High expression of RTEL1 predicates worse progression in gliomas and promotes tumorigenesis through JNK/ELK1 cascade.

Gliomas are the most common primary intracranial tumor worldwide. The maintenance of telomeres serves as an important biomarker of some subtypes of glioma. In order to investigate the biological role of RTEL1 in glioma. Relative telomere length (RTL) and RTEL1 mRNA was explored and regression analysis was performed to further examine the relationship of the RTL and the expression of RTEL1 with clinicopathological characteristics of glioma patients. We observed that high expression of RTEL1 is positively correlated with telomere length in glioma tissue, and serve as a poor prognostic factor in TERT wild-type patients. Further in vitro studies demonstrate that RTEL1 promoted proliferation, formation, migration and invasion ability of glioma cells. In addition, in vivo studies also revealed the oncogene role of RTEL1 in glioma. Further study using RNA sequence and phospho-specific antibody microarray assays identified JNK/ELK1 signaling was up-regulated by RTEL1 in glioma cells through ROS. In conclusion, our results suggested that RTEL1 promotes glioma tumorigenesis through JNK/ELK1 cascade and indicate that RTEL1 may be a prognostic biomarker in gliomas.

Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application.

Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely available at https://aomp.alphama.com.cn.

Coronary Microvascular Dysfunction and Diffuse Myocardial Fibrosis in Patients With Type 2 Diabetes Using Quantitative Perfusion MRI.

BACKGROUND: Imaging techniques that quantitatively and automatically measure changes in the myocardial microcirculation in patients with diabetes are lacking. PURPOSE: To detect diabetic myocardial microvascular complications using a novel automatic quantitative perfusion MRI technique, and to explore the relationship between myocardial microcirculation dysfunction and fibrosis. STUDY TYPE: Prospective. SUBJECTS: 101 patients with type 2 diabetes mellitus (T2DM) (53 without and 48 with complications), 20 healthy volunteers. FIELD STRENGTH/SEQUENCE: 3.0T; modified Look-Locker inversion-recovery sequence; saturation recovery sequence and dual-bolus technique; segmented fast low-angle shot sequence. ASSESSMENT: All participants underwent MRI to determine the rest myocardial blood flow (MBF), stress MBF, myocardial perfusion reserve (MPR), and extracellular volume (ECV), which represents the extent of myocardial fibrosis. STATISTICAL TESTS: Kolmogorov-Smirnov test, Shapiro-Wilk test, Kruskal-Wallis H test, Mann-Whitney U test, chi-square test, Spearman correlation coefficient, multivariable linear regression analysis. P < 0.05 was considered statistically significant. RESULTS: The rest MBF was not significantly different between the T2DM without complications group (1.1, IQR: 0.9-1.3) and the control group (1.1, 1.0-1.3) (P = 1.000), but it was significantly lower in the T2DM with complications group (0.8, 0.6-1.0) than in both other groups. The stress MBF and MPR were significantly lower in the T2DM without complications group (1.9, 1.5-2.3, and 1.7, 1.4-2.1, respectively) than in the control group (3.0, 2.6-3.5, and 2.7, 2.4-3.1, respectively), and were also significantly lower in the T2DM with complications group (1.1, 0.9-1.4, and 1.4, 1.2-1.8, respectively) than in the T2DM without complications group. A decrease in MBF and MPR were significantly associated with an increase in the ECV. DATA CONCLUSION: Quantitative perfusion MRI can evaluate myocardial microcirculation dysfunction. In T2DM, there was a significant decrease in both MBF and MPR compared to healthy controls, with the decrease being significantly different between T2DM with and without complications groups. The decrease of MBF was significantly associated with the development of myocardial fibrosis, as determined by ECV. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Targeting JMJD1C to selectively disrupt tumor Treg cell fitness enhances antitumor immunity.

