed. Finally, we propose potential clinical applications for exosomes in pancreatic cancer.

Exosomes participate in the carcinogenesis and the malignant behavior of gastric cancer.

OBJECTIVE: In order to summarize the role of exosomes in invasion and metastasis in gastric cancer (GC). MATERIAL: Exosomes are vesicles of endocytic origin ranging from 30 to 100 nm in size; they are composed of a lipid bilayer and contain DNA, mRNA, miRNA, circular RNA and multiple proteins. Recently, increasing evidence shows that exosomes play a crucial role in the tumorigenesis of GC. RESULTS: In this review, we focus on the latest findings on GC exosomes, mainly summarizing their role in invasion and metastasis in GC. Then, exosomes? potential functions as novel diagnostic and therapeutic biomarkers for GC are briefly discussed. At last, we prospect the clinical application perspective of exosomes in GC. CONCLUSIONS: Exosomes play a vital role in gastric cancer carcinogenesis and metastasis.

Discovery and verification of urinary peptides in type 2 diabetes mellitus with kidney injury.

Varying degrees of renal injury could lead to different changes in urinary protein composition. We want to find urinary candidate peptide biomarkers in type 2 diabetic patients with different extents of kidney injury. Two sets of patients were recruited. Discovery set: weak cationic-exchange magnetic beads coupled with matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used to profile the low-molecular weight peptidome in urine samples from type 2 diabetes patients with normoalbuminura and microalbuminuria. The differently expressed urinary peptides were screened by ClinProTools2.1 bioinformatics software and identified through nano-liquid chromatography-tandem mass spectrometry. Verification set: the above screened urinary peptides were validated by use matrix-assisted laser desorption ionization time-of-flight mass spectrometry on another group of type 2 diabetes patients with different extents use of kidney injury. In the screening and identification stages, seven urinary peptides were selected as the most promising biomarker candidates, and they were identified as fragments of vitronectin precursor, isoform 1 of fibrinogen alpha chain precursor, prothrombin precursor and inter-alpha-trypsin inhibitor heavy chain H4. The diagnostic efficacy of these urinary peptides was evaluated by area under the receiver operating characteristic curve, and they were 0.767, 0.768, 0.868, 0.910, 0.860, 0.843, and 0.865, respectively. In the verification stage, m/z 1743.9, 2154, 2175.5, and 2184.9 were decreased as albumin-to-creatinine (Alb/Cre) increased and m/z 2231.1, 2430.8, and 2756.1 were elevated as Alb/Cre rose. These small molecule peptides are related to type 2 diabetes kidney damage, and they may play an important role in monitoring type 2 diabetes.

Screening High Abundance of Peptide for Making Examination Possible in Human Urine.

OBJECTIVE: We aim to explore and identify the high abundance of peptides in urine. METHODS: Random urine samples from 30 healthy individuals were purified by weak cationic-exchange magnetic beads (MB-WCX) and then analyzed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Then the generated mass spectra of peptides were handled by ClinPro-Tools2.1 bioinformatics software and the high abundance of urinary peptide was filtered. Subsequently, the amino acid sequences of highly expressed peptides were identified by a nano-liquid chromatography-tandem mass spectrometry and the corresponding protein names were found by Sequest search. RESULTS: There were 159 urinary peptides of which mass to charge ratios (m/z) varied between 1,000 and 10,000 in the 30 healthy samples. Only peaks with average intensity >600 and the frequency >50% in the whole group were filtered. There were 15 peptides passed though the threshold and they were identified as fragments of fibrinogen alpha chain precursor, vitronectin precursor, inter-alpha-trypsin inhibitor heavy chain H4, complement component 3, prothrombin, apolipoprotein C-II, and alpha-fetoprotein. CONCLUSION: These urinary peptides could be used for further research on urine.

The Difference Quantity of Urinary Peptides between Two Groups of Type 2 Diabetic Patients with or without Coronary Artery Disease.

Objectives. We aim to explore urinary biomarkers that could monitor CAD in type 2 diabetic patients. Materials and Methods. Urine samples from two groups, twenty-eight type 2 diabetic patients with coexisting CAD and thirty type 2 diabetic patients without CAD, were purified by MB-WCX and then analyzed by MALDI-TOF-MS. Subsequently, we compared the urinary peptide signatures of the two groups by use of ClinProTools2.1 and evaluated the potential ability of the differently expressed peptides to distinguish type 2 diabetic patients with coexisting CAD from type 2 diabetic patients without CAD by ROC analysis. Finally, the differently expressed peptides were identified by nanoliquid chromatography-tandem mass spectrometry. Results. There were six differently expressed peptides (m/z 1305.2, 1743.9, 2184.9, 2756.1, 3223.2, and 6196.1) between the two groups of subjects, and they were identified as fragments of isoform 1 of fibrinogen alpha chain precursor, prothrombin precursor, and interalpha-trypsin inhibitor heavy chain H4. The diagnostic efficacy of m/z 2756.1 and m/z 3223.2 was better than the other peptides. Area under ROC of the m/z 2756.1, and m/z 3223.2 was 0.98 and 0.93, respectively. Conclusions. These urinary peptides are potential urinary biomarkers for monitoring of type 2 diabetic patients with CAD.

Two urinary peptides associated closely with type 2 diabetes mellitus.

OBJECTIVE: To monitor of type 2 diabetes more simply, conveniently and noninvasively, we are trying to identify the potential urinary peptides that associated with different stages of glucose control in type 2 diabetes mellitus. METHODS: Firstly, we collected urine samples from type 2 diabetic patients and normal controls. These type 2 diabetic patients were divided into two groups according to fasting plasma glucose (FPG) and hemoglobin A1c% (HbA1c), respectively. Magnetic beads based weak cation exchange chromatography (MB-WCX) was used to condense urinary peptides. The eluates were then analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Subsequently, ClinProt was used to profile and screen the polypeptide patterns based on different methods of grouping in diabetic patients and normal controls. Finally, the amino acid sequences of differentially expressed peptides were identified by nano-liquid chromatography-tandem mass spectrometry and the protein sources of the corresponding peptide were matched in IPI Human database. RESULTS: Proteomics analysis found two up-regulated peptide (m/z 2756.1 and m/z 3223.2) representations in diabetic subjects, and the two peptides increased with increases in the amount of glycosylated hemoglobin. Further, the parallelism between m/z 3223.2 and glycosylated hemoglobin was better than the parallelism between m/z 2756.1 and glycosylated hemoglobin. Area under the receiver operating characteristic of the two peptides was 0.722 and 0.661, respectively. The above-mentioned peptide m/z 2756.1 was further identified as fragment of fibrinogen alpha chain precursor and m/z 3223.2 was fragment of prothrombin precursor. CONCLUSION: These results suggested the two urinary biomarkers enable monitor of type 2 diabetes patients with different stages of glucose control.

Identification of urinary biomarkers for type 2 diabetes using bead-based proteomic approach.

AIMS: To seek urinary peptides as biomarkers distinguishing type 2 diabetes mellitus (T2DM) patients from healthy controls. METHODS: Random urine samples obtained from 28 patients with T2DM and 29 healthy individuals were analyzed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) after purification using weak cationic-exchange magnetic beads (MB-WCX). Then the generated mass spectra of peptides were analyzed by ClinProTools2.1 bioinformatics software. Subsequently, the amino acid sequences of differently expressed peptides were identified by a nano-liquid chromatography-tandem mass spectrometry and a Sequest search found the corresponding protein name. RESULTS: Three differently expressed peptides and their mass to charge ratios (m/z) were found. Compared with healthy controls, the peak areas of the three differently expressed peptides were all reduced in T2DM, and the m/z were 1056.1 (m/z), 1963.5 (m/z), 2123.5 (m/z), respectively. The above-mentioned peptides were further identified as fragments of histidine triad nucleotide-binding protein 1 (HINT1), bifunctional aminoacyl-tRNA synthetase (EPRS), and clusterin precursor protein (CLU). CONCLUSIONS: Histidine triad nucleotide-binding protein 1, bifunctional aminoacyl-tRNA synthetase, and clusterin precursor protein may serve as potential biomarkers distinguishing type 2 diabetes mellitus patients from healthy controls.