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Abstract O6‐methylguanine DNA methyltransferase (MGMT) removes alkyl adducts from the guanine O6 position (O6‐MG) and repairs DNA damage. High MGMT expression results in poor response to temozolomide (TMZ). However, the biological importance of MGMT and the mechanism underlying its high expression in pancreatic neuroendocrine tumors (PanNETs) remain elusive. Here, it is found that MGMT expression is highly elevated in PanNET tissues compared with paired normal tissues and negatively associated with progression‐free survival (PFS) time in patients with PanNETs. Knocking out MGMT inhibits cancer cell growth in vitro and in vivo. Ectopic MEN1 expression suppresses MGMT transcription in a manner that depends on β‐Catenin nuclear export and degradation. The Leucine 267 residue of MEN1 is crucial for regulating β‐Catenin‐MGMT axis activation and chemosensitivity to TMZ. Interference with β‐Catenin re‐sensitizes tumor cells to TMZ and significantly reduces the cytotoxic effects of high‐dose TMZ treatment, and MGMT overexpression counteracts the effects of β‐Catenin deficiency. This study reveals the biological importance of MGMT and a new mechanism by which MEN1 deficiency regulates its expression, thus providing a potential combinational strategy for treating patients with TMZ‐resistant PanNETs.

Abstract For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role.

ObjectivesHip involvement is an important reason of disability in patients with ankylosing spondylitis (AS). Unveiling the potential phenotype of hip involvement in AS remains an unmet need to understand its biological mechanisms and improve clinical decision-making. Radiomics, a promising quantitative image analysis method that had been successfully used to describe the phenotype of a wide variety of diseases, while it was less reported in AS. The objective of this study was to investigate the feasibility of radiomics-based approach to profile hip involvement in AS.MethodsA total of 167 patients with AS was included. Radiomic features were extracted from pelvis MRI after image preprocessing and feature engineering. Then, we performed unsupervised machine learning method to derive radiomics-based phenotypes. The validation and interpretation of derived phenotypes were conducted from the perspectives of clinical backgrounds and MRI characteristics. The association between derived phenotypes and radiographic outcomes was evaluated by multivariable analysis.Results1321 robust radiomic features were extracted and four biologically distinct phenotypes were derived. According to patient clinical backgrounds, phenotype I (38, 22.8%) and II (34, 20.4%) were labelled as high-risk while phenotype III (24, 14.4%) and IV (71, 42.5%) were at low risk for hip involvement. Consistently, the high-risk phenotypes were associated with higher prevalence of MRI-detected lesion than the low-risk. Moreover, phenotype I had significant acute inflammation signs than phenotype II, while phenotype IV was enthesitis-predominant. Importantly, the derived phenotypes were highly predictive of radiographic outcomes of patients, as the high-risk phenotypes were 3 times more likely to have radiological hip lesion than the low-risk [27 (58.7%) vs 16 (28.6%); adjusted odds ratio (OR) 2.95 (95% CI 1.10, 7.92)].ConclusionWe confirmed for the first time, the clinical actionability of profiling hip involvement in AS by radiomics method. Four distinct phenotypes of hip involvement in AS were identified and importantly, the high-risk phenotypes could predict structural damage of hip involvement in AS.

[INLINE:1] The safety and effectiveness of magnetic resonance-guided focused ultrasound thalamotomy has been broadly established and validated for the treatment of essential tremor. In 2018, the first magnetic resonance-guided focused ultrasound system in Chinese mainland was installed at the First Medical Center of the PLA General Hospital. This prospective, single center, open-label, single-arm study was part of a worldwide prospective multicenter clinical trial (ClinicalTrials.gov Identifier: NCT03253991) conducted to confirm the safety and efficacy of magnetic resonance-guided focused ultrasound for treating essential tremor in the local population. From 2019 to 2020, 10 patients with medication refractory essential tremor were recruited into this open-label, single arm study. The treatment efficacy was determined using the Clinical Rating Scale for Tremor. Safety was evaluated according to the incidence and severity of adverse events. All of the subjects underwent a unilateral thalamotomy targeting the ventral intermediate nucleus. At the baseline assessment, the estimated marginal mean of the Clinical Rating Scale for Tremor total score was 58.3 ± 3.6, and this improved after treatment to 23.1 ± 6.4 at a 12-month follow-up assessment. A total of 50 adverse events were recorded, and 2 were defined as serious. The most common intraoperative adverse events were nausea and headache. The most frequent postoperative adverse events were paresthesia and equilibrium disorder. Most of the adverse events were mild and usually disappeared within a few days. Our findings suggest that magnetic resonance-guided focused ultrasound for the treatment of essential tremor is effective, with a good safety profile, for patients in Chinese mainland.

Abstract Big data serves as the cornerstone for constructing real-world deep learning systems across various domains. In medicine and healthcare, a single clinical site lacks sufficient data, thus necessitating the involvement of multiple sites. Unfortunately, concerns regarding data security and privacy hinder the sharing and reuse of data across sites. Existing approaches to multi-site clinical learning heavily depend on the security of the network firewall and system implementation. To address this issue, we propose Relay Learning, a secure deep-learning framework that physically isolates clinical data from external intruders while still leveraging the benefits of multi-site big data. We demonstrate the efficacy of Relay Learning in three medical tasks of different diseases and anatomical structures, including structure segmentation of retina fundus, mediastinum tumors diagnosis, and brain midline localization. We evaluate Relay Learning by comparing its performance to alternative solutions through multi-site validation and external validation. Incorporating a total of 41,038 medical images from 21 medical hosts, including 7 external hosts, with non-uniform distributions, we observe significant performance improvements with Relay Learning across all three tasks. Specifically, it achieves an average performance increase of 44.4%, 24.2%, and 36.7% for retinal fundus segmentation, mediastinum tumor diagnosis, and brain midline localization, respectively. Remarkably, Relay Learning even outperforms central learning on external test sets. In the meanwhile, Relay Learning keeps data sovereignty locally without cross-site network connections. We anticipate that Relay Learning will revolutionize clinical multi-site collaboration and reshape the landscape of healthcare in the future.