Regulatory T (Treg) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving Treg cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral Treg cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral Treg cell-specific epigenetic regulators have been unexplored. Here, we show that JMJD1C, a histone demethylase upregulated by cytokines in the tumor microenvironment, is essential for tumor Treg cell fitness but dispensable for systemic immune homeostasis. JMJD1C deletion enhanced AKT signals in a manner dependent on histone H3 lysine 9 dimethylation (H3K9me2) demethylase and STAT3 signals independently of H3K9me2 demethylase, leading to robust interferon-γ production and tumor Treg cell fragility. We have also developed an oral JMJD1C inhibitor that suppresses tumor growth by targeting intratumoral Treg cells. Overall, this study identifies JMJD1C as an epigenetic hub that can integrate signals to establish tumor Treg cell fitness, and we present a specific JMJD1C inhibitor that can target tumor Treg cells without affecting systemic immune homeostasis.

Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D.

KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRASG12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRASG12D induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRASG12D mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRASG12D-driven cancers as the complementary therapeutic strategy to KRAS inhibition.

Endovascular Thrombectomy for a Progressive Stroke Patient With a High-Burden Carotid Free-Floating Thrombus.

Carotid free-floating thrombus (FFT) is a rare cause of acute ischemic events. The optimal management of carotid FFT remains unclear. The optimal and individualized management of carotid FFT should be determined based on the underlying etiology, clinical manifestation, and imaging characteristics. we reported a case with endovascular thrombectomy for a progressive stroke patient with a high-burden carotid free-floating thrombus. ANN NEUROL 2024;95:362-364.

Residual inflammatory risk predicts long-term outcomes following stenting for symptomatic intracranial atherosclerotic stenosis.

BACKGROUND AND PURPOSE: Residual inflammatory risk (RIR) can predict the unfavourable outcomes in patients with minor ischaemic stroke. However, the impact of preprocedural RIR on long-term outcomes in patients with symptomatic intracranial atherosclerotic stenosis (sICAS) who underwent stenting remains understudied. METHODS: This retrospective, single-centre cohort study evaluated consecutive patients with severe sICAS who underwent intracranial stenting. Patients were categorised into four groups based on preprocedural high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein cholesterol (LDL-C): residual cholesterol inflammatory risk (RCIR, hs-CRP ≥3 mg/L and LDL-C ≥2.6 mmol/L), RIR (hs-CRP ≥3 mg/L and LDL-C <2.6 mmol/L), residual cholesterol risk (RCR, hs-CRP <3 mg/L and LDL-C ≥2.6 mmol/L) and no residual risk (NRR, hs-CRP <3 mg/L and LDL-C <2.6 mmol/L). The long-term clinical outcomes included recurrent ischaemic stroke and death. The long-term imaging outcomes consisted of in-stent restenosis (ISR) and symptomatic ISR (sISR) after stenting. RESULTS: In this study, 952 patients were included, with 751 (78.9%) being male. Forty-six cases were categorised into the RCIR group, 211 into the RIR group, 107 into the RCR group and 588 into the NRR group. Patients with RCIR (adjusted HR 6.163; 95% CI 2.603 to 14.589; p<0.001) and RIR (adjusted HR 2.205; 95% CI 1.294 to 3.757; p=0.004) had higher risks of recurrent ischaemic stroke than those with NRR during the 54 months of median follow-up time. Patients with RCIR (adjusted HR 3.604; 95% CI 1.431 to 9.072; p=0.007) were more likely to occur ISR, and patients in the RIR group showed a significant increase in the risk of sISR (adjusted HR 2.402; 95% CI 1.078 to 5.351; p=0.032) compared with those in the NRR group with a median follow-up time of 11.9 months. CONCLUSIONS: In patients with sICAS, preprocedural RIR may predict long-term recurrent ischaemic stroke, ISR and sISR following intracranial stenting.

Examining the impact of Tetragenococcus halophilus, Zygosaccharomyces rouxii, and Starmerella etchellsii on the quality of soy sauce: a comprehensive review of microbial population dynamics in fermentation.

