Multiomics and blood-based biomarkers of moyamoya disease: protocol of Moyamoya Omics Atlas (MOYAOMICS).

BACKGROUND: Moyamoya disease (MMD) is a rare and complex cerebrovascular disorder characterized by the progressive narrowing of the internal carotid arteries and the formation of compensatory collateral vessels. The etiology of MMD remains enigmatic, making diagnosis and management challenging. The MOYAOMICS project was initiated to investigate the molecular underpinnings of MMD and explore potential diagnostic and therapeutic strategies. METHODS: The MOYAOMICS project employs a multidisciplinary approach, integrating various omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, to comprehensively examine the molecular signatures associated with MMD pathogenesis. Additionally, we will investigate the potential influence of gut microbiota and brain-gut peptides on MMD development, assessing their suitability as targets for therapeutic strategies and dietary interventions. Radiomics, a specialized field in medical imaging, is utilized to analyze neuroimaging data for early detection and characterization of MMD-related brain changes. Deep learning algorithms are employed to differentiate MMD from other conditions, automating the diagnostic process. We also employ single-cellomics and mass cytometry to precisely study cellular heterogeneity in peripheral blood samples from MMD patients. CONCLUSIONS: The MOYAOMICS project represents a significant step toward comprehending MMD's molecular underpinnings. This multidisciplinary approach has the potential to revolutionize early diagnosis, patient stratification, and the development of targeted therapies for MMD. The identification of blood-based biomarkers and the integration of multiple omics data are critical for improving the clinical management of MMD and enhancing patient outcomes for this complex disease.

The potential of mesenchymal stem cells to induce immune tolerance to allogeneic transplants.

Organ allograft transplantation is an effective treatment plan for patients with organ failure. Although the application of continuous immunosuppressants makes successful allograft survival possible, the patients' long-term survival rate and quality of life are not ideal. Therefore, it is necessary to find a new strategy to alleviate transplant rejection by developing therapies for permanent allograft acceptance. One promising approach is the application of tolerogenic mesenchymal stem cells (MSCs). Extensive research on MSCs has revealed that MSCs have potent differentiation potential and immunomodulatory properties. This review describes the molecular markers and functional properties of MSCs as well as the immunomodulatory mechanisms of MSCs in transplantation, focuses on the research progress in clinical trials of MSCs, and expounds on the future development prospects and possible limitations.

Determining the mechanism of pulsatilla decoction for treating gastric cancer: a network pharmacology-based study.

Background and aim: Gastric cancer (GC) is a prevalent malignancy worldwide. Pulsatilla decoction (PD), a traditional Chinese medicine formula, can treat inflammatory bowel disease and cancers. In this study, we explored the bioactive components, potential targets, and molecular mechanisms of PD in the treatment of GC. Methods: We conducted a thorough search of online databases to gather gene data, active components, and potential target genes associated with the development of GC. Subsequently, we conducted bioinformatics analysis utilizing protein-protein interaction (PPI), network construction, and Kyoto Encyclopedia of Genes and Genomes (KEGG) to identify potential anticancer components and therapeutic targets of PD. Finally, the efficacy of PD in treating GC was further validated through in vitro experiments. Results: Network pharmacological analysis identified 346 compounds and 180 potential target genes associated with the impact of PD on GC. The inhibitory effect of PD on GC may be mediated through modulation of key targets such as PI3K, AKT, NF-κB, FOS, NFKBIA, and others. KEGG analysis showed that PD mainly exerted its effect on GC through the PI3K-AKT, IL-17, and TNF signaling pathways. Cell viability and cell cycle experiments showed that PD could significantly inhibit proliferation and kill GC cells. Moreover, PD primarily induces apoptosis in GC cells. Western blotting analysis confirmed that the PI3K-AKT, IL-17, and TNF signaling pathways are the main mechanisms by which PD exerts its cytotoxic effects on GC cells. Conclusion: We have validated the molecular mechanism and potential therapeutic targets of PD in treating GC through network pharmacological analysis, thereby demonstrating its anticancer efficacy against GC.

Prevalence and Procedural Risk of Intracranial Atherosclerotic Stenosis Coexisting With Unruptured Intracranial Aneurysm.

BACKGROUND: Coexistence of intracranial atherosclerotic stenosis (ICAS) and unruptured intracranial aneurysms (UIAs) is increasingly encountered in clinical practice. This study aims to determine the prevalence of ICAS in patients with UIAs and procedural ischemic risk associated with ICAS when treating UIAs. METHODS: Based on the CAIASA study (Coexistence of Atherosclerotic Intracranial Arterial Stenosis With Intracranial Aneurysms), we prospectively included patients undergoing treatment procedures for UIAs from October 2015 to December 2020 at Beijing Tiantan Hospital, China. We used computed tomography angiography or digital subtraction angiography to diagnose ICAS (stenosis≥50%). Multivariable logistic regression and propensity-score matching were performed to evaluate the risk of procedure-related ischemic stroke and unfavorable outcome associated with ICAS. The ICAS score was used to explore the association between different burden of ICAS and procedure-related ischemic risk. RESULTS: Among 3949 patients who underwent endovascular or open surgical procedures for UIAs, 245 (6.2%) had ICAS. After exclusion, 15.7% (32/204) of patients with ICAS experienced procedure-related ischemic stroke compared with 5.0% (141/2825) of patients without ICAS. From the unmatched and matched cohort, ICAS was significantly associated with increased risk of procedure-related ischemic stroke (unmatched: adjusted odds ratio=3.11 [1.89-5.11]; and matched: adjusted odds ratio=2.99 [1.38-6.48]). This association became more evident among patients not receiving antiplatelet therapy (Pinteraction=0.022). For patients undergoing different treatment modalities, similar increased risks were observed (clipping: adjusted odds ratio=3.43 [1.73-6.79]; and coiling: adjusted odds ratio=3.59 [1.94-6.65]). Higher ICAS score was correlated with higher procedural ischemic risk (Ptrend<0.001). CONCLUSIONS: The occurrence of ICAS is not infrequent in patients with UIAs. ICAS confers an ~2-fold increased procedural ischemic risk, irrespective of clipping or coiling. Previous antiplatelet therapy may decrease the risk. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02795078.

Infarction Patterns and Recurrent Adverse Cerebrovascular Events in Moyamoya Disease.

For moyamoya disease (MMD) patients who suffered an acute ischemic attack, the infarction patterns on DWI and its association with recurrent adverse cerebrovascular events (ACEs) after bypass surgery remain unknown. 327 patients who suffered an acute ischemic attack and received following revascularization surgery were retrospectively reviewed and were divided into three patterns according to the lesion number and distribution on DWI that obtained within 7 days of onset: no acute infarction (NAI), single acute infarction (SAI), and multiple acute infarctions (MAIs). We used Cox proportional hazard models to estimate hazard ratios (HR) for associations of infarction patterns and the risk of recurrent ACEs and strokes. Over a median follow-up of 41 months (IQR 26-60), there were 61 ACEs and 27 strokes. Compared to the NAI cohort, patients with SAI (HR, 2.92; 95% CI, 1.41-6.05; p = 0.004) and MAIs (HR, 4.44; 95% CI, 2.10-9.41; p < 0.001) were associated with higher risk of ACEs recurrences. In analysis adjusted for age and surgery modalities, the corresponding HR was 2.90 (95% CI: 1.41-5.98) for SAI and 4.10 (95% CI: 1.95-8.63) for MAIs, and this effect remained persistent on further adjustment for several potential confounders. Similar but less precise association was found in separate analysis that only takes into account stroke recurrences. Thus, different infarction patterns on DWI imply different risks of recurrent ACEs, and more attention should be paid to prevent ACEs in MMD patients with MAIs.

Macrophages in transplant rejection.

Transplant rejection is one of the primary factors leading to loss of allograft function, and macrophages are involved in allograft rejection. Macrophages polarize into different phenotypes according to stimulation by different external factors. Different types of macrophages play distinct roles in inflammation, tumors, and autoimmune diseases and are involved in transplant rejection. In this review, we introduce the origin and migration of macrophages, outline the classification of macrophages and their polarization mechanisms, and review the currently understood mechanisms of their involvement in transplant rejection. Finally, we discuss the regulation of macrophage polarization and miRNA expression with respect to transplant rejection, which is important for the development of new anti-rejection therapies.

Right-hemispheric language reorganization in patients with brain arteriovenous malformations: A functional magnetic resonance imaging study.

