Altered dynamic spontaneous neural activity in minimal hepatic encephalopathy.

Background and aims: Abnormal regional neural activity has been identified by the analysis of the static amplitude of low-frequency fluctuation (ALFF) in the setting of minimal hepatic encephalopathy (MHE). Brain activity is highly dynamic. This work sought to evaluate the temporal variability of ALFF to reveal MHE-related alterations in the dynamics of spontaneous neural activity. Methods: A total of 29 healthy controls and 49 patients with cirrhosis [including 20 patients with MHE and 29 patients without MHE (NHE)] who underwent resting-state functional magnetic resonance imaging and Psychometric Hepatic Encephalopathy Score (PHES) examination were enrolled in this investigation. Utilizing a sliding-window approach, we calculated the dynamic ALFF (dALFF) variability to reflect the temporal dynamics of regional neural activity. An analysis of the correlation between dALFF variability and PHES was performed, and receiver operating characteristic (ROC) curve analysis to determine the potential of the dALFF variability index in identifying MHE was completed. Results: The dALFF variability in the bilateral precuneus/posterior cingulate gyrus and left middle frontal gyrus progressively decreased from NHE to MHE group. In cirrhotic patients, the value of dALFF variability in the bilateral precuneus/posterior cingulate gyrus was positively correlated with their neurocognitive performance (r = 0.383 and P = 0.007). The index of dALFF variability in the bilateral precuneus/posterior cingulate gyrus could be used to distinguish NHE and MHE patients, with moderate power (area under the ROC curve = 0.712 and P = 0.012). Conclusion: Our findings highlight the existence of aberrant dynamic brain function in MHE, which could underlie the neural basis of cognitive impairments and could be associated with the development of the disease. Analyzing dALFF could facilitate new biomarker identification for MHE.

Aberrant stability of brain functional architecture in cirrhotic patients with minimal hepatic encephalopathy.

To investigate the stability changes of brain functional architecture and the relationship between stability change and cognitive impairment in cirrhotic patients. Fifty-one cirrhotic patients (21 with minimal hepatic encephalopathy (MHE) and 30 without MHE (NHE)) and 29 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging and neurocognitive assessment using the Psychometric Hepatic Encephalopathy Score (PHES). Voxel-wise functional connectivity density (FCD) was calculated as the sum of connectivity strength between one voxel and others within the entire brain. The sliding window correlation approach was subsequently utilized to calculate the FCD dynamics over time. Functional stability (FS) is measured as the concordance of dynamic FCD. From HCs to the NHE and MHE groups, a stepwise reduction of FS was found in the right supramarginal gyrus (RSMG), right middle cingulate cortex, left superior frontal gyrus, and bilateral posterior cingulate cortex (BPCC), whereas a progressive increment of FS was observed in the left middle occipital gyrus (LMOG) and right temporal pole (RTP). The mean FS values in RSMG/LMOG/RTP (r = 0.470 and P = 0.001; r = -0.458 and P = 0.001; and r = -0.384 and P = 0.005, respectively) showed a correlation with PHES in cirrhotic patients. The FS index in RSMG/LMOG/BPCC/RTP showed moderate discrimination potential between the NHE and MHE groups. Changes in FS may be linked to neuropathological bias of cognitive impairment in cirrhotic patients and could serve as potential biomarkers for MHE diagnosis and monitoring the progression of hepatic encephalopathy.

Dynamic Alterations in Functional Connectivity Density in Amyotrophic Lateral Sclerosis: A Resting-State Functional Magnetic Resonance Imaging Study.

Background and Aims: Current knowledge on the temporal dynamics of the brain functional organization in amyotrophic lateral sclerosis (ALS) is limited. This is the first study on alterations in the patterns of dynamic functional connection density (dFCD) involving ALS. Methods: We obtained resting-state functional magnetic resonance imaging (fMRI) data from 50 individuals diagnosed with ALS and 55 healthy controls (HCs). We calculated the functional connectivity (FC) between a given voxel and all other voxels within the entire brain and yield the functional connection density (FCD) value per voxel. dFCD was assessed by sliding window correlation method. In addition, the standard deviation (SD) of dFCD across the windows was computed voxel-wisely to measure dFCD variability. The difference in dFCD variability between the two groups was compared using a two-sample t-test following a voxel-wise manner. The receiver operating characteristic (ROC) curve was used to assess the between-group recognition performance of the dFCD variability index. Results: The dFCD variability was significantly reduced in the bilateral precentral and postcentral gyrus compared with the HC group, whereas a marked increase was observed in the left middle frontal gyrus of ALS patients. dFCD variability exhibited moderate potential (areas under ROC curve = 0.753-0.837, all P < 0.001) in distinguishing two groups. Conclusion: ALS patients exhibit aberrant dynamic property in brain functional architecture. The dFCD evaluation improves our understanding of the pathological mechanisms underlying ALS and may assist in its diagnosis.

Tryptophan and tumor immunity / 药学学报

As an essential amino acid, tryptophan (Trp) has various physiological functions and is of great significance in the metabolic process of tumors. In the human body, tryptophan is mainly transformed through kynurenine metabolic pathway, which not only promotes the inherent malignant properties of tumor cells, but also leads to immune-suppressive tumor microenvironment. Changes in tryptophan metabolism often occur in tumors, accompanied by abnormal gene expression of tryptophan-related enzymes, among which indoleamine 2,3-bioxygenase (IDO)-related gene expression and tryptophan 2,3-dioxygenase (TDO)-related gene changes are the most significant. A large number of clinical trials on IDO inhibitors, TDO inhibitors and combination therapy have been carried out. This paper reviewed the tryptophan metabolic pathway, regulation of IDO (TDO), kynurenine (KYN) and other related genes in tumor cells, and outlined the development of therapeutic schedule targeting tryptophan-related genes. The new progress provides new ideas for the further exploration of tumor treatment options.

The immunomodulatory effect of lactic acid within the tumor microenvironment / 药学学报

Tumor cells leads to enhanced glucose uptake and the conversion of a larger fraction of pyruvate into lactate even under the circumstance of abundant oxygen. This phenomenon of aerobic glycolysis is known as the Warburg effect. Lactic acid, as an important tool for tumor cells to modify the tumor microenvironment, promotes the process of tumor invasion and metastasis, and contributes to tumor development by inducing and recruiting immunosuppression-related cells and molecules. Lactic acid could efflux out of the cancer cells via the monocarboxylate transporters to prevent intracellular acidification. Lactate can inhibit the cytolytic activity of T cells and natural killer (NK) cells, promoting the differentiation of tolerogenic interleukin 10 (IL-10)-producing dendritic cells. Moreover, the lactate-derived lactylation of histone lysine residues can promote macrophage polarization toward the M2-like phenotype, suppressing the immune response within the tumor microenvironment. In this review, we discuss the role of lactate as an immunosuppressor molecule that contributes to tumor evasion from the aspects of lactic acid metabolism and its effect on immune cells. And we explore the possibility of targeting potential targets in lactate metabolism for tumor treatment. At last, we proposed a tumor immunotherapy strategy by inhibiting the pathway of aerobic glycolysis and proteins associated with the production and transport of lactic acid.

Abnormal Stability of Dynamic Functional Architecture in Amyotrophic Lateral Sclerosis: A Preliminary Resting-State fMRI Study.

Purpose: Static and dynamic analyses for identifying functional connectivity (FC) have demonstrated brain dysfunctions in amyotrophic lateral sclerosis (ALS). However, few studies on the stability of dynamic FC have been conducted among ALS patients. This study explored the change of functional stability in ALS and how it correlates with disease severity. Methods: We gathered resting-state functional magnetic resonance data from 20 patients with ALS and 22 healthy controls (HCs). The disease severity was assessed with the Revised ALS Functional Rating Scale (ALSFRS-R). We used a sliding window correlation approach to identify dynamic FC and measured the concordance of dynamic FC over time to obtain the functional stability of each voxel. We assessed the between-group difference in functional stability by voxel-wise two-sample t-test. The correlation between the functional stability index and ALSFRS-R in ALS patients was evaluated using Spearman's correlation analysis. Results: Compared with the HC group, the ALS group had significantly increased functional stability in the left pre-central and post-central gyrus and right temporal pole while decreased functional stability in the right middle and inferior frontal gyrus. The results revealed a significant correlation between ALSFRS-R and the mean functional stability in the right temporal pole (r = -0.452 and P = 0.046) in the ALS patients. Conclusions: ALS patients have abnormal stability of brain functional architecture, which is associated with the severity of the disease.