Soy sauce is a popular fermented seasoning due to its distinct flavor and rich umami taste. Its traditional production involves two stages: solid-state fermentation and moromi (brine fermentation). During moromi, the dominant microbial population in the soy sauce mash changes, which is called microbial succession and is essential for the formation of soy sauce flavor compounds. Research has identified the sequence of succession, starting with Tetragenococcus halophilus, then Zygosaccharomyces rouxii, and lastly, Starmerella etchellsii. Factors such as the environment, microbial diversity, and interspecies relationships drive this process. Salt and ethanol tolerance influence microbial survival, while nutrients in the soy sauce mash support the cells in resisting external stress. Different microbial strains have varying abilities to survive and respond to external factors during fermentation, which impacts soy sauce quality. In this review, we would examine the factors behind the succession of common microbial populations in the soy sauce mash and explore how microbial succession affects soy sauce quality. The insights gained can help better manage the dynamic changes in microbes during fermentation, leading to improved production efficiency.

Sequence-based drug design as a concept in computational drug design.

Drug development based on target proteins has been a successful approach in recent decades. However, the conventional structure-based drug design (SBDD) pipeline is a complex, human-engineered process with multiple independently optimized steps. Here, we propose a sequence-to-drug concept for computational drug design based on protein sequence information by end-to-end differentiable learning. We validate this concept in three stages. First, we design TransformerCPI2.0 as a core tool for the concept, which demonstrates generalization ability across proteins and compounds. Second, we interpret the binding knowledge that TransformerCPI2.0 learned. Finally, we use TransformerCPI2.0 to discover new hits for challenging drug targets, and identify new target for an existing drug based on an inverse application of the concept. Overall, this proof-of-concept study shows that the sequence-to-drug concept adds a perspective on drug design. It can serve as an alternative method to SBDD, particularly for proteins that do not yet have high-quality 3D structures available.

Multiple doses of SHR-1222, a sclerostin monoclonal antibody, in postmenopausal women with osteoporosis: A randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial.

SHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50-400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned. Twenty-one received placebo and eighty-four received SHR-1222 sequentially (100 mg QM, n=4; 200 or 300 mg QM, n=20; and 400 or 600 mg Q2M, n=20). The most common adverse events included increased blood parathyroid hormone, increased low-density lipoprotein, increased blood alkaline phosphatase, increased blood cholesterol, back pain, and arthralgia, the majority of which were mild in severity without noticeable safety concerns. Serum SHR-1222 exposure (Cmax,ss and AUC0-tau,ss) increased in a greater than dose-proportional manner. Following multiple doses of SHR-1222, the bone formation markers (terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and osteocalcin) increased in a dose-dependent manner, whereas the bone resorption marker (ß-C-telopeptide) was downregulated. Accordingly, BMD gains in the lumbar spine, total hip, and femoral neck were observed. The maximum BMD increase from baseline at the lumbar spine was detected in the 300 mg QM cohort (14.6% vs. 0.6% in the placebo group on day 169). Six (6/83; 7.2%) subjects developed anti-SHR-1222 antibodies with no discernible effects on PKs, PDs, and safety. Thus, multiple doses of SHR-1222 showed an acceptable safety profile and dose-dependent plasma exposure in women with POP, and could improve their BMD rapidly and prominently by promoting bone formation and inhibiting bone resorption. These findings further support SHR-1222 as a potential alternative agent for the treatment of POP.

High-Resolution Magnetic Resonance Imaging in Endovascular Treatment of Vertebrobasilar Junction Stenosis.

INTRODUCTION: Vertebrobasilar junction (VBJ) stenosis is a challenge in endovascular treatment due to structural variants and complexities. The role of high-resolution magnetic resonance imaging (HRMRI) in endovascular treatment for patients with severe VBJ stenosis is uncertain. CASE REPORT: Four patients with symptomatic VBJ stenosis underwent HRMRI of the vessel wall before endovascular treatment. In 3 patients, the VBJ could not be visualized on luminal imaging. One of them had a hypoplastic artery and 2 of them had severe stenotic arteries on HRMRI. HRMRI showed an artery with a negative remodeling in a patient with a hypoplastic vertebral artery. One patient had intraplaque hemorrhage and calcification, and 2 patients had calcification in VBJ lesions. Endovascular treatment was performed utilizing HRMRI findings to guide the decision-making process. CONCLUSION: HRMRI provides additional information about the structure and angle of the VBJ, the characteristics and vulnerability of the plaques, and the lesion size, thus helping to improve the operation process and reduce the risk of complications.