Brain arteriovenous malformation (AVM), a presumed congenital lesion, may involve traditional language areas but usually does not lead to language dysfunction unless it ruptures. The objective of this research was to study right-hemispheric language reorganization patterns in patients with brain AVMs using functional magnetic resonance imaging (fMRI). We prospectively enrolled 30 AVM patients with lesions involving language areas and 32 age- and sex-matched healthy controls. Each subject underwent fMRI during three language tasks: visual synonym judgment, oral word reading, and auditory sentence comprehension. The activation differences between the AVM and control groups were investigated by voxelwise analysis. Lateralization indices (LIs) for the frontal lobe, temporal lobe, and cerebellum were compared between the two groups, respectively. Results suggested that the language functions of AVM patients and controls were all normal. Voxelwise analysis showed no significantly different activations between the two groups in visual synonym judgment and oral word reading tasks. In auditory sentence comprehension task, AVM patients had significantly more activations in the right precentral gyrus (BA 6) and right cerebellar lobule VI (AAL 9042). According to the LI results, the frontal lobe in oral word reading task and the temporal lobe in auditory sentence comprehension task were significantly more right-lateralized in the AVM group. These findings suggest that for patients with AVMs involving language cortex, different language reorganization patterns may develop for different language functions. The recruitment of brain areas in the right cerebral and cerebellar hemispheres may play a compensatory role in the reorganized language network of AVM patients.

Impact of AVM location on language cortex right-hemisphere reorganization: A voxel-based lesion-symptom mapping study.

OBJECTIVES: Cerebral arteriovenous malformations (AVMs) are congenital malformations, and right-sided dominance of the language cortex is not a rare phenomenon for patients with AVM involving language area. We tried to use voxel-based lesion-symptom mapping (VLSM) method to depict the location of AVM nidus and to demonstrate the relationship between AVM location and the pattern of language cortex reorganization. PATIENTS AND METHODS: The authors retrospectively reviewed clinical and imaging data of 70 adult patients with unruptured cerebral AVMs who underwent blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) of language task. All patients were right handed, and all lesions were located in the left cerebral hemisphere. Lateralization indexes (LI) of the BOLD signals were calculated for Broca and Wernicke areas separately and were used to reflect the degree of right-sided dominance of the two language areas. VLSM method was applied to study the relationship between AVM location and LI of language task activations. RESULTS: Statistical analysis revealed that the change of LI of Broca area was significantly associated with lesions located in the inferior frontal gyrus, pre- and post-central gyrus, supramarginal gyrus and middle frontal gyrus. The change of LI of Wernicke area was significantly associated with lesions located in the left superior, middle, inferior and transverse temporal gyrus. CONCLUSION: These findings provide new evidence that the language cortex reorganization patterns in AVM patients have anatomic specificity.

Comparison of Long-Term Effect Between Direct and Indirect Bypass for Pediatric Ischemic-Type Moyamoya Disease: A Propensity Score-Matched Study.

Objectives: This study aimed to compare the postoperative risks and long-term effects between direct bypass surgery (DB) and indirect bypass (IB) surgery for pediatric patients with ischemic-type moyamoya disease (MMD). Method: Pediatric patients (under or equal to 18 years old) who were diagnosed as MMD and given surgical treatments at our center between 2009 and 2015 were retrospectively reviewed from a prospective database. Pediatric hemorrhagic-type MMD patients and those who did not undergo digital subtraction angiography (DSA) were excluded. Patients who underwent DB were matched with patients who underwent IB using 1:1 propensity score matching. Postoperative complications, recurrent ischemic stroke events and modified Rankin Scale (mRS) scores at the last follow-up were compared between the matched pairs. Results: A total of 223 pediatric patients were screened, and 138 patients (DB:34, IB:104) were considered for the propensity score match. Thirty four pairs were obtained. Nine patients had postoperative complications, including 6 (17.6%) in the DB group and 3 (8.8%) in the IB group (P = 0.476). The mean follow-up period was 71.9 ± 22.2 months for the DB group and 60.2 ± 24.3 months for the IB group (P = 0.041). Kaplan-Meier analysis showed a longer stroke-free time in the DB group than in the IB group (P = 0.025). At last follow-up, good neurological status (mRS ≤ 1) was achieved in 32 (94.1%) of the DB group and 34 (100.0%) of the IB group. MRS score at last follow-up were significantly lower than at time of admission (all pts: 1.09 ± 0.45 vs. 0.28 ± 0.51, P < 0.001; DB group: 1.12 ± 0.48 vs. 0.32 ± 0.59, P < 0.001; IB group: 1.06 ± 0.42 vs. 0.24 ± 0.43, P < 0.001). Conclusion: Both techniques were effective in improving the neurological status of pediatric ischemic-type MMD patients, and direct bypass surgery might be more superior in preventing recurrent ischemic strokes in the short-term.

Modified encephalo-duro-periosteal-synangiosis (EDPS) for the revascularization of anterior cerebral artery territory in moyamoya disease: A single-center experience.

OBJECTIVES: Anterior cerebral artery (ACA) territory, a crucial area of intellectual development in children, is frequently involved in the progress of moyamoya disease (MMD). However, revascularization surgeries for this area are not as established as surgeries for middle cerebral artery (MCA) territory. This study aimed to describe our experience and study the effect of revascularizing ACA territory with periocranium and dural leaflets, which is referred to as 'encephalo-duro-periosteal-synangiosis (EDPS)'. PATIENTS AND METHOD: Fourteen hemispheres of 9 MMD patients who had undergone EDPS from November 2015 till July 2017 in our hospital were retrospectively included. Clinical characteristics and procedure-related information were recorded. Cerebral perfusion was evaluated by computed tomography perfusion (CTP). Absolute and relative (r) CTP parameters of ROIs in ACA territory at the level of centrum semiovale and middle basal ganglia were calculated. Preoperative and postoperative parameters were compared. RESULTS: All EDPS procedures were technically successful with no postoperative complications. The mean operating time was 75.00 ± 22.53 min per hemisphere. Postoperative absolute cerebral blood flow (CBF), rCBF were significantly increased and absolute time to peak (TTP), rTTP, absolute mean transit time (MTT) were significantly reduced in ACA territory at centrum semiovale level (P = 0.002, 0.045, 0.007, 0.005 and 0.039 respectively). Improved outcomes were achieved in five patients, stabilization in three and one patient had deterioration out of intracerebral hemorrhage during follow-up. CONCLUSION: EDPS is a simple but effective technique to revascularize ACA territory for MMD. EDPS significantly improved cerebral blood perfusion of frontal lobe in the majority of patients without increasing procedure-related risks.

Direct Bypass Surgery Vs. Combined Bypass Surgery for Hemorrhagic Moyamoya Disease: A Comparison of Angiographic Outcomes.

Objective: Extracranial-intracranial bypass is currently recognized as the optimal treatment for hemorrhagic-type moyamoya disease (MMD) which reduces incidence of rebleeding. Recent studies have reported the advantage of combined bypass over direct bypass for the general MMD patients. However, the effect of direct bypass and combined bypass surgery specifically for hemorrhagic-type MMD had not been investigated yet. Methods: Hemorrhagic-type MMD patients who underwent direct and combined bypass surgery with complete clinical and radiological documentation from a multicenter cohort between 2009 and 2017 were retrospectively included. Surgical methods included superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis (direct bypass), combined STA-MCA bypass with encephalodurosynangiosis (EDS), and combined STA-MCA bypass with encephaloduroarteriosynangiosis (EDAS). Matsushima standard on follow-up catheter angiography was used to assess surgical outcome. Modified Rankin Scale, incidence of rebleeding and ischemia during follow-up were recorded. Rebleeding-free survival rates between direct and combined bypass were compared by Kaplan-Meier analysis. Results: Sixty eight hemorrhagic-onset MMD patients were included in this study, among which 71 hemispheres were treated with surgery (direct bypass: 17; bypass+EDS: 24; bypass+EDAS: 30). Forty six (64.8%) hemispheres had satisfactory revascularization (Matsushima level 2-3) and 26 (36.6%) had poor neoangiogenesis. Matsushima level was not significantly different between surgical groups (P = 0.258). Good neoangiogenesis from dural grafts was achieved in 26 (36.6%) hemispheres, and good neoangiogenesis from STA grafts was only seen in 4 (out of 30, 12.5%) hemispheres. Multivariate analysis showed bypass patency [P < 0.001, OR (95%CI): 13.41 (3.28-54.80)] and dural neoangiogenesis [P < 0.001, OR (95%CI): 13.18 (3.26-53.36)] both independently contributed to good angiographic outcome. During follow-up, incidences of rebleeding or ischemic events, and re-bleeding free survival rate were not significantly different between surgical groups (P = 0.433, P = 0.559, and P = 0.997). However, patients who underwent combined bypass surgery had significantly lower mRS at follow-up comparing to patients who underwent direct bypass (P = 0.006). Conclusion: Combined bypass surgery and direct bypass surgery offered similar revascularization for hemorrhagic MMD. Bypass patency and dural angiogenesis both contributed to revascularization independently. The potential of indirect bypass to grow new vessels in hemorrhagic-MMD patients was generally limited, but dural leaflets offered better neoangiogenesis than STA grafts and was therefore recommended for surgical revascularization of hemorrhagic MMD.