Thalamic Structural Connectivity Abnormalities in Minimal Hepatic Encephalopathy.

Background and Aims: Numerous studies have demonstrated thalamus-related structural, functional, and metabolic abnormalities in minimal hepatic encephalopathy (MHE). We conducted the first study to investigate thalamic structural connectivity alterations in MHE. METHODS: Diffusion tensor imaging (DTI)-based probabilistic tractography was employed to determine the structural linkage between the thalamus and cortical/subcortical regions in 52 cirrhotic patients [22 with MHE; 30 without MHE (NHE)] and 30 controls. We measured these thalamic connections, which included connectivity strength (CS), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), and then compared these among the three groups. Neurocognitive assessment was also performed. Correlation analysis was conducted to investigate the relationship between neurocognitive performance and the above measurements. Classification analysis was performed to determine whether thalamic connection measurements can distinguish MHE from NHE. RESULTS: The probabilistic tractography revealed thalamic structural connections, which were disrupted in cirrhotic patients (as reflected by a decrease in CS/FA and an increase in MD/AD/RD). Abnormal thalamic connections primarily involved the prefrontal cortex, sensorimotor cortex, parietal cortex, medial temporal cortex and hippocampus, and striatum. Thalamic connectivity abnormalities deteriorated from NHE to MHE, and they were correlated with patients' neurocognitive performance. The moderate classification accuracy was obtained using CS and MD as discriminating indexes. CONCLUSION: Our results demonstrated the altered thalamic structural connectivity involving both cortical and subcortical regions in MHE, which could be regarded as representative of MHE-related widespread impairments in white matter pathways. The disturbed thalamic connectivity may underlie the mechanism of cognitive deficits in MHE and may potentially be utilized as a biomarker for diagnosing MHE and in monitoring disease progression. In addition to thalamic-cortical/subcortical connections, further studies are recommended to explore the structural alterations in other white matter pathways in MHE.

Dynamic Changes in Functional Network Connectivity Involving Amyotrophic Lateral Sclerosis and Its Correlation With Disease Severity.

BACKGROUND: Aberrant static functional connectivity (FC) has been well demonstrated in amyotrophic lateral sclerosis (ALS); however, ALS-related alterations in FC dynamic properties remain unclear, although dynamic FC analyses contribute to uncover mechanisms underlying neurodegenerative disorders. PURPOSE: To explore dynamic functional network connectivity (dFNC) in ALS and its correlation with disease severity. STUDY TYPE: Prospective. SUBJECTS: Thirty-two ALS patients and 45 healthy controls. FIELD STRENGTH/SEQUENCE: Multiband resting-state functional images using gradient echo echo-planar imaging and T1-weighted images were acquired at 3.0 T. ASSESSMENT: Disease severity was evaluated with the revised ALS Functional Rating Scale (ALSFRS-R) and patients were stratified according to diagnostic category. Independent component analysis was conducted to identify the components of seven intrinsic brain networks (ie, visual/sensorimotor (SMN)/auditory/cognitive-control (CCN)/default-mode (DMN)/subcortical/cerebellar networks). A sliding-window correlation approach was used to compute dFNC. FNC states were determined by k-mean clustering, and state-specific FNC and dynamic indices (fraction time/mean dwell time/transition number) were calculated. STATISTICAL TESTS: Two-sample t test used for comparisons on dynamic measures and Spearman's correlation analysis. RESULTS: ALS patients showed increased FNC between DMN-SMN in state 1 and between CCN-SMN in state 4. Patients remained in state 2 (showing the weakest FNC) for a significantly longer time (mean dwell time: 49.8 ± 40.1 vs. 93.6 ± 126.3; P < 0.05) and remained in state 1 (showing a relatively strong FNC) for a shorter time (fraction time: 0.27 ± 0.25 vs. 0.13 ± 0.20; P < 0.05). ALS patients exhibited less temporal variability in their FNC (transition number: 10.2 ± 4.4 vs. 7.8 ± 3.8; P < 0.05). A significant correlation was observed between ALSFRS-R and mean dwell time in state 2 (r = -0.414, P < 0.05) and transition number (r = 0.452, P < 0.05). No significant between-subgroup difference in dFNC properties was found (all P > 0.05). DATA CONCLUSION: Our findings suggest aberrant dFNC properties in ALS, which is associated with disease severity. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

[A Review of Progress of the Relation Between Stress Response and Diabetes Mellitus].

Stress response is an adaptive process of the organism to confront environmental perturbation. Moderate stress response induces the organism to establish effective adaptive strategies for survival, while excessive stress response results in stress injury, which is a major cause of a variety of physical or psychological diseases, including diabetes mellitus. Diabetes mellitus is a typical stress-related disease, with numerous evidence indicating that the development and progression of diabetes mellitus are closely related to stress response, such as metabolic stress, oxidative stress and endoplasmic reticulum stress. However, the detailed mechanisms of stress response mediated regulation of diabetes mellitus and how to prevent or treat diabetes mellitus via modification of stress response remain to be further investigated. Here, we will introduce the definition and regulatory mechanisms of stress response, as well as discuss the biological functions and mechanisms of various stress responses during the pathogenesis of diabetes mellitus. This review highlights recent advances of stress medicine associated with diabetes mellitus, in order to provide theoretical basis and reference for prevention and treatment of diabetes mellitus. Future studies should focus on elucidating the clinical application potential of the key factors of stress response that mediate the pathogenesis of diabetes mellitus, as well as boosting the related translational medicine studies.

Intrinsic Brain Abnormalities in Patients with Hepatitis C Virus Infection with Cognitive Impairment: A Preliminary Resting-State fMRI Study.

PURPOSE: Patients with a hepatitis C virus (HCV) infection frequently exhibit various neuropsychiatric complications such as cognitive decline. This study is aimed at investigating alterations in regional and network-level neural function in patients with HCV infection and examining the association between these alterations and patients' cognition dysfunction. METHODS: The study included 17 patients with HCV infection and 17 healthy controls. These individuals had undergone resting-state functional magnetic resonance imaging as well as cognitive assessment using a battery of tests that were collectively called the "psychometric hepatic encephalopathy score (PHES)" examination. Analyses of amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) were conducted to assess, respectively, regional neural function and functional integration. RESULTS: HCV-infected patients performed significantly worse in cognitive tests. In the HCV group, ALFF decreased in Region 1 (left medial frontal gyrus and bilateral anterior cingulate gyrus) and Region 2 (right middle and superior frontal gyrus). The HCV group showed lower FC between Region 1 and right middle frontal gyrus, whereas they presented an increase in FC between Region 2 and the left supramarginal gyrus/superior temporal gyrus and right supramarginal gyrus. No significant correlation was observed between ALFF/FC measurements and PHES result. CONCLUSION: This preliminary study presents additional evidence that HCV infection affects brain function, including local intrinsic neural activity and global functional integration.

Aberrant dynamic functional network connectivity in cirrhotic patients without overt hepatic encephalopathy.

PURPOSE: Neurocognitive impairment is a common complication in cirrhosis and is associated with alterations in static functional network connectivity (FNC) between distinct brain systems. However, accumulating evidence suggests temporal variability in FNC even at rest. This study aimed to explore dynamic FNC (dFNC) differences and to elucidate their association with neurocognitive changes in cirrhotic patients. METHODS: Fifty-four cirrhotic patients and 42 controls underwent resting-state functional magnetic resonance imaging. Psychometric hepatic encephalopathy score (PHES) was used to assess neurocognitive function. Independent component analysis was performed to identify the components of seven intrinsic brain networks, including sensorimotor (SMN), auditory, visual, cognitive control (CCN), default mode (DMN), subcortical (SC), and cerebellar networks. Sliding window correlation approach was employed to calculate dFNC. FNC states were determined by k-means clustering method, and then functional state analysis was conducted to measure dynamic indices. RESULTS: The patients showed decreased dFNC in State 2, involving the connectivity between posterior subsystem of DMN and CCN (represented by bilateral insular cortex), and in State 3, involving the connectivity between SMN (represented by bilateral precentral gyrus) and SC (represented by bilateral putamen and caudate). The patients spent significantly longer time in State 4 that was with weakest FNC across all networks. We observed a significant correlation between PHES and fraction time/mean dwell time in State 4. CONCLUSIONS: Aberrant dFNC may be the underlying mechanism of neurocognitive impairments in cirrhosis. Dynamic FNC analysis may potentially be utilized in investigating cirrhosis-related neuropathological processes.

Disturbance of thalamic metabolism and its association with regional neural dysfunction and cognitive impairment in minimal hepatic encephalopathy.

PURPOSE: To conduct the first investigation on thalamic metabolic alterations in minimal hepatic encephalopathy (MHE) and elucidate their association with intrinsic neural activity change and cognitive dysfunction. METHODS: Thirty-eight cirrhotic patients [18 with MHE, 20 without MHE (NHE)] and 21 healthy controls (HC) were included, all of whom underwent 1H-magnetic resonance spectroscopy, resting-state functional magnetic resonance imaging (fMRI), as well as cognitive assessment based on the Psychometric Hepatic Encephalopathy Score (PHES). Metabolite ratios in the thalamus were measured, including N-acetyl aspartate (NAA)/creatine (Cr), glutamate plus glutamine (Glx)/Cr, choline (Cho)/Cr, and myo-inositol (mI)/Cr. Intrinsic neural activity was evaluated based on frequency-specific amplitude of low-frequency fluctuations (ALFF) using fMRI signals. RESULTS: MHE patients showed an increase in Glx/Cr and a decrease in Cho/Cr and mI/Cr, compared with HC. These changes were aggravated from NHE to MHE. Cho/Cr and mI/Cr were positively correlated with regional ALFF derived from the frequency-specific band (0.01-0.027 Hz) and PHES. Receiver operating characteristic curve analysis showed that Cho/Cr and mI/Cr measurements exhibited moderate discrimination ability between NHE and MHE. CONCLUSION: Our findings provide evidence that MHE is associated with disturbed metabolism in the thalamus, which may contribute to the altered neural activity and underlie the mechanisms of cognitive impairments. MRS measurements in the thalamus could serve as the potential biomarker for diagnosing MHE among cirrhotic patients.

Review on clinical research progress of immunotherapy in liver cancer / 药学学报

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, which is characterized by complex pathogenesis, inconspicuous early symptoms, rapid progress and poor prognosis. Immunotherapy and targeted therapy are important methods to treat advanced and metastatic liver cancer in recent years. With the FDA's approval of sorafenib and other tyrosine kinase inhibitors and programmed cell death protein 1 and cytotoxic T lymphocyte-associated antigen-4 immune checkpoint inhibitors for the treatment of liver cancer, great progress has been made in single-agent therapy and combination therapy, bringing a new turning point for the improvement of survival rate of patients with advanced liver cancer. However, the mechanism of immunotherapy and drug resistance is still unclear, and its clinical application combined with targeted and other therapies is still under research, which needs to be further explored by researchers. In this paper, the clinical research progress of immunotherapy combined with other therapies in advanced hepatocellular carcinoma was reviewed, in order to grasp the current development trend of the treatment of hepatocellular carcinoma and provide reference for the further development direction of immunotherapy.

The mechanism and research progress of drug resistance of PD-1/PD-L1 immunotherapy in tumors / 药学学报

Programmed cell death protein 1 (PD-1) is an important immunosuppressive molecule, which combines with programmed cell death 1 ligand 1 (PD-L1) to initiate programmed T-cell death, leading to immune escape of tumor cells. Immune checkpoint inhibitors kill tumor cells by blocking the binding of PD-1 to PD-L1 and reactivating the patient's own immune system. With the approval of anti-PD-1 monoclonal antibodies nivolumab, pembrolizumab and anti-PD-L1 monoclonal antibody atezolizumab by FDA for the treatment of melanoma, advanced non-small cell lung cancer and other cancers, cancer treatment has ushered in a new dawn. However, only 20% of patients achieved long-term efficacy after treatment, and most patients relapsed later. Therefore, it is significant to identify effective biomarkers and develop new targets to improve the response of patients to immunotherapy. This article reviews on the mechanism of action of anti-PD-1/PD-L1 drugs in tumors, potential biomarkers and the mechanism of acquired drug resistance, as well as combination therapy under research.