Association between basilar artery stenosis features, vertebral artery stenosis and perforator stroke after stenting.

BACKGROUND AND PURPOSE: We investigated the relationship between basilar artery (BA) atherosclerotic stenosis features and vertebral artery (VA) stenosis and explored whether BA stenosis features are associated with perforator stroke after stenting. METHODS: Patients with BA stenosis who underwent HRMRI and DSA were recruited. Patients were divided into proximal BA stenosis and middle-or-distal BA stenosis groups, and then subgroup analyses were performed based on whether they had VA stenosis. BA plaque features were evaluated by HRMRI. Artery stenosis was measured by DSA. The incidence of perforator stroke after BA stenting was recorded, and the potential association between BA stenosis features and perforator stroke was analyzed. RESULTS: One hundred and seventy-four patients were consecutively enrolled. Patients with proximal BA stenosis had a higher proportion of severe stenosis than those with middle-or-distal BA stenosis (P = 0.027). In the subgroup analysis, this difference mainly existed in patients complicated with VA stenosis (P = 0.023). Patients with proximal BA stenosis had a higher proportion of strong plaque enhancement than those with middle-or-distal BA stenosis (P < 0.001), especially in those with vertebrobasilar junction (VBJ) stenosis (P < 0.001). Perforator stroke after BA stenting occurred in five patients, of whom four had lateral wall BA plaques, four had plaque enhancement and four had proximal BA stenosis. CONCLUSION: Patients with proximal BA stenosis had a higher proportion of severe stenosis and strong plaque enhancement, particularly in patients complicated with VA stenosis and VBJ stenosis. Perforator stroke after BA stenting may be related to distribution, burden and characteristics of BA lesions.

Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers.

The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays a critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, the basics and underlying mechanisms of chemical modifications of the linker structure causing dramatic changes in the PROTAC degradation activity warrant further investigation. Herein, we report the design and characterization of a highly potent and selective SOS1 PROTAC ZZ151. After systematically modifying the linker length and composition, we observed that subtle modification of just one atom of the linker moiety of ZZ151 resulted in remarkable changes in the formation of the ternary complex and thus dramatically affected the degradation activities. ZZ151 quickly, specifically, and effectively induced SOS1 degradation; displayed potent antiproliferation activities against a broad panel of KRAS mutant-driven cancer cells; and showed superior anticancer activities in the KRASG12D- and G12V-mutant xenografts in mice. ZZ151 is a promising lead for developing new chemotherapies targeting KRAS mutants.

Endovascular treatment versus standard medical treatment for basilar artery occlusion: a meta-analysis of randomized controlled trials.

OBJECTIVE: Acute ischemic stroke caused by basilar artery occlusion (BAO) is devastating, but the optimal treatment for patients with BAO remains controversial. In this study, the authors aimed to investigate the safety and efficacy of endovascular treatment (ET) versus standard medical treatment (SMT) in patients with BAO. METHODS: The PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials (RCTs). The primary outcome was good functional outcome, defined as a modified Rankin Scale (mRS) score of 0-3 at 90 days. The secondary efficacy outcome was excellent functional outcome defined as an mRS score of 0-2 at 90 days. The safety outcomes included mortality at 90 days and symptomatic intracranial hemorrhage (sICH). Subgroup analyses were carried out based on race (Asian or non-Asian). RESULTS: Four RCTs of 988 patients (556 in the ET group and 432 in the SMT group) were included in this meta-analysis. The proportion of good functional outcome in the ET group was significantly higher than that in the SMT group (45.1% vs 29.6%; number needed to treat 6.45; RR 1.54, 95% CI 1.16-2.06; p = 0.003, I2 = 60%). The subgroup analysis based on race showed a significant difference between Asian and non-Asian race in the primary outcome (p = 0.03, I2 = 78.5%). Patients in the ET group had a higher rate of excellent functional outcome at 90 days than those in the SMT group (34.9% vs 20.6%; RR 1.83, 95% CI 1.07-3.12; p = 0.03, I2 = 80%). Patients in the ET group had a lower mortality at 90 days (35.6% vs 45.4%; RR 0.77, 95% CI 0.66-0.89; p = 0.0007, I2 = 0%) but a higher rate of sICH (5.4% vs 0.5%; RR 8.29, 95% CI 2.49-27.66; p = 0.0006, I2 = 0%) than those in the SMT group. CONCLUSIONS: ET may improve the functional outcome and reduce mortality at 90 days but increase the risk of sICH compared with SMT in patients with BAO. This conclusion needs to be confirmed in non-Asian populations in future studies. Systematic review registration no.: CRD42022357718 (https://www.crd.york.ac.uk/prospero/).

Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists.

The development of stimulator of interferon genes (STING) agonists has been of potential applications for the treatment of cancer and infectious diseases. Based on the crystal structure of SR-717 bound to hSTING, we designed and synthesized a novel series of bipyridazine derivatives as highly potent STING agonists. Among them, compound 12L led to significant thermal stability shifts of the common alleles of hSTING, as well as that of mSTING. 12L also displayed potent activities in various hSTING alleles and mSTING competition binding assay. Specifically, 12L displayed higher cell-based activities than SR-717 in both human THP1 (EC50 = 0.38 ± 0.03 µM) and mouse RAW 264.7 cells (EC50 = 12.94 ± 1.78 µM), and was validated to activate the downstream signaling pathway of STING via a STING-dependent manner. Furthermore, compound 12L showed favorable pharmacokinetic (PK) properties and antitumor efficacy. These findings suggested that compound 12L has development potential as an antitumor agent.

Predictors of hyperperfusion syndrome after stent implantation in symptomatic intracranial atherosclerotic stenosis.

Background: Hyperperfusion syndrome (HPS) is a serious complication after stent implantation in symptomatic intracranial atherosclerotic stenosis (ICAS). This study aims to explore the predictive value of preprocedural computed tomography perfusion (CTP) for HPS after intracranial stenting. Methods: In this retrospective case-control study we collected data from consecutive patients from June 2012 to September 2019 who underwent stent implantation due to severe symptomatic ICAS. Patients who underwent CTP before the procedure were enrolled. CTP was postprocessed using the automated RAPID software to assess the preoperative cerebral perfusion. According to the presence or absence of HPS, the patients were classified into two groups: the HPS group and the non-HPS group. The baseline data, lesion characteristics, and preoperative CTP parameters between the two groups were compared. The receiver operating characteristic (ROC) curve analysis was performed to determine the optimal predictor of HPS. Results: Among the 170 eligible patients, 6 patients (3.53%) had HPS, including 3 who presented with intracranial hemorrhages (ICHs), 1 who had dysphoria, 1 who had delirium, and 1 who had a headache. There were no significant differences in baseline and lesion characteristics between the HPS and non-HPS groups. Compared with the non-HPS group, the HPS group had a significantly higher volume of time-to-maximum (Tmax) >4 s (429.5 vs. 93 mL; P=0.006) and Tmax >6 s (200 vs. 0 mL; P=0.003). The optimal volume threshold for maximizing sensitivity in predicting HPS was 65.5 mL with Tmax >4 s [area under the curve (AUC), 0.832; 95% confidence interval (CI): 0.650 to 1.000; P=0.006]. Conclusions: Tmax >4 s volume may be a predictor of HPS after stent implantation in symptomatic ICAS. Further prospective studies should be conducted to confirm our conclusion.

Reconceptualizing the clinicopathological features, locoregional therapy and prognostic factors of occult breast cancer in the era of molecular subtyping.

To evaluate the clinical features, molecular subtypes, therapeutic strategies, and prognostic factors of occult breast cancer (OBC). Patients with T0-3/N1-3/M0 breast cancer diagnosed in 2010-2018 (n = 114,303, including 691 with OBC) were retrieved from the Surveillance, Epidemiology, and End-Results (SEER) database. The endpoints were overall survival (OS) and breast cancer-specific survival (BCSS). Compared with non-OBC, OBC presented significantly more adverse clinicopathological prognostic features. More patients with OBC underwent breast-conserving treatment (BCT) and less had axillary lymphadenectomy (ALD). Outcomes were more favorable in OBC cases compared with non-OBC cases (p = .002 for OS, p = .002 for BCSS). Triple-negative (TNBC) and HER2-enriched were the subtypes with the worst prognosis in OBC (p < .05). Prognosis was better for triple-negative OBC compared with the same subtype of non-OBC. N-stage was not a strong prognostic indicator of OBC (p > .05 for OS). Cases who underwent systemic chemotherapy alone without surgery had the worst prognosis among OBC patients. For locoregional therapy, mastectomy and radiotherapy could confer survival advantage; standard axillary lymph node dissection (ALND) and positive lymph node dissection (PLND) contributed notably to OS in OBC patients. Both OS and BCSS were better in OBC cases compared with non-OBC. Systemic chemotherapy alone without surgery is not appropriate for OBC treatment, and mastectomy plus standard axillary surgery is recommended. Patients with hormone receptor-positive and low burden of axillary lymph node metastasis may be spared from radiotherapy after undergoing standard axillary lymphadenectomy.

Impact of cerebral small vessel disease on symptomatic in-stent restenosis in intracranial atherosclerosis.

OBJECTIVE: Cerebral small vessel disease (CSVD) commonly coexists with intracranial atherosclerotic stenosis (ICAS). In-stent restenosis (ISR) affects the nonprocedural outcome of severe symptomatic ICAS after intracranial stenting. However, only 8%-27% of ISR patients are symptomatic, which highlights the importance of the investigation of risk factors associated with symptomatic ISR (SISR) to improve long-term functional outcome. Whether CSVD is associated with SISR remains unclear. The authors tested the hypothesis that CSVD is associated with SISR in ICAS patients after intracranial stenting. METHODS: This retrospective study enrolled 97 patients who were symptomatic due to severe anterior circulation ICAS treated with intracranial stenting. SISR was evaluated with clinical and vascular imaging follow-up. CSVD subtypes, including white matter hyperintensities (WMHs), enlarged perivascular spaces, and chronic lacunar infarctions, were evaluated. Cox regression analysis was used to compare the incidence of SISR between patients with and without CSVD. RESULTS: Of the enrolled patients, 58.8% had CSVD. The 1- and 2-year ISR rates were 24.7% and 37.1%, respectively. Of the CSVD subtypes, SISR was associated with deep WMHs (DWMHs; HR 5.39, 95% CI 1.02-28.44). DWMH Fazekas scale grades 2 (HR 85.54, 95% CI 2.42-3018.93) and 3 (HR 66.24, 95% CI 1.87-2352.32) were associated with SISR, but DWMH Fazekas grades 0 and 1 were not. The proportions of SISR in patients with DWMH Fazekas grades 0, 1, 2, and 3 were 16.7%, 33.3%, 50%, and 100%, respectively. CONCLUSIONS: Patients with CSVD have a higher risk of SISR than those without CSVD. Of the CSVD subtypes, patients with DWMHs are associated with SISR. The DWMH Fazekas scale score is considered to be a predictor for SISR.

Dipeptidyl Peptidase-4 Stabilizes Integrin α4ß1 Complex to Promote Thyroid Cancer Cell Metastasis by Activating Transforming Growth Factor-Beta Signaling Pathway.

Background: Metastatic disease is a major cause of thyroid cancer-related death. However, the mechanisms responsible for thyroid cancer metastasis are unclear. Dipeptidyl peptidase-4 (DPP4) is a multifunctional cell surface glycoprotein that has been reported to be a negative prognostic factor in thyroid cancer. We explored the molecular mechanism of the role of DPP4 in thyroid cancer cell metastasis. Methods: The effects of DPP4 on thyroid cancer cell migration/invasion in vitro were assessed by transwell assays. A lung metastatic mouse model was also established to determine the effect of DPP4 on tumor metastasis in vivo. DPP4 inhibitor sitagliptin was used to test its effect on thyroid cancer cell metastasis. The mechanism of which DPP4 promotes thyroid cancer cell metastasis was explored by a series of molecular and biochemical experiments. Results: We observed that DPP4 was significantly upregulated in papillary thyroid cancers compared with control subjects, and its expression was positively associated with lymph node metastasis and BRAFV600E mutation. Functