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Abstract Background Magnetic resonance spectroscopy (MRS) studies have indicated that the imbalance between gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels was the potential cause of migraine development. However, the changes in the GABA and Glx levels in patients with New daily persistent headache (NDPH) remain unclear. This study aimed to investigate the changes in GABA and Glx levels in the periaqueductal gray (PAG) and dentate nucleus (DN) in patients with NDPH using the MEGA-PRESS sequence. Methods Twenty-one NDPH patients and 22 age- and sex-matched healthy controls (HCs) were included and underwent a 3.0T MRI examination, using the MEGA-PRESS sequence to analyze GABA and Glx levels of PAG and DN. The correlations between these neurotransmitter levels and clinical characteristics were also analyzed. Results There were no significant differences in the GABA+/Water, GABA+/Cr, Glx/Water, and Glx/Cr levels in both PAG and DN between the two groups (all p > 0.05). Moderate-severe NDPH patients had lower levels of Glx/Water (p = 0.034) and Glx/Cr (p = 0.012) in DN than minimal-mild NDPH patients. In patients with NDPH, higher Glx/Water levels in the PAG (r=-0.471, p = 0.031, n = 21) and DN (r=-0.501, p = 0.021, n = 21) and higher Glx/Cr levels in DN (r=-0.483, p = 0.026, n = 21) were found to be correlated with lower Visual Analogue Scale scores. Additionally, a positive correlation was observed between the GABA+/Cr levels in the DN and the Generalized Anxiety Disorder-7 scores (r = 0.519, p = 0.039, n = 16). Conclusions The results of this study indicated that the GABA and Glx levels in the PAG and DN may not be the primary contributor to the development of NDPH. The correlations between certain clinical scales and the neurotransmitter levels may be derived from the NDPH related symptoms.

Abstract Background New daily persistent headache (NDPH) is a rare primary headache with unclear pathogenesis. Neuroimaging studies of NDPH are limited, and controversy still exists. Diffusion tensor imaging (DTI) is commonly used to study the white matter. However, lacking specificity, the potential pathological mechanisms of white matter microstructural changes remain poorly understood. In addition, the intricacy of gray matter structures impedes the application of the DTI model. Here, we applied an advanced diffusion model of neurite orientation dispersion and density imaging (NODDI) to study the white matter and cortical gray matter microstructure in patients with NDPH. Methods This study assessed brain microstructure, including 27 patients with NDPH, and matched 28 healthy controls (HCs) by NODDI. The differences between the two groups were assessed by tract-based spatial statistics (TBSS) and surface-based analysis (SBA), focusing on the NODDI metrics (neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF)). Furthermore, we performed Pearson’s correlation analysis between the NODDI indicators and clinical characteristics. Results Compared to HCs, patients with NDPH had a reduction of density and complexity in several fiber tracts. For robust results, the fiber tracts were defined as comprising more than 100 voxels, including bilateral inferior fronto-occipital fasciculus (IFOF), left superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF), as well as right corticospinal tract (CST). Moreover, the reduction of neurite density was uncovered in the left superior and middle frontal cortex, left precentral cortex, and right lateral orbitofrontal cortex and insula. There was no correlation between the NODDI metrics of these brain regions and clinical variables or scales of relevance after the Bonferroni correction. Conclusions Our research indicated that neurite loss was detected in both white matter and cortical gray matter of patients with NDPH.

Abstract The illegal water injection into meat not only breaks the market equity, but also deteriorates the meat quality and produces harmful substances. In this work, we proposed a fiber Bragg grating (FBG) sensor that enabled fast, quantitative, and in-situ detection of the moisture content of water-injected meat. The FBG was written in the erbium-ytterbium (Er/Yb) co-doped fiber, which could perform the self-photothermal effect by injecting the near infrared laser into the fiber. As the heated fiber sensor probe was inserted into the meat sample, the temperature decreased due to the heat dissipation mediated by moisture. The intracore Bragg grating could monitor the temperature loss by recording the Bragg wavelength shift, which reflected the water content quantitatively. The results revealed that the sensor could complete the detection within 15 s. The sensor’s sensitivity to detect changes in the pork water content was theoretically calculated to be 0.090847%. The proposed sensor is expected to provide a novel approach for examination of the meat moisture.

Abstract Background Observational studies have shown that smoking is related to the diffusing capacity of the lungs for carbon monoxide (DLCO) in individuals with idiopathic pulmonary fibrosis (IPF). Nevertheless, further investigation is needed to determine the causal effect between these two variables. Therefore, we conducted a study to investigate the causal relationship between smoking and DLCO in IPF patients using two-sample Mendelian randomization (MR) analysis. Methods Large-scale genome-wide association study (GWAS) datasets from individuals of European descent were analysed. These datasets included published lifetime smoking index (LSI) data for 462,690 participants and DLCO data for 975 IPF patients. The inverse-variance weighting (IVW) method was the main method used in our analysis. Sensitivity analyses were performed by MR‒Egger regression, Cochran’s Q test, the leave-one-out test and the MR-PRESSO global test. Results A genetically predicted increase in LSI was associated with a decrease in DLCO in IPF patients [ORIVW = 0.54; 95% CI 0.32–0.93; P = 0.02]. Conclusions Our study suggested that smoking is associated with a decrease in DLCO. Patients diagnosed with IPF should adopt an active and healthy lifestyle, especially by quitting smoking, which may be effective at slowing the progression of IPF.

Extracellular vesicles (EVs) and EV proteins are promising biomarkers for cancer liquid biopsy. Herein, we designed a case–control study involving 100 controls and 100 patients with esophageal, stomach, colorectal, liver, or lung cancer to identify common and type‐specific biomarkers of plasma‐derived EV surface proteins for the five cancers. EV surface proteins were profiled using a sequencing‐based proximity barcoding assay. In this study, five differentially expressed proteins (DEPs) and eight differentially expressed protein combinations (DEPCs) showed promising performance (area under curve, AUC > 0.900) in pan‐cancer identification [e.g., TENM2 (AUC = 0.982), CD36 (AUC = 0.974), and CD36‐ITGA1 (AUC = 0.971)]. Our classification model could properly discriminate between cancer patients and controls using DEPs (AUC = 0.981) or DEPCs (AUC = 0.965). When distinguishing one cancer from the other four, the accuracy of the classification model using DEPCs (85–92%) was higher than that using DEPs (78–84%). We validated the performance in an additional 14 cancer patients and 14 controls, and achieved an AUC value of 0.786 for DEPs and 0.622 for DEPCs, highlighting the necessity to recruit a larger cohort for further validation. When clustering EVs into subpopulations, we detected cluster‐specific proteins highly expressed in immune‐related tissues. In the context of colorectal cancer, we identified heterogeneous EV clusters enriched in cancer patients, correlating with tumor initiation and progression. These findings provide epidemiological and molecular evidence for the clinical application of EV proteins in cancer prediction, while also illuminating their functional roles in cancer physiopathology.

Abstract Background The brain functional network topology in new daily persistent headache (NDPH) is not well understood. In this study, we aim to assess the cortical functional network topological characteristics of NDPH using non-invasive neural signal recordings. Methods Resting-state magnetoencephalography (MEG) was used to measure power fluctuations in neuronal oscillations from distributed cortical parcels in 35 patients with NDPH and 40 healthy controls (HCs). Their structural data were collected by 3T MRI. Functional connectivity (FC) of neural networks from 1 to 80 Hz frequency ranges was analyzed with topographic patterns and calculated network topological parameters with graph theory. Results In the delta (1–4 Hz) and beta (13–30 Hz) bands, the lateral occipital cortex and superior frontal gyrus FC were increased in NDPH groups compared to HCs. Graph theory analysis revealed that the NDPH had significantly increased global efficiency in the delta band and decreased nodal clustering coefficient (left medial orbitofrontal cortex) in the theta (4–8 Hz) band. The clinical characteristics had a significant correlation with network topological parameters. Age at onset of patients showed a positive correlation with global efficiency in the delta band. The degree of depression of patients showed a negative correlation with the nodal clustering coefficient (left medial orbitofrontal cortex) in the theta band. Conclusion The FC and topology of NDPH in brain networks may be altered, potentially leading to cortical hyperexcitability. Moreover, medial orbitofrontal cortex is involved in the pathophysiological mechanism of depression in patients with NDPH. Increased FC observed in the lateral occipital cortex and superior frontal gyrus during resting-state MEG could serve as one of the imaging characteristics associated with NDPH.

Abstract Background Preliminary evidence suggests that several headache disorders may be associated with glymphatic dysfunction. However, no studies have been conducted to examine the glymphatic activity in migraine chronification. Purposes To investigate the glymphatic activity of migraine chronification in patients with episodic migraine (EM) and chronic migraine (CM) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. Methods In this cross-sectional study, patients with EM, CM, and healthy controls (HCs) were included. All participants underwent a standard brain magnetic resonance imaging (MRI) examination. Bilateral DTI-ALPS indexes were calculated for all participants and compared among EM, CM, and HC groups. Correlations between the DTI-ALPS index and clinical characteristics were analyzed. Results A total of 32 patients with EM, 24 patients with CM, and 41 age- and sex-matched HCs were included in the analysis. Significant differences were found in the right DTI-ALPS index among the three groups (p = 0.011), with CM showing significantly higher values than EM (p = 0.033) and HCs (p = 0.015). The right DTI-ALPS index of CM group was significantly higher than the left DTI-ALPS index (p = 0.005). And the headache intensity was correlated to DTI-ALPS index both in the left hemisphere (r = 0.371, p = 0.011) and in the right hemisphere (r = 0.307, p = 0.038), but there were no correlations after Bonferroni correction. Conclusions Glymphatic system activity is shown to be increased instead of impaired during migraine chronification. The mechanism behind this observation suggests that increased glymphatic activity is more likely to be a concomitant phenomenon of altered vascular reactivity associated with migraine pathophysiology rather than a risk factor of migraine chronification.

Abstract Background Several observational studies have found that physical inactivity and sedentary time are associated with idiopathic pulmonary fibrosis (IPF) risk. However, the causality between them still requires further investigation. Therefore, our study aimed to investigate the causal effect of physical activity (PA) and sedentary time on the risk of IPF via two-sample Mendelian randomization (MR) analysis. Methods Multiple genome-wide association study (GWAS) data involving individuals of European ancestry were analyzed. The datasets encompassed published UK Biobank data (91,105–377,234 participants) and IPF data (2018 cases and 373,064 controls) from FinnGen Biobank. The inverse variance weighting (IVW) method was the primary approach for our analysis. Sensitivity analyses were implemented with Cochran’s Q test, MR-Egger regression, MR-PRESSO global test, and leave-one-out analysis. Results Genetically predicted self-reported PA was associated with lower IPF risk [OR = 0.27; 95% CI 0.09–0.82; P = 0.02]. No causal effects of accelerometry-based PA or sedentary time on the risk of IPF were observed. Conclusions Our findings supported a protective relationship between self-reported PA and the risk for IPF. The results suggested that enhancing PA may be an effective preventive strategy for IPF.

Abstract Background Amygdala, an essential element of the limbic system, has served as an important structure in pain modulation. There is still a lack of clarity about altered cerebral perfusion of amygdala in migraine. This study aimed to investigate the perfusion variances of bilateral amygdala in episodic migraine (EM) and chronic migraine (CM) using multi-delay pseudo-continuous arterial spin-labeled magnetic resonance imaging (pCASL-MRI). Methods Twenty-six patients with EM, 55 patients with CM (33 CM with medication overuse headache (MOH)), and 26 age- and sex-matched healthy controls (HCs) were included. All participants underwent 3D multi-delay pCASL MR imaging to obtain cerebral perfusion data, including arrival-time-corrected cerebral blood flow (CBF) and arterial cerebral blood volume (aCBV). The CBF and aCBV values in the bilateral amygdala were compared among the three groups. Correlation analyses between cerebral perfusion parameters and clinical variables were performed. Results Compared with HC participants, patients with CM were found to have increased CBF and aCBV values in the left amygdala, as well as increased CBF values in the right amygdala (all P 0.05). In patients with CM, the increased perfusion parameters of bilateral amygdala were positively correlated with MIDAS score after adjustments for age, sex, and body mass index (BMI). Conclusion Hyperperfusion of bilateral amygdala might provide potential hemodynamics evidence in the neurolimbic pain network of CM.

Abstract Objective To explore whether MRI‐visible enlarged perivascular spaces (EPVS) are associated with migraine and may serve as a predictor of migraine. Then further explore its correlation with migraine chronification. Methods A total of 231 participants (healthy control [HC] = 57, episodic migraine [EM] = 59, chronic migraine [CM] = 115) were included in this case–control study. A 3T MRI device and the validated visual rating scale were used to assess the grades of EPVS in centrum semiovale (CSO), midbrain (MB), and basal ganglia (BG). Comparisons between the two groups were made using the chi‐square or Fisher's exact tests to initially determine whether high‐grade EPVS were associated with migraine and migraine chronification. A multivariate logistic regression model was constructed to further investigate the role of high‐grade EPVS in migraine. Results The prevalence of high‐grade EPVS in CSO and MB were significantly higher in patients with migraine than in HCs (CSO: 64.94% vs. 42.11%, P = 0.002; MB: 55.75% vs. 29.82%, P = 0.001). Subgroup analysis showed no statistical difference between patients with EM and CM (CSO: 69.94% vs. 62.61%, P = 0.368; MB: 50.85% vs. 58.26%, P = 0.351). Individuals with high‐grade EPVS in CSO (odds ratio [OR]: 2.324; 95% confidence interval [CI]: 1.136–4.754; P = 0.021) and MB (OR: 3.261; 95% CI: 1.534–6.935; P = 0.002) were more likely to suffer from migraine. Interpretation This case–control study showed that high‐grade EPVS in CSO and MB in clinical practice with the underlying mechanism of dysfunction of the glymphatic system could be a predictor of migraine, but no significant correlation had been found with migraine chronification.

Abstract Background New daily persistent headache (NDPH) is a rare primary headache disorder characterized by daily and persistent sudden onset headaches. The pathogenesis of NDPH remains unclear, and there are few white matter imaging studies related to NDPH. The purpose of this study was to investigate the micro-structural abnormalities of white matter in NDPH and provided insights into the pathogenesis of this disease based on tract-based spatial statistics (TBSS). Methods Twenty-one patients with NDPH and 25 healthy controls (HCs) were included in this study. T1 structural and diffusion magnetic resonance imaging (MRI) were acquired from all participants. Differences in the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) between patients with NDPH and HCs were investigated using TBSS analysis. Results Significantly decreased FA, increased MD and RD were found in patients with NDPH compared to HCs. White matter regions overlaid with decreased FA, increased MD and RD were found in 16 white matter tracts from the Johns Hopkins University ICBM-DTI-81 White-Matter Atlas and Johns Hopkins University White-Matter Tractography Atlas. Specifically, these white matter regions included the right anterior thalamic radiation (ATR), body of the corpus callosum (BCC), bilateral cingulum, left hippocampal cingulum (CGH), left corticospinal tract (CST), forceps major, fornix, left inferior fronto-occipital fasciculus (IFOF), bilateral inferior longitudinal fasciculus (ILF), left posterior limb of the internal capsule (PLIC), right retrolenticular part of the internal capsule (RPIC), splenium of the corpus callosum (SCC), right superior longitudinal fasciculus (SLF) and left uncinate fasciculus (UF). After Bonferroni correction, there were no correlations between the FA, MD, AD and RD values and the clinical characteristics of patients with NDPH (p > 0.05/96). Conclusion The results of our research indicated that patients with NDPH might have widespread abnormalities in the white matter of the brain.

Abstract Background Defects in DNA damage repair (DDR) pathways lead to genomic instability and oncogenesis. DDR deficiency is prevalent in esophageal squamous cell carcinoma (ESCC), but the effects of DDR alterations on mutational processes and tumor immune microenvironment in ECSS remain unclear. Methods Whole‐exome and transcriptome sequencing data of 45 ESCC samples from Taizhou, China, were used to identify genomic variations, gene expression modulation in DDR pathways, and the abundance of tumor‐infiltrating immune cells. Ninety‐six ESCC cases from The Cancer Genome Atlas (TCGA) project were used for validation. Results A total of 57.8% (26/45) of the cases in the Taizhou data and 70.8% (68/96) of the cases in the TCGA data carried at least one functional impact DDR mutation. Mutations in the DDR pathways were associated with a high tumor mutation burden. Several DDR deficiency‐related mutational signatures were discovered and were associated with immune cell infiltration, including T cells, monocytes, dendritic cells, and mast cells. The expression levels of two DDR genes, HFM1 and NEIL1, were downregulated in ESCC tumor tissues and had an independent effect on the infiltration of mast cells. In the Taizhou data, increased expression of HFM1 was associated with a poor prognosis, and the increased expression of NEIL1 was associated with a good outcome, but no reproducible correlation was observed in the TCGA data. Conclusion This research demonstrated that DDR alterations could impact mutational processes and immune cell infiltration in ESCC. The suppression of HFM1 and NEIL1 could play a crucial role in ESCC progression and may also serve as prognostic markers.

Abstract Background New daily persistent headache (NDPH) is a rare but debilitating primary headache disorder that poses a significant burden on individuals and society. Despite its clinical importance, the underlying pathophysiological mechanisms of NDPH remain unclear. In this study, we aimed to investigate the brain structural changes and neural activity patterns in patients with NDPH using multimodal brain imaging analysis of structural magnetic resonance imaging (sMRI) combined with magnetoencephalography (MEG). Methods Twenty-eight patients with NDPH and 37 healthy controls (HCs) were recruited for this study, and their structural and resting-state data were collected by 3.0 Tesla MRI and MEG. We analyzed the brain morphology using voxel-based morphometry and source-based morphometry. In each brain region, MEG sensor signals from 1 to 200 Hz were analyzed using an adapted version of Welch's method. MEG source localization was conducted using the dynamic statistical parametric mapping, and the difference of source distribution between patients with NDPH and HCs was examined. Results Our results revealed significant differences in the regional grey matter volume, cortical thickness, and cortical surface area between the two groups. Specifically, compared with HCs, patients with NDPH showed a significant decrease in cortical thickness of the left rostral cortex in the middle frontal gyrus, decreased cortical surface area of the left fusiform gyrus, decreased grey matter volume of the left superior frontal gyrus and the left middle frontal gyrus, and increased grey matter volume of the left calcarine. Furthermore, the power of the whole brain, bilateral frontal lobes, and right temporal lobe in the NDPH group were higher than that in HCs in the ripple frequency band (80-200 Hz). Functional and structural analysis suggested that there were structural changes and abnormal high frequency cortical activity in both frontal and temporal lobes in patients with NDPH. Conclusion Our findings indicated that patients with NDPH have abnormalities in brain morphology, such as cortical area, cortical thickness, and grey matter volume, accompanied by abnormal cortical neural activity. Brain structural changes in the frontotemporal cortex and abnormalities in cortical ripple activity may be involved in the pathogenesis of NDPH.

Abstract Background and purpose The pathogenesis of new daily persistent headache (NDPH) is not fully understood. We aim to map aberrant functional connectivity (FC) in patients with NDPH using resting-state functional magnetic resonance imaging (MRI). Methods Brain structural and functional MRI data were acquired from 29 patients with NDPH and 37 well-matched healthy controls (HCs) in this cross-sectional study. Region of interest (ROI) based analysis was used to compare FC between patients and HCs, with 116 brain regions in the automated anatomical labeling (AAL) atlas were defined as seeds. The correlations between aberrant FC and patients’ clinical characteristics, and neuropsychological evaluation were also investigated. Results Compared with HCs, patients with NDPH showed increased FC in the left inferior occipital gyrus, right thalamus and decreased FC in right lingual gyrus, left superior occipital gyrus, right middle occipital gyrus, left inferior occipital gyrus, right inferior occipital gyrus, right fusiform gyrus, left postcentral gyrus, right postcentral gyrus, right thalamus and right superior temporal gyrus. There were no correlation between FC of these brain regions and clinical characteristics, neuropsychological evaluation after Bonferroni correction (p > 0.05/266). Conclusions Patients with NDPH showed aberrant FC in multiple brain regions involved in perception and regulation of emotion and pain. Trial registration ClinicalTrials.gov Identifier: NCT05334927.

Abstract Background New daily persistent headache (NPDH) is a rare primary headache that is highly disabling. The pathophysiology of NDPH is still unclear, and we aimed to reveal the underlying mechanism of NDPH through functional magnetic resonance imaging (fMRI) analysis. Methods In this cross-sectional study, thirty patients with NDPH and 30 healthy controls (HCs) were recruited. The blood oxygen level-dependent (BOLD) sequences of all participants were obtained using the GE 3.0 T system. We performed ReHo, ALFF (conventional band: 0.01–0.08 Hz, slow-5: 0.01–0.027 Hz, slow-4: 0.027–0.073 Hz) and seed-based to the whole brain functional connectivity (FC) analysis in the NDPH and HC groups. The sex difference analysis of ReHo, ALFF, and FC values was conducted in the NDPH group. We also conducted Pearson’s correlation analysis between ReHo, ALFF, FC values and clinical characteristics (pain intensity, disease duration, HIT-6, GAD-7, PHQ-9, and PSQI scores). Results Both increased ReHo (PFWE-corr = 0.012) and ALFF values (0.01–0.08 Hz, PFWE-corr = 0.009; 0.027–0.073 Hz, PFWE-corr =0.044) of the left middle occipital gyrus (MOG_L) were found in the NDPH group compared to the HC group. There was no significant difference in FC maps between the two groups. Compared to the HC group, no difference was found in ReHo (p = 0.284), ALFF (p = 0.246), and FC (p = 0.118) z scores of the MOG_L in the NDPH group. There was also no sex difference in ReHo (p = 0.288), ALFF (p = 0.859), or FC z score (p = 0.118) of the MOG_L in patients with NDPH. There was no correlation between ReHo, ALFF, FC z scores and clinical characteristics after Bonferroni correction (p

Abstract Background and purpose New daily persistent headache (NDPH) and chronic migraine (CM) are two different types of headaches that might involve vascular dysregulation. There is still a lack of clarity about altered brain perfusion in NDPH and CM. This study aimed to investigate the cerebral perfusion variances of NDPH and CM using multi-delay pseudo-continuous arterial spin-labeled magnetic resonance imaging (pCASL-MRI). Methods Fifteen patients with NDPH, 18 patients with CM, and 15 age- and sex-matched healthy controls (HCs) were included. All participants underwent 3D multi-delay pCASL-MRI to obtain cerebral perfusion data, including arrival-time-corrected cerebral blood flow (CBF) and arterial cerebral blood volume (aCBV). The automated anatomical labeling atlas 3 (AAL3) was used to parcellate 170 brain regions. The CBF and aCBV values in each brain region were compared among the three groups. Correlation analyses between cerebral perfusion parameters and clinical variables were performed. Results Compared with HC participants, patients with NDPH were found to have decreased CBF and aCBV values in multiple regions in the right hemisphere, including the right posterior orbital gyrus (OFCpost.R), right middle occipital gyrus (MOG.R), and ventral anterior nucleus of right thalamus (tVA.R), while patients with CM showed increased CBF and aCBV values presenting in the ventral lateral nucleus of left thalamus (tVL.L) and right thalamus (tVL.R) compared with HCs (all p

Abstract Background The definitive pathogenic mechanisms underlying chronic migraine (CM) remain unclear. Mounting evidence from functional and structural magnetic resonance imaging (MRI) studies suggests that the caudate nucleus (CN) plays a role in the cognitive, sensory, and emotional integration of pain information in patients with migraine. However, evidence concerning the role played by CN in CM patients is limited. Here, we used the CN as the seed to explore patterns of functional connectivity (FC) among healthy controls (HCs), patients with episodic migraine (EM), and patients with CM. Methods We included 25 HCs, 23 EM patients, and 46 CM patients in this study. All participants underwent resting-state functional MRI scans on a GE 3.0T MRI system. We performed seed-based FC analyses among the three groups using the bilateral CNs as seeds. We also compared the subgroups of CM (with and without medication overuse headache, males and females) and performed Pearson’s correlation analyses between FC values and the clinical features of CM patients. Results FC values between the right CN and five clusters (mainly involved in emotion, cognition, and sensory-related brain regions) were higher in CM patients than in HCs. Compared to EM patients, enhanced FC values between the bilateral precuneus, left anterior cingulate gyrus, right middle cingulate cortex, right lingual gyrus, and right CN were shown in the CM patients. There were no significant differences between CM patients with and without MOH, males and females. FC values between the bilateral calcarine cortex, lingual gyrus, and right CN were positively correlated with body mass index. Moreover, right CN-related FC values in the left calcarine cortex and right lingual gyrus were inversely correlated with visual analogue scale scores for headaches. Conclusion Our results revealed abnormal right CN-based FC values in CM patients, suggesting dysfunction of brain networks associated with pain perception and multi-regulation (emotion, cognition, and sensory). Aberrant FC of the CN can provide potential neuroimaging markers for the diagnosis and treatment of CM.

Abstract Background The pathogenesis of migraine chronification remains unclear. Functional and structural magnetic resonance imaging studies have shown impaired functional and structural alterations in the brains of patients with chronic migraine. The cerebellum and periaqueductal gray (PAG) play pivotal roles in the neural circuits of pain conduction and analgesia in migraine. However, few neurotransmitter metabolism studies of these migraine-associated regions have been performed. To explore the pathogenesis of migraine chronification, we measured gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels in the dentate nucleus (DN) and PAG of patients with episodic and chronic migraine and healthy subjects. Methods Using the MEGA-PRESS sequence and a 3-Tesla magnetic resonance scanner (Signa Premier; GE Healthcare, Chicago, IL, USA), we obtained DN and PAG metabolite concentrations from patients with episodic migraine (n = 25), those with chronic migraine (n = 24), and age-matched and sex-matched healthy subjects (n = 16). Patients with chronic migraine were further divided into those with (n = 12) and without (n = 12) medication overuse headache. All scans were performed at the Beijing Tiantan Hospital, Capital Medical University. Results We found that patients with chronic migraine had significantly lower levels of GABA/water (p = 0.011) and GABA/creatine (Cr) (p = 0.026) in the DN and higher levels of Glx/water (p = 0.049) in the PAG than healthy controls. In all patients with migraine, higher GABA levels in the PAG were significantly associated with poorer sleep quality (GABA/water: r = 0.515, p = 0.017, n = 21; GABA/Cr: r = 0.522, p = 0.015, n = 21). Additionally, a lower Glx/Cr ratio in the DN may be associated with more severe migraine disability (r = -0.425, p = 0.055, n = 20), and lower GABA/water (r = -0.424, p = 0.062, n = 20) and Glx/Water (r = -0.452, p = 0.045, n = 20) may be associated with poorer sleep quality. Conclusions Neurochemical levels in the DN and PAG may provide evidence of the pathological mechanisms of migraine chronification. Correlations between migraine characteristics and neurochemical levels revealed the pathological mechanisms of the relevant characteristics.

PurposeOsteoporosis is a complex bone disease influenced by numerous factors. Previous studies have found that some metabolites are related to bone mineral density (BMD). However, the associations between metabolites and BMD under the influence of genes and lifestyle have not been fully investigated.MethodsWe analyzed the effect of metabolites on BMD under the synergistic effect of genes and lifestyle, using the data of 797 participants aged 55–65 years from the Taizhou Imaging Study. The cumulative sum method was used to calculate the polygenic risk score of SNPs, and the healthful plant-based diet index was used to summarize food intake. The effect of metabolites on BMD changes under the influence of genes and lifestyle was analyzed through interaction analysis and mediation analysis.ResultsNineteen metabolites were found significantly different in the osteoporosis, osteopenia, and normal BMD groups. We found two high-density lipoprotein (HDL) subfractions were positively associated with osteopenia, and six very-low-density lipoprotein subfractions were negatively associated with osteopenia or osteoporosis, after adjusting for lifestyles and genetic factors. Tea drinking habits, alcohol consumption, smoking, and polygenic risk score changed BMD by affecting metabolites.ConclusionWith the increased level of HDL subfractions, the risk of bone loss in the population will increase; the risk of bone loss decreases with the increased level of very-low-density lipoprotein subfractions. Genetic factors and lifestyles can modify the effects of metabolites on BMD. Our results show evidence for the precise prevention of osteoporosis.

Abstract Background Selection of high-risk subjects for endoscopic screening of esophageal squamous cell carcinoma (ESCC) lacks individual predictive tools based on environmental risk factors. Methods We performed a large population-based case-control study of 1418 ESCC cases and 1992 controls in a high-risk area of China. Information on potential risk factors was collected via face-to-face interview using an electronic structured questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models, and predictive nomograms were established accordingly. A weighted analysis was further conducted to introduce age into predictive nomograms due to frequency matching study design. Results Most cases were usually exposed to 4 to 6 risk factors, but most controls were usually exposed to 3 to 5 risk factors. The AUCs of male and female predictive nomograms were 0.75 (95%CI: 0.72, 0.77) and 0.76 (95%CI: 0.73, 0.79), respectively. The weighted analysis adding age in the predictive model improved the AUC in both men and women (0.81 (95%CI: 0.79, 0.84) and 0.88 (95%CI: 0.85, 0.90), respectively). Conclusions An easy-to-use preclinical predictive tool is provided to select candidate population with high ESCC risk for endoscopic screening. Its usefulness needs to be further evaluated in future screening practice.

Abstract Background Early diagnosis of esophageal squamous cell carcinoma (ESCC) remains a challenge due to the lack of specific blood biomarkers. We aimed to develop a serum multi-protein signature for the early detection of ESCC. Methods We selected 70 healthy controls, 30 precancerous patients, 60 stage I patients, 70 stage II patients and 70 stage III/IV ESCC patients from a completed ESCC case-control study in a high-risk area of China. Olink Multiplex Oncology II targeted proteomics panel was used to simultaneously detect the levels of 92 cancer-related proteins in serum using proximity extension assay. Results We found that 10 upregulated and 13 downregulated protein biomarkers in serum could distinguish the early-stage ESCC from healthy controls, which were validated by the significant dose-response relationships with ESCC pathological progression. Applying least absolute shrinkage and selection operator (LASSO) regression and backward elimination algorithm, ANXA1 (annexin A1), hK8 (kallikrein-8), hK14 (kallikrein-14), VIM (vimentin), and RSPO3 (R-spondin-3) were kept in the final model to discriminate early ESCC cases from healthy controls with an area under curve (AUC) of 0.936 (95% confidence interval: 0.899 ~ 0.973). The average accuracy rates of the five-protein classifier were 0.861 and 0.825 in training and test data by five-fold cross-validation. Conclusions Our study suggested that a combination of ANXA1, hK8, hK14, VIM and RSPO3 serum proteins could be considered as a potential tool for screening and early diagnosis of ESCC, especially with the establishment of a three-level hierarchical screening strategy for ESCC control.

The standard therapy administered to patients with advanced esophageal cancer remains uniform, despite its two main histological subtypes, namely esophageal squamous cell carcinoma (SCC) and esophageal adenocarcinoma (AC), are being increasingly considered to be different. The identification of potential drug target genes between SCC and AC is crucial for more effective treatment of these diseases, given the high toxicity of chemotherapy and resistance to administered medications. Herein we attempted to identify and rank differentially expressed genes (DEGs) in SCC vs. AC using ensemble feature selection methods. RNA-seq data from The Cancer Genome Atlas and the Fudan-Taizhou Institute of Health Sciences (China). Six feature filters algorithms were used to identify DEGs. We built robust predictive models for histological subtypes with the random forest (RF) classification algorithm. Pathway analysis also be performed to investigate the functional role of genes. 294 informative DEGs (87 of them are newly discovered) have been identified. The areas under receiver operator curve (AUC) were higher than 99.5% for all feature selection (FS) methods. Nine genes (i.e., ERBB3, ATP7B, ABCC3, GALNT14, CLDN18, GUCY2C, FGFR4, KCNQ5, and CACNA1B) may play a key role in the development of more directed anticancer therapy for SCC and AC patients. The first four of them are drug targets for chemotherapy and immunotherapy of esophageal cancer and involved in pharmacokinetics and pharmacodynamics pathways. Research identified novel DEGs in SCC and AC, and detected four potential drug targeted genes (ERBB3, ATP7B, ABCC3, and GALNT14) and five drug-related genes.

Patients whose disease is diagnosed in its early stages have better outcomes. In this study, the authors develop a non invasive blood test based on circulating tumor DNA methylation that can potentially detect cancer occurrence even in asymptomatic patients.

Background: We aimed to explore the relationship between lifestyle factors, cancer family history, and gastric cancer risk.Methods: We examined the association between lifestyle factors, cancer family history, and gastric cancer risk based on a population-based case-control study in Taixing, China, with 870 cases and 1928 controls. A lifestyle score was constructed considering body shape, smoking, alcohol drinking, tooth brushing habit, and food storage method. Unconditional logistic regression models were used to calculate odd ratios (ORs) and 95% confidence intervals (CIs).Results: Compared with participants with a lifestyle score of 0, subjects with a lifestyle score of 1 (OR 0.59, 95%CI 0.43–0.83), 2 (OR 0.42, 95%CI 0.30–0.59), 3 (OR 0.29, 95%CI 0.20–0.41), 4 (OR 0.20, 95%CI 0.13–0.32), or 5 (OR 0.10, 95%CI 0.04–0.22) had a lower risk of gastric cancer (P for trend < 0.001). Overall, 34% of gastric cancer cases (95%CI 27–41%) can be attributed to non-compliance with ≥3 healthy lifestyle. Family history of early-onset cancer is closely related to the occurrence of gastric cancer, with an OR ranging from 1.77 to 3.27. Regardless of family history, a good lifestyle is associated with a reduced risk of gastric cancer, with an OR value between 0.38 and 0.70.Conclusions: The early-onset cancer family history is closely related to the occurrence of gastric cancer and a good lifestyle is associated with a reduced risk of gastric cancer regardless of family history. Our results provide a basis for identifying and providing behavior guidance of high-risk groups of gastric cancer.

Abstract The relationship between risk of esophageal squamous cell carcinoma (ESCC) and adult height, changes in individual body mass index (BMI) and body shape is not established. We performed a large population‐based case‐control study, which enrolled a total of 1414 ESCC cases and 1989 controls in a high‐incidence area in China. Using face‐to‐face interview with a structured questionnaire, information on participants' heights, weights, and perceived body shapes at 20 years of age was collected. Additionally, data on weight and perceived body shape among the same participants 10 years prior to ascertainment were collected using the same method. Odd ratios (ORs) of ESCC risk in relation to BMI and body shape were estimated using unconditional logistic regression models. The adjusted results indicated that ESCC risk in adults rapidly rose as height increased, plateauing at 170 cm among men and 157 cm among women. Among participants who were underweight, normal weight, or thinner than body shape 4, body weight loss was associated with increased risk of ESCC, and body weight gain was associated with decreased incidence of ESCC (ORs ranging from 0.40 to 0.76). Notably, however, changes in body weight did not significantly affect ESCC risk among participants who were overweight, obese, or larger than body shape 3. Maintaining a fit body shape and a reasonable BMI is advisable and of vital importance to reduce the risk of ESCC, especially in high‐risk areas.

Two meta-analysis of genome wide association studies identified two variants at adenylate cyclase 5 (ADCY5) associated with type 2 diabetes mellitus, fasting and 2-hour glucose in non-pregnant individuals of European descent. The objective of our study was to explore the role of common variants in ADCY5 on gestational glycemic traits, including plasma glucose, insulin values, β cell function and insulin resistance in the fasted state as well as plasma glucose 1 hour after a 50-gram glucose challenge test among Chinese Han women. Homoeostasis model assessment (HOMA) was used to quantify β cell function (HOMA1-β and HOMA2-β) and insulin resistance (HOMA1-IR and HOMA2-IR). Thirty-five single nucleotide polymorphisms (SNPs) in ADCY5 were genotyped in 929 unrelated Chinese Han women with singleton pregnancies. Three SNPs (rs6797915, rs9856662 and rs9875803) displayed evidence for association with plasma glucose 1 hour after a 50-gram glucose challenge test (P = 0.042, 0.018 and 0.018, respectively), one (rs6777397) displayed evidence for association with HOMA1-β (P = 0.014), and one (rs6762009) displayed evidence for association with HOMA1-IR (P = 0.033). These results provide additional insight into the effects of genetic variation within ADCY5 in glucose metabolism, especially during pregnancy and in non-European descent populations.

Abstract Recent studies suggested that maternal and placental leptin receptor (LEPR) may be involved in maternal glucose metabolism in pregnancy. To identify maternal and fetal LEPR common variants influencing gestational glycemic traits, we performed association study of 24-28-week maternal fasting glucose, glucose 1 hour after the consumption of a 50-g oral glucose load, fasting insulin and indices of beta-cell function (HOMA-β) and insulin resistance (HOMA-IR) in 1,112 unrelated women and their children. Follow-up of 36 LEPR loci identified 3 maternal loci (rs10889567, rs1137101 and rs3762274) associated with fasting glucose, these 3 fetal loci associated with fasting insulin and HOMA1-IR, as well as these 3 maternal-fetal loci combinations associated with HOMA2-β. We also demonstrated association of maternal locus rs7554485 with HOMA2-β and HOMA2-IR, maternal locus rs10749754 with fasting glucose, fetal locus rs10749754 with HOMA2-IR. However, these associations were no longer statistically significant after Bonferroni correction. In conclusion, our results first revealed multiple associations between maternal and fetal LEPR common variants and gestational glycemic traits. These associations did not survive Bonferroni correction. These corrections are overly conservative for association studies. We therefore believe the influence of these nominally significant variants on gestational glycometabolism will be confirmed by additional studies.

Background: Cerebral microbleeds (CMBs) are considered to be risk factors for cognitive dysfunction. The specific pathology and clinical manifestations of CMBs are different based on their locations. We investigated the association between CMBs at different locations and cognitive dysfunction and explored the potential underlying pathways in a rural Han Chinese population. Methods: We used baseline data from 562 community-dwelling adults (55–65 years old) in the Taizhou Imaging Study between 2013 and 2015. All individuals underwent multimodal brain magnetic resonance imaging (MRI) and 444 subjects completed neuropsychological tests: the Mini-Mental Status Examination and the Montreal Cognitive Assessment. Multinomial logistic regression was used to estimate the association between CMBs and cognitive dysfunction. The volume of brain regions and white matter microstructure were analyzed using Freesurfer and tract-based spatial statistics, respectively. Results: CMBs were detected in 104 individuals (18.5%) in our study. Multinomial logistic regression found deep/mixed CMBs were associated with global cognitive dysfunction (OR 3.52; 95% CI 1.21 to 10.26), whereas lobar CMBs (OR 1.76; 95% CI 0.56 to 5.53) were not. Quantification of multimodal brain MRI showed that deep/mixed CMBs were accompanied by decreased thalamic volume and loss of fractional anisotropy of bilateral anterior thalamic radiations. Conclusion: Deep/mixed CMBs were associated with cognitive dysfunction in this Chinese cross-sectional study. Disruption of thalamocortical connectivity might be a potential pathway underlying this relationship. Keywords: Cerebral microbleeds, Cognitive impairment, Multimodal imaging

Non-small cell lung cancer is one of the most common cancers and the leading cause of cancer death worldwide. Genetic variants in regulatory regions of some miRNAs might be involved in non-small cell lung cancer susceptibility and survival. rs12220909 (G/C) genetic polymorphism in miR-4293 has been shown to be associated with decreased risk of esophageal squamous cell carcinoma. However, the influence of rs12220909 genetic variation on non-small cell lung cancer susceptibility has not been reported. In order to evaluate the potential association between miR-4293 rs12220909 and non-small cell lung cancer risk in a Chinese population, we performed a case-control study among 998 non-small cell lung cancer cases and 1471 controls. The data shows that miR-4293 rs12220909 was significantly associated with decreased susceptibility to non-small cell lung cancer (GC vs.GG: OR = 0.681, 95%CI = 0.555-0.835, P = 2.19E-4; GG vs. GC+CC: OR = 0.687, 95%CI = 0.564-0.837, P = 1.95E-4), which indicates that rs12220909 in miR-4293 may play a significant role in the development of non-small cell lung cancer.

Poor oral health has been linked with an increased risk of esophageal squamous cell carcinoma (ESCC). We investigated whether alteration of oral microbiota is associated with ESCC risk. Fasting saliva samples were collected from 87 incident and histopathologicallly diagnosed ESCC cases, 63 subjects with dysplasia and 85 healthy controls. All subjects were also interviewed with a questionnaire. V3-V4 region of 16S rRNA was amplified and sequenced by 454-pyrosequencing platform. Carriage of each genus was compared by means of multivariate-adjusted odds ratios derived from logistic regression model. Relative abundance was compared using Metastats method. Beta diversity was estimated using Unifrac and weighted Unifrac distances. Principal coordinate analysis (PCoA) was applied to ordinate dissimilarity matrices. Multinomial logistic regression was used to compare the coordinates between different groups. ESCC subjects had an overall decreased microbial diversity compared to control and dysplasia subjects (P

To evaluate the reproducibility and validity of a food frequency questionnaire (FFQ) developed to investigate the relationship between dietary factors and diseases in the adult Chinese population in East China.A total of 78 males and 129 females aged 30-75 years completed four inconsecutive 24-hour dietary recalls (24-HRs, served as a reference method) and two FFQs (FFQ1 and FFQ2) over a nine-month interval. The reproducibility of the FFQ was estimated with correlation coefficients, cross-classification, and weighted kappa statistic. The validity was assessed by comparing the data obtained from FFQ and 24-HRs.The median nutrient intakes assessed with FFQs were higher than the average of four 24-HRs. For the food groups, Spearman, Pearson, and intraclass correlation coefficients between FFQ1 and FFQ2 ranged from 0.23 to 0.61, 0.27 to 0.64, and 0.26 to 0.65, respectively. For total energy and nutrient intakes, the corresponding coefficients ranged from 0.25 to 0.61, 0.28 to 0.64, and 0.28 to 0.62, respectively. The correlations between FFQ1 and FFQ2 for most nutrients decreased after adjustment with total energy intake. More than 70% of the subjects were classified into the same and adjacent categories by both FFQs. For food groups, the crude, energy-adjusted, and de-attenuated Spearman correlation coefficients between FFQ2 and the 24-HRs ranged from 0.17 to 0.59, 0.10 to 0.57, and 0.11 to 0.64, respectively. For total energy and nutrient intakes, the corresponding coefficients ranged from 0.20 to 0.58, 0.08 to 0.54, and 0.09 to 0.56, respectively. More than 67% of the subjects were classified into the same and adjacent categories by both instruments. Both weighted kappa statistic and Bland-Altman Plots showed reasonably acceptable agreement between the FFQ2 and 24-HRs.The FFQ developed for adults in the Taizhou area is reasonably reliable and valid for assessment of most food and nutrient intakes.

Polymethoxyflavones (PMFs) are a class of abundant specialized metabolites with remarkable anticancer properties in citrus. Multiple methoxy groups in PMFs are derived from methylation modification catalyzed by a series of hydroxylases and O-methyltransferases (OMTs). However, the specific OMTs that catalyze the systematic O-methylation of hydroxyflavones remain largely unknown. Here, we report that PMFs are highly accumulated in wild mandarins and mandarin-derived accessions, while undetectable in early-diverging citrus species and related species. Our results demonstrated that three homologous genes, CreOMT3, CreOMT4, and CreOMT5, are crucial for PMF biosynthesis in citrus, and their encoded methyltransferases exhibit multisite O-methylation activities for hydroxyflavones, producing seven PMFs in vitro and in vivo. Comparative genomic and syntenic analyses indicated that the tandem CreOMT3, CreOMT4, and CreOMT5 may be duplicated from CreOMT6 and contributes to the genetic basis of PMF biosynthesis in the mandarin group through neofunctionalization. We also demonstrated that N17 in CreOMT4 is an essential amino acid residue for C3-, C5-, C6-, and C3'-O-methylation activity and provided a rationale for the functional deficiency of OMT6 to produce PMFs in early-diverging citrus and some domesticated citrus species. A 1,041-bp deletion in the CreOMT4 promoter, which is found in most modern cultivated mandarins, has reduced the PMF content relative to that in wild and early-admixture mandarins. This study provides a framework for reconstructing PMF biosynthetic pathways, which may facilitate the breeding of citrus fruits with enhanced health benefits. [ABSTRACT FROM AUTHOR]