Abstract DddA-derived cytosine base editors (DdCBEs) greatly facilitated the basic and therapeutic research of mitochondrial DNA mutation diseases. Here we devise a saturated spacer library and successfully identify seven DddA homologs by performing high-throughput sequencing based screen. DddAs of Streptomyces sp. BK438 and Lachnospiraceae bacterium sunii NSJ-8 display high deaminase activity with a strong GC context preference, and DddA of Ruminococcus sp. AF17-6 is highly compatible to AC context. We also find that different split sites result in wide divergence on off-target activity and context preference of DdCBEs derived from these DddA homologs. Additionally, we demonstrate the orthogonality between DddA and DddIA, and successfully minimize the nuclear off-target editing by co-expressing corresponding nuclear-localized DddIA. The current study presents a comprehensive and unbiased strategy for screening and characterizing dsDNA cytidine deaminases, and expands the toolbox for mtDNA editing, providing additional insights for optimizing dsDNA base editors.

Background: MR-guided focused ultrasound (MRgFUS) thalamotomy is a novel and effective treatment for medication-refractory tremor in essential tremor (ET), but how the brain responds to this deliberate lesion is not clear. Objective: The current study aimed to evaluate the immediate and longitudinal alterations of functional networks after MRgFUS thalamotomy. Methods: We retrospectively obtained preoperative and postoperative 30-day, 90-day, and 180-day data of 31 ET patients subjected with MRgFUS thalamotomy from 2018 to 2020. Their archived resting-state functional MRI data were used for functional network comparison as well as graph-theory metrics analysis. Both partial least squares (PLS) regression and linear regression were conducted to associate functional features to tremor symptoms. Results: MRgFUS thalamotomy dramatically abolished tremors, while global functional network only sustained immediate fluctuation within one week after the surgery. Network-based statistics have identified a long-term enhanced corticostriatal subnetwork by comparison between 180-day and preoperative data (P = 0.019). Within this subnetwork, network degree, global efficiency and transitivity were significantly recovered in ET patients right after MRgFUS thalamotomy compared to the pre-operative timepoint (P

Double-stranded DNA-specific cytidine deaminase (DddA) base editors hold great promise for applications in bio-medical research, medicine, and biotechnology. Strict sequence preference on spacing region presents a challenge for DddA editors to reach their full potential. To overcome this sequence-context constraint, we analyzed a protein dataset and identified a novel DddAtox homolog from Ruminococcus sp. AF17-6 (RsDddA). We engineered RsDddA for mitochondrial base editing in a mammalian cell line and demonstrated RsDddA-derived cytosine base editors (RsDdCBE) offered a broadened NC sequence compatibility and exhibited robust editing efficiency. Moreover, our results suggest the average frequencies of mitochondrial genome-wide off-target editing arising from RsDdCBE are comparable to canonical DdCBE and its variants.

Abstract. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel and minimally invasive technology. Since the US Food and Drug Administration approved unilateral ventral intermediate nucleus-MRgFUS for medication-refractory essential tremor in 2016, studies on new indications, such as Parkinson's disease (PD), psychiatric diseases, and brain tumors, have been on the rise, and MRgFUS has become a promising method to treat such neurological diseases. Currently, as the second most common degenerative disease, PD is a research hotspot in the field of MRgFUS. The actions of MRgFUS on the brain range from thermoablation, blood-brain barrier (BBB) opening, to neuromodulation. Intensity is a key determinant of ultrasound actions. Generally, high intensity can be used to precisely thermoablate brain targets, whereas low intensity can be used as molecular therapies to modulate neuronal activity and open the BBB in conjunction with injected microbubbles. Here, we aimed to summarize advances in the application of MRgFUS for the treatment of PD, with a focus on thermal ablation, BBB opening, and neuromodulation, in the hope of informing clinicians of current applications.

Focused ultrasound is a noninvasive, radiation-free and real-time therapeutic approach to treat deep-seated targets, which benefits numerous diseases otherwise requiring surgeries. Treatment efficiency is one of the key factors determining therapeutic outcomes, but improving it solely by increasing the total power can be limited by the performance of general ultrasound devices. To address this, multi-frequency therapeutic ultrasound, using additional ultrasound waves of different frequencies on top of the standard single-frequency wave, provides a promising method for treatment efficiency enhancement with limited power. Several applications and numerical works have demonstrated its superiority on treatment enhancement. This paper presents an overview of the mechanisms, implementations, applications and decisive parameters of the multi-frequency therapeutic ultrasound, which could help to pave the way for better understanding and further developing this technology in the future.

ObjectiveSpinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a rare neurodegenerative disease for which there is no specific treatment. Very few cases have been treated with single-target deep brain stimulation (DBS), and the results were not satisfactory. We applied multi-target DBS to an SCA3/MJD patient and performed positron emission computed tomography (PET) before and after DBS to explore the short-term clinical therapeutic effect.Materials and methodsA 26-year-old right-hand-dominant female with a family history of SCA3/MJD suffered from cerebellar ataxia and dystonia. Genetic testing indicated an expanded CAG trinucleotide repeat in the ATXN3 gene and a diagnosis of SCA3/MJD. Conservative treatment had no obvious effect; therefore, leads were implanted in the bilateral dentate nucleus (DN) and the globus pallidus internus (GPi) and connected to an external stimulation device. The treatment effect was evaluated in a double-blind, randomized protocol in five phases (over a total of 15 days): no stimulation, GPi, DN, or sham stimulation, and combined GPi and DN stimulation. 18F-fluoro-2-deoxy-d-glucose and dopamine transporter PET, Scale for the Assessment and Rating of Ataxia, Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM), Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), and SF-36 quality of life scores were compared before and after DBS.ResultsThe Total Scale for the Assessment and Rating of Ataxia scores improved by ~42% (from 24 to 14). The BFMDRS movement scores improved by ~30% (from 40.5 to 28.5). The BFMDRS disability scores improved by ~12.5% (from 16 to 14). Daily living activities were not noticeably improved. Compared with the findings in pre-DBS imaging, 18F-fluoro-2-deoxy-d-glucose uptake increased in the cerebellum, while according to dopamine transporter imaging, there were no significant differences in the bilateral caudate nucleus and putamen.ConclusionMulti-target acute stimulation (DN DBS and GPi DBS) in SCA3/MJD can mildly improve cerebellar ataxia and dystonia and increase cerebellar metabolism.

ObjectiveTinnitus is frequently found in patients with vestibular schwannoma (VS), but its underlying mechanisms are currently unclear.MethodsBoth preoperative (VSpre) and postoperative (VSpost) functional MR images were collected from 32 patients with unilateral VS and matched healthy controls (HCs). Connectome gradients were generated for the identification of altered regions and perturbed gradient distances. Tinnitus measurements were conducted for predictive analysis with neuroimaging–genetic integration analysis.ResultsThere were 56.25% of preoperative patients and 65.63% of postoperative patients suffering from ipsilateral tinnitus, respectively. No relevant factors were identified including basic demographics info, hearing performances, tumor features, and surgical approaches. Functional gradient analysis confirmed atypical functional features of visual areas in VSpre were rescued after tumor resection, while the gradient performance in the postcentral gyrus continues to maintain (VSpost vs. HC : P = 0.016). The gradient features of the postcentral gyrus were not only significantly decreased in patients with tinnitus (PFDR = 0.022), but also significantly correlated with tinnitus handicap inventory (THI) score (r = −0.30, P = 0.013), THI level (r = −0.31, P = 0.010), and visual analog scale (VAS) rating (r = −0.31, P = 0.0093), which could be used to predict VAS rating in the linear model. Neuropathophysiological features linked to the tinnitus gradient framework were linked to Ribosome dysfunction and oxidative phosphorylation.ConclusionAltered functional plasticity in the central nervous system is involved in the maintenance of VS tinnitus.

Background: Predictors of recurrent stroke after endovascular treatment for symptomatic intracranial atherosclerotic stenosis (ICAS) remain uncertain. Objectives: Among baseline characteristics, lesion features, and cerebral perfusion changes, we try to explore which factors are associated with the risk of recurrent stroke in symptomatic ICAS after endovascular treatment. Design: Consecutive patients with symptomatic ICAS of 70–99% receiving endovascular treatment were enrolled. All patients underwent whole-brain computer tomography perfusion (CTP) within 3 days before and 3 days after the endovascular treatment. Baseline characteristics, lesion features, and cerebral perfusion changes were collected. Methods: Cerebral perfusion changes were evaluated with RAPID software and calculated as preprocedural cerebral blood flow (CBF) 6 s, and Tmax > 4 s volumes minus postprocedural. Cerebral perfusion changes were divided into periprocedural perfusion improvement (>0 ml) and non-improvement (⩽ 0 ml). Recurrent stroke within 180 days was collected. The Cox proportional hazards analysis analyses were performed to evaluate factors associated with recurrent stroke. Results: From March 2021 to December 2021, 107 patients with symptomatic ICAS were enrolled. Of the 107 enrolled patients, 30 (28.0%) patients underwent balloon angioplasty alone and 77 patients (72.0%) underwent stenting. The perioperative complications occurred in three patients. Among CBF 6 s, and Tmax > 4 s volumes, Tmax > 4 s volume was available to evaluate cerebral perfusion changes. Periprocedural perfusion improvement was found in 77 patients (72.0%) and non-improvement in 30 patients (28.0%). Nine patients (8.4%) suffered from recurrent stroke in 180-day follow-up. In Cox proportional hazards analysis adjusted for age and sex, perfusion non-improvement was associated with recurrent stroke [hazards ratio (HR): 4.472; 95% CI: 1.069–18.718; p = 0.040]. Conclusion: In patients with symptomatic ICAS treated with endovascular treatment, recurrent stroke may be related to periprocedural cerebral perfusion non-improvement. Registration: http://www.chictr.org.cn . Unique identifier: ChiCTR2100052925.

Abstract Background Moyamoya disease (MMD) is an uncommon cerebrovascular disease which leads to progressive stenosis and occlusion of the bilateral internal carotid artery and main intracerebral arteries. Concerns are always on how the hemisphere with infarction affects cognitive function, while little attention is paid to the role that the non-infarcted hemisphere plays. Therefore, we aimed to detect cortical indexes, especially cortical complexity in the left or right hemisphere separately in patients with MMD after stroke. Methods 28 patients with MMD (14 males, 14 females) and 14 healthy controls were included in this study. All participants underwent cognitive tests and magnetic resonance imaging (MRI) scan. The preprocessing of three-dimensional T1 weighted images were performed by standard surface-based morphometry. Surface-based morphometry statistical analysis was carried out with a threshold of False Discovery Rate (FDR) P

BackgroundTumor grade determined by the Ki67 index is the best prognostic factor for pancreatic neuroendocrine tumors (PanNETs). However, we often observe that the grade of metastases differs from that of their primary tumors. This study aimed to investigate the frequency of grade changes between primary tumors and metastases, explore its association with clinical characteristics, and correlate the findings with the prognosis.MethodsSix hundred forty-eight patients with pancreatic neuroendocrine neoplasms treated at Fudan University Shanghai Cancer Center were screened for inclusion, and 103 patients with PanNETs who had paired primary tumors and metastases with an available Ki67 index were included. Re-evaluation of Ki67 was performed on 98 available samples from 69 patients.ResultsFifty cases (48.5%) had a Ki67 index variation, and 18 cases (17.5%) displayed a grade increase. Metachronous metastases showed significantly higher Ki67 index variation than synchronous metastases (P=0.028). Kaplan–Meier analyses showed that high-grade metastases compared to low-grade primary tumors were significantly associated with decreased progression-free survival (PFS, P=0.012) and overall survival (OS, P=0.027). Multivariable Cox regression analyses demonstrated that a low-grade increase to high-grade was an unfavorable and independent prognostic factor for PFS and OS (P=0.010, and P=0.041, respectively).ConclusionsA high-grade increase in metastases was an unfavorable predictor of PanNETs, which emphasized the importance of accurate pathological grading and could provide a reference for clinical decision-making.

Abstract Background Asymptomatic Moyamoya disease (MMD) impairs hemodynamic and cognitive function. The relationship between these changes, cerebral blood flow (CBF), and network connectivity remains largely unknown. The aim of this study was to increase understanding of the relationship between CBF, functional networks, and neurocognition in adults with asymptomatic MMD. We compared CBF and functional status in 26 patients with MMD and 20 healthy controls using arterial spin labeling and resting state functional magnetic resonance imaging sequences. At the same time, a detailed cognitive test was performed in 15 patients with no cerebral or lumen infarction who were selected by magnetic resonance imaging-T2 FLAIR screening. Results Compared to the controls, the patients showed varying degrees of decline in their computational ability (simple subtraction, p = 0.009; complex subtraction, p = 0.006) and short-term memory (p = 0.042). The asymptomatic MMD group also showed decreased CBF in the left anterior central and left inferior frontal gyri of the island flap with multiple node abnormalities in the brain network and reduced network connectivity. There was a significant association of these changes with cognitive decline in the MMD group. Conclusions In patients with asymptomatic MMD, disturbance of CBF and impaired brain network connections may be important causes of cognitive decline and appear before clinical symptoms. Clinical trial registration-URL: http://www.chictr.org.cn Unique identifier: ChiCTR1900023610

Level shifters are widely used in low-power, multi-threshold integrated circuit chips.A novel physical unclonable function (PUF) design based on cross-coupled level shifter was proposed.In this work, a single switching transistor was inserted in the level shifter, which was the only overhead per response bit to change the operation mode of the cross-coupled level shifter from differential to common.The signature of the PUF was extracted while in common mode, by exploiting the uncertainty of the output voltage due to the difference of the switching time of the two PMOS in the cross-coupled network.Simulated with a standard 65 nm CMOS process, the results show the proposed PUF can produce a uniqueness of 49.11% and a reliability of 96.09% with the power supply voltage ranged from 1.0 V to 1.5 V and 95.31% with the temperature ranged from -20 ℃ to 100 ℃.The energy per bit is only 0.72 pJ at a high throughput of 20 Mbit/s (1.2 V, 27 ℃).

Abstract This study aimed to investigate the relationship between the new-onset hyperintense lesions on diffusion-weighted images (DWI) and the changes of cerebral blood flow (CBF) before and after carotid artery stenting (CAS) in patients with symptomatic unilateral carotid artery stenosis. Twenty-four patients with symptomatic unilateral carotid stenosis (50–99%) were enrolled. Routine head magnetic resonance imaging and three-dimensional pseudo-continuous arterial spin labeling were taken 7 days before the surgery and for four consecutive days post CAS. While the incidence of new DWI lesions were high (17/24, 70.8%) and 176 lesions were observed among the 17 cases, there was only one subject showing the symptoms. The majority of the lesions were located at the cortex/subcortex of the ipsilateral frontal and parietal lobes (60.8%) with 92.6% of the lesions size being less than 3 mm. The CBFs in this area were significantly higher than that of the temporal lobe on the first 3 days post stenting (p

Abstract The innate and adaptive immune cells have complex signaling pathways for sensing and initiating immune responses against disease. These pathways are interrupted at different levels to occur immune evasion, including by N6-methyladenosine (m6A) modification. In this review, we discuss studies revealing the immune evasion mechanism by m6A modification, which underlies the retouching of these signaling networks and the rapid tolerance of innate and adaptive immune molecules during disease. We also focus on the functions of m6A in main chemokines regulation, and their roles in promotive and suppressive immune cell recruitment. We then discuss some of the current challenges in the field and describe future directions for the immunological mechanisms of m6A modification.

AbstractPre-trained Transformer-based models have achieved state-of-the-art performance for various Natural Language Processing (NLP) tasks. However, these models often have billions of parameters, and thus are too resource- hungry and computation-intensive to suit low- capability devices or applications with strict latency requirements. One potential remedy for this is model compression, which has attracted considerable research attention. Here, we summarize the research in compressing Transformers, focusing on the especially popular BERT model. In particular, we survey the state of the art in compression for BERT, we clarify the current best practices for compressing large-scale Transformer models, and we provide insights into the workings of various methods. Our categorization and analysis also shed light on promising future research directions for achieving lightweight, accurate, and generic NLP models.

Conventional computer vision algorithms, including stereo matching algorithms, take finely rendered color images as input. However, existing image signal processing (ISP) pipelines for color image generation are designed for photography with a goal of generating pleasing images for human eyes. This paper describes a new end-to-end pipeline for stereo matching from raw Bayer pattern images to disparity maps with customized ISP. Unlike conventional stereo matching systems which need a complete ISP module to render full-size standard RGB (sRGB) images, a subsampling-based demosaicing-downsampling (SDD) operation is introduced in the proposed pipeline to demosaic and downsample the Bayer pattern images. The resultant half-size color image pairs are processed with simple denoising and tone mapping algorithms to generate the final input images of stereo matching algorithms. It is found that the simple nearest neighbor upsampling method is good enough to generate the final full-size disparity maps. Experimental results show that the proposed pipeline is capable of generating comparable or even better stereo matching results than the conventional pipeline. By skipping most of the unnecessary ISP steps and reducing the size of input images, the computational complexity of the end-to-end stereo matching pipeline is significantly reduced.

BackgroundThe four major pathways in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) including chromatin remodeling, DNA damage repair, activation of mTOR signaling, and telomere maintenance were mediated by some critical molecules and constituted critical processes of regulation in cancer-causing processes. However, the interplay and potential role of these pathway-related molecules in the tumor microenvironment of the primary and metastatic site remained unknown.MethodsWe systematically evaluated the mRNA expression of 34 molecules associated with the four pathways in 227 GEP−NEN samples from 5 datasets. We assigned the samples into two expression patterns of pathway-related molecules by an unsupervised clustering method. Subsequently, we explored the specific cell-related molecules, especially immune and stromal cells using the WGCNA method, based on differentially expressed genes (DEGs) responsible for the different patterns of pathway-related molecules, which provided a new method to qualify the pathway-related subtypes of individual tumors, then the PC_Score and PI_Score scoring systems were also constructed using obtained specific cell-related molecules. Furthermore, we performed the association of pathway-related subtypes with characteristics of immune landscape in primary and metastatic GEP-NENs.ResultsWe demonstrated that the specific pathway-related molecules (SMARCA4, MLH1, TSC1, ATRX, and ATR) were associated with cytolytic activity. Then we identified the two distinct patterns of pathway-related molecules, which were characteristic with a significantly distinct immune landscape. Using WGCNA, we also identified the fibroblast-related molecules, including ASPN, COL10A1, COL3A1, EDNRA, MYL9, PRELP, RAB31, SPARC, and THBS2, and immune-related molecules including CASP1, CCL5, CTSS, CYBRD1, PMP22, and TFEC. Based on these specific markers, we identified four distinct pathway-related subtypes, characterized by immune and fibrotic enriched (I/FE), immune enriched (IE), fibrotic enriched (FE), and immune and fibrotic desert (I/FD), of which I/FE was characteristic with the highest PC_Score and PI_Score whereas I/FD presents the opposite trend. I/FE was positively correlated with immune landscape of T-cell activation and immunosuppression. Furthermore, the I/FE marked GEP-NENs with increased immune activation scores (T-cell costimulation, MHC I presentation, and APC costimulation). Importantly, the four distinct pathway-related subtypes were not conserved in different tumor sites, because I/FE was lacking in the liver metastatic site even though IE, FE, and I/FD also could be observed in the metastatic site.ConclusionsThis study was the first to perform a comprehensive analysis of the four major pathways in GEP-NENs. We demonstrated the potential function of these pathway-related molecules in immune landscapes. Our findings indicated that the primary and metastatic GEP-NENs had distinct antitumor phenotypes. This work highlighted the interplay and potential clinical utility of these pathway-related molecules in GEP-NENs.

Abstract Background Few studies have delved into the prevalence of distant metastasis (DM +) and survival for patients with lymph node metastases (LN +) by primary site. We aimed to detect differences in distant metastasis and prognosis between pancreatic head and bodytail tumors for LN + patients. Methods Patients with chemotherapy, histologically diagnosed, primary site between 2004 and 2016 were included from the SEER (Surveillance, Epidemiology, and End Results) database. Pancreatic head tumors were compared with pancreatic bodytail tumors using the odds ratio (OR) for rates of distant metastasis, hazard ratios (HR) for overall survival (OS) and cancer-specific survival (CSS). The competing risk model and propensity score matching (PSM) were performed to further explore. Results Of 5726 LN + patients identified from the SEER database, pancreatic head tumors account for 85.2% (4877 of 5726) and 14.8% (849 of 5726) were pancreatic bodytail tumors. The incidence of DM was lower in pancreatic head than in pancreatic bodytail tumors (OR, 0.29; 95% CI 0.23–0.37; P

Abstract Background The relationship between intracranial vessel configuration and wall features remains poorly investigated. Therefore, we aimed to investigate the relationship between the distal and proximal anatomical configuration of basilar artery (BA) and BA vessel wall features on high-resolution magnetic resonance imaging (HRMRI). Methods From September 2014 to January 2017, patients with suspected symptomatic intracranial arterial stenosis underwent HRMRI. Patients with severe BA stenosis were selected for this prospective study and divided into two groups corresponding to complete and incomplete BA configuration based on characteristics of the bilateral vertebral arteries and posterior cerebral arteries. Culprit blood vessel wall features on HRMRI included plaque enhancement, intraplaque hemorrhage, remodeling patterns, and plaque distribution. Culprit vessel wall features were compared between patients in the complete and incomplete BA configuration groups. Results Among the 298 consecutively enrolled patients, 34 had severe BA stenosis. Twenty patients had complete anatomical BA configuration and another 14 of them displayed incomplete configuration. There were no significant differences in vessel wall features between the complete and incomplete configuration patient groups. However, the proximal configuration of BA was associated with intraplaque hemorrhage (p = 0.002) while the distal configuration of BA correlated with strong enhancement of BA plaque (p = 0.041). Conclusions No association was found between the complete and incomplete BA configuration groups and blood vessel wall features. The proximal configuration of BA was related with intraplaque hemorrhage and the distal configuration of BA was associated with strong plaque enhancement. Further studies are warranted to confirm these findings. Trial registration URL: Unique identifier: NCT02705599 (March 10, 2016).

Summary: Magnetic resonance imaging (MRI) provides structural and functional information, but it did not probe chemistry. Chemical information could help improve specificity of detection. Herein, we introduce a general method based on a modular design to construct a molecular building block Xe probe to help image intracellular biothiols (glutathione (GSH), cysteine (Cys) and homocysteine (Hcy)), the abnormal content of which is related to various diseases. This molecular building block possesses a high signal-to-noise ratio and no background signal effects. Its detection threshold was 100 pM, which enabled detection of intracellular biothiols in live cells. The construction strategy can be easily extended to the detection of any other biomolecule or biomarker. This modular design strategy promotes efficiency of development of low-cost multifunctional probes that can be combined with other readout parameters, such as optical readouts, to complement 129Xe MRI to usher in new capabilities for molecular imaging.

MRgFUS has just been made available for the 1.7 million Parkinson's disease patients in China. Despite its non-invasive and rapid therapeutic advantages for involuntary tremor, some concerns have emerged about outcomes variability, non-specificity, and side-effects, as little is known about its impact on the long-term plasticity of brain structure. We sought to dissect the characteristics of long-term changes in brain structure caused by MRgFUS lesion and explored potential biological mechanisms. One-year multimodal imaging follow-ups were conducted for nine tremor-dominant Parkinson's disease patients undergoing unilateral MRgFUS thalamotomy. A structural connectivity map was generated for each patient to analyze dynamic changes in brain structure. The human brain transcriptome was extracted and spatially registered for connectivity vulnerability. Genetic functional enrichment analysis was performed and further clarified using in vivo emission computed tomography data. MRgFUS not only abolished tremors but also significantly disrupted the brain network topology. Network-based statistics identified a U-shape MRgFUS-sensitive subnetwork reflective of hand tremor recovery and surgical process, accompanied by relevant cerebral blood flow and gray matter alteration. Using human brain gene expression data, we observed that dopaminergic signatures were responsible for the preferential vulnerability associated with these architectural alterations. Additional PET/SPECT data not only validated these gene signatures, but also suggested that structural alteration was significantly correlated with D1 and D2 receptors, DAT, and F-DOPA measures. There was a long-term dynamic loop between structural alteration and dopaminergic signature for MRgFUS thalamotomy, which may be closely related to the long-term improvements in clinical tremor.

Objective: There are limited data regarding the characteristics of intracranial plaques according to stroke mechanism in the posterior circulation. This study aims to compare whether the plaque characteristics and baseline features are different in patients with artery-to-artery (A-to-A) embolism and those with parent artery disease in the intracranial vertebrobasilar atherosclerotic disease.Methods: From September 2014 to January 2017, patients with recent posterior circulation stroke due to intracranial vertebrobasilar atherosclerotic disease were retrospectively analyzed. Patients with the following eligibility criteria were included: (1) age ≥18 years old, (2) ischemic stroke in the vertebrobasilar territory, (3) 70–99% stenosis of the intracranial vertebral artery or basilar artery, and (4) two or more atherosclerotic risk factors. Patients with concomitant ipsilateral or bilateral extracranial vertebral artery >50% stenosis, cardio-embolism, or non-atherosclerotic stenosis were excluded. The plaque characteristics, including intraplaque compositions (intraplaque hemorrhage and intraplaque calcification), intraplaque enhancement, and remodeling index, were evaluated by using 3T high-resolution magnetic resonance imaging (HRMRI). The baseline features including vascular risk factors and the involved artery were collected. Patients were divided into A-to-A embolism and parent artery disease groups based on the diffusion-weighted images, T2-weighted images, or computed tomography. The plaque characteristics and baseline features were compared between the two groups.Results: Among consecutive 298 patients, 51 patients were included. Twenty-nine patients had A-to-A embolism and 22 patients had parent artery disease. Compared with parent artery disease, the occurrence rates of intraplaque enhancement and intracranial vertebral involvement were higher in the A-to-A embolism group (79.3 vs. 36.4%; p = 0.002 and 62.1 vs. 18.2%; p = 0.002, respectively). Multivariable logistic regression analysis showed that intraplaque enhancement and intracranial vertebral artery plaques were also associated with A-to-A embolism (adjusted OR, 7.31; 95% CI 1.58–33.77; p = 0.011 and adjusted OR, 9.42; 95% CI 1.91–46.50; p = 0.006, respectively).Conclusion: Intraplaque enhancement and intracranial vertebral artery plaques seem to be more closely associated with A-to-A embolism than parent artery disease in patients with symptomatic intracranial vertebrobasilar disease.Clinical Trial Registration:http://www.clinicaltrials.gov, identifier: NCT02705599.

Background and Purpose: The Enterprise stent has been used for treating intracranial atherosclerotic stenosis (ICAS), but its long-term outcome remains unclear. The purpose of this study was to evaluate the long-term clinical efficacy of the Enterprise stent used for patients with symptomatic ICAS due to hypoperfusion.Method: Patients with symptomatic ICAS due to hypoperfusion treated with the Enterprise stents from a high-volume stroke center were evaluated. The successful recanalization was defined as the Modified Thrombolysis In Cerebral Infarction (mTICI) ≥ 2b. The stroke and neurological death that occurred within 72 h after the procedure as well as long-term clinical and imaging outcomes were analyzed.Results: Overall, 130 patients with 130 ICAS treated with the Enterprise stent were included in our study. The successful recanalization rate was 100%. The mean pre- and postprocedural stenosis was 82.9 ± 8.9% vs. 15.1 ± 8.4%. Periprocedural complications occurred in 5 (3.8%) patients within 72 h after the procedure. Clinical follow-up data were available in 125 (96.2%) patients (median, 24 months) and any stroke or neurological death was encountered in 6 (4.8%) patients. Angiographic follow-up data was obtained from 118 (90.8%) patients (median, 13.5 months). In addition, 1-year in-stent restenosis (>70%) was found in 17 (14.4%) patients, and among them, 4 (23.5%) patients were symptomatic.Conclusion: Deployment of Enterprise stent is safe for ICAS. The short-term and long-term outcomes were acceptable, but the efficacy of the Enterprise stent needs to be further evaluated in future studies.

Abstract Liver cancer is the most common cancer and is the epitome of a recalcitrant cancer. Increasing evidence shown that long noncoding RNAs (lncRNA) were associated with cancer‐related death and could function as a competing endogenous RNA (ceRNA). To explore regulatory roles and potential prognostic biomarkers of lncRNA for liver cancer, RNA‐sequencing expression data were downloaded from the TCGA database and GEO database. A total of 357 patients were randomly divided into a discovery group and a validation group, of which 313 patients can obtain clinical data. In discovery phrase, 58 lncRNAs, 16 miRNAs, and 34 mRNAs were screened to construct the ceRNA network based on 252 patients employed from discovery group. Univariate and multivariate Cox hazard regression analysis model revealed that five lncRNAs (AATK‐AS1, C10orf91, LINC00162, LINC00200, and LINC00501) from 58 lncRNAs were formulated to predict the overall survival (OS). We used the value of gene expression and regression coefficients to construct a risk score based on the five lncRNAs. Next, we validated our model in the GSE116174 dataset (n = 64) and the validation group (n = 94) from TCGA database. Subgroup analysis suggest that the five lncRNAs played critical parts in early stage in cancer from both discovery and validation groups. The five lncRNAs were also found to be associated with immune cells infiltration including CD4+ memory activated, NK cells activated and mast cells activated, then the results were also validated according to the validation group. Furthermore, KEGG pathway enrichment analysis showed that these nine coexpressed modules using the method of WGCNA, and many of these pathways are associated with the development and progression of disease. At last, the transcription factor binding sites (TFBS) of the five lncRNAs were predicted, which help us to understand the potential mechanism that the TFBS adjusted the ceRNA network. In summary, the ceRNA regulatory network may contribute to a better understanding of liver cancer mechanism and provide potential prognostic biomarkers and therapeutic targets.

Although the lungs are the primary organ involved, increasing evidence supports the neuroinvasive potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study investigates the potential relationship between coronavirus disease (COVID-19)-related deterioration of brain structure and the degree of damage to lung function. Nine COVID-19 patients were recruited in critical condition from Jin Yin-tan Hospital (Wuhan, China) who had been discharged between 4 February and 27 February 2020. The demographic, clinical, treatment, and laboratory data were extracted from the electronic medical records. All patients underwent chest CT imaging, 129Xe gas lung MRI, and 1H brain MRI. Four of the patients were followed up for 8 months. After nearly 12 months of recovery, we found no significant difference in lung ventilation defect percentage (VDP) between the COVID-19 group and the healthy group (3.8 ± 2.1% versus 3.7 ± 2.2%) using 129Xe MRI, and several lung-function-related parameters—such as gas–blood exchange time (T)—showed improvement (42.2 ms versus 32.5 ms). Combined with 1H brain MRI, we found that the change in gray matter volume (GMV) was strongly related to the degree of pulmonary function recovery—the greater the increase in GMV, the higher degree of pulmonary function damage.

As the main constituent of the largest cellular ribonucleoprotein complex, the evolutionary highly conserved major vault protein (MVP) has been proposed play vital roles in the regeneration of multiple organs. In current study, we use a mvp knockout zebrafish line recently generated to characterize the function of MVP during organ regeneration. We found the regenerative capacity of heart, spinal cord and fin is preserved in mvp knockout zebrafish. Further experiments demonstrated in injured mvp knockout zebrafish, the cell death is enhanced while the transcriptome landscape is largely unchanged. These data showed MVP acts as an anti-apoptotic factor at early phase of injury response while plays a dispensable role in the regenerative programs in zebrafish.

Background: We constructed a high-volume registry to identify whether risk factors of intracranial atherosclerotic plaque (ICAP) features differ in the posterior and anterior circulation in patients with symptomatic intracranial atherosclerotic stenosis (ICAS) investigated by high-resolution magnetic resonance imaging (HRMRI). Methods: The registry was constructed for patients with symptomatic ICAS who underwent HRMRI for culprit plaques. ICAP-vulnerable features included positive remodelling, diffuse distribution, intraplaque haemorrhage and strong enhancement. Results: We analysed risk factors for the same ICAP features between the posterior and anterior circulation in data of 97 patients in the posterior circulation and 105 patients in the anterior circulation ICAPs. In patients with diffuse distribution, the probability of being female were lower [odds ratio (OR):0.08; 95% confidence interval (CI):0.02–0.34; p = 0.001] and having diabetes mellitus was higher (OR: 7.75; 95% CI:1.75–34.39; p = 0.007) in posterior circulation patients. In patients with strong enhancement, the probability of having diabetes was higher in posterior circulation patients (OR:6.71; 95% CI:1.37–32.81; p = 0.019). Conclusions: Our results demonstrate more risk factors in the posterior than in the anterior circulation in patients with the same ICAP-vulnerable features, highlighting the need for stratification of risk factors in symptomatic ICAPs. Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02705599.

Aim: To establish a Friend murine leukemia virus (FLV)-induced immunodeficient BALB/C mouse model and investigate the effects of Fuzheng Paidu tablets on the body weight, thymus, spleen, and CD4+ and CD8+ T lymphocytes of FLV-infected mice. FLV was passaged twice in BALB/c mice. The infected mice were divided into six groups of ten mice based on their weights. The groups included the normal control group; virus control group; AZT group; high- (2.8 g/kg), medium- (1.4 g/kg), and low-dose (0.7 g/kg) Fuzheng Paidu tablet groups; and Fuzheng Paidu decoction (10 g/kg) group. The mice were administered Fuzheng Paidu tablets via gavage for 21 days. The body weight and changes in the thymus, spleen, and CD4+ and CD8+ T lymphocytes of each mouse were measured. Results: The splenic weight of the virus control group is significantly higher than that of the normal control group, with significant splenomegaly. In addition, the splenic inhibition indices of the AZT group and the high- and medium-dose Fuzheng Paidu tablet groups were approximately 93.80%, 37.80%, and 28.07%, respectively. Furthermore, the high and medium dose Fuzheng Paidu tablets could increase the thymus weights of the infected mice. Conclusion: Fuzheng Paidu tablets could inhibit splenomegaly, lower the splenic indices, and increase the thymic weights and thymic indices of FLV-induced immunodeficient mice. Keywords: Friend murine leukemia virus, BALB/c mice, AZT

In the design of multiplierless finite impulse response (FIR) filters, tremendous efforts have been made to reduce the number of adders of the multiplier block for the reduction of overall chip area and power consumption. However, fewer in the multiplier block do not necessarily lead to lower power consumption, since the structural adders dominate the power consumption of an FIR filter circuit. In this paper, we propose a power-oriented optimization method for linear phase FIR filters. In the proposed algorithm, the power index, which is the average adder depth of the structural adders, is used as the optimization objective in the discrete coefficients search. A gate-level simulation of benchmark filters shows that the proposed technique designs filters consuming less power than those obtained by the best available algorithms, which aim to minimize the number of adders. The power savings over existing designs can be as much as 19.6%.

Background and purpose We investigated the baseline demographics of patients with severe unilateral atherosclerotic stenosis of the middle cerebral artery (MCA) using multimodal MRI and evaluated the haemodynamic impairments and plaque characteristics of patients who had a recurrent stroke.Materials and methods We retrospectively recruited consecutive patients with severe unilateral atherosclerotic MCA stenosis who underwent arterial spin labelling (ASL) with postlabelling delay (PLD) of 1.5 and 2.5 s, and vessel wall MRI. For each PLD, cerebral blood flow (CBF) maps were generated. Hypoperfusion volume ratio (HVR) from 2 PLD CBF was calculated. An HVR value ≥50% was considered as severe HVR. Plaque areas, plaque burden, plaque length and remodelling index were measured. Plaque enhancement at maximal lumen narrowing site were graded. Baseline clinical and imaging characteristics were compared between patients with (event+) and without (event−) 1 year ischaemic events.Results Forty-three patients (47.23±12.15 years; 28 men) were enrolled in this study. Seven patients had an HVR ≥50%. During the 1-year follow-up, 7 patients had experienced a recurrent stroke. HVR were significantly higher in the event+ than event− (53.17%±29.82% vs 16.9%±15.57%, p=0.0002), whereas no significant difference was detected in plaque areas, plaque burden, remodelling index, plaque length and plaque enhancement grade. The multivariable analysis revealed that a severe HVR was significantly associated with a recurrent stroke (Odds ratio=12.93, 95% confidence interval 1.57 to 106.24, p=0.017) after adjusted by hypertension and smoking.Conclusion HVR obtained from two PLD ASL may be a useful imaging predictor of recurrent stroke.

The Multiple-Network Poroelastic Theory (MPET) is a numerical model to characterize the transport of multiple fluid networks in the brain, which overcomes the problem of conducting separate analyses on individual fluid compartments and losing the interactions between tissue and fluids, in addition to the interaction between the different fluids themselves. In this paper, the blood perfusion results from MPET modeling are partially validated using cerebral blood flow (CBF) data obtained from arterial spin labeling (ASL) magnetic resonance imaging (MRI), which uses arterial blood water as an endogenous tracer to measure CBF. Two subjects—one healthy control and one patient with unilateral middle cerebral artery (MCA) stenosis are included in the validation test. The comparison shows several similarities between CBF data from ASL and blood perfusion results from MPET modeling, such as higher blood perfusion in the gray matter than in the white matter, higher perfusion in the periventricular region for both the healthy control and the patient, and asymmetric distribution of blood perfusion for the patient. Although the partial validation is mainly conducted in a qualitative way, it is one important step toward the full validation of the MPET model, which has the potential to be used as a testing bed for hypotheses and new theories in neuroscience research.

An optimal restoration strategy for supply chain networks can efficiently schedule the repair activities under resource limits. However, a wide range of previous studies solve this problem from the perspective of cost-effectiveness instead of a resilient manner. This research formulates the problem as a network maximum-resilience decision. We develop two metrics to measure the resilience of the supply chain networks, i.e., the resilience of cumulative performance loss and the resilience of restoration rapidity. Then, we propose a bi-objective nonlinear programming model, which aims to maximize the network resilience under the budget and manpower constraints. A modified simulated annealing algorithm is employed to solve the model. Finally, a testing supply chain network is utilized to illustrate the effectiveness of the proposed method framework. The results show that the optimal restoration schedule generated by the proposed model is a tradeoff between the cumulative performance loss and the restoration rapidity. Additionally, the sensitivity analysis of parameters indicates that decision-maker’s preference, tolerance factor of delivery time, number of work crews, and availability of budget all have significant impacts on the restoration schedule.

The CRISPR/Cas9 system has been developed as an easy-handle and multiplexable approach for engineering eukaryotic genomes by zygote microinjection of Cas9 and sgRNA, while preparing Cas9 for microinjection is laborious and introducing inconsistency into the experiment. Here, we describe a modified strategy for gene targeting through using oocyte-specific Cas9 transgenic mouse. With this mouse line, we successfully achieve precise gene targeting by injection of sgRNAs only into one-cell-stage embryos. Through comprehensive analysis, we also show allele complexity and off-target mutagenesis induced by this strategy is obviously lower than Cas9 mRNA/sgRNA injection. Thus, injection of sgRNAs into oocyte-specific Cas9 transgenic mouse embryo provides a convenient, efficient and reliable approach for mouse genome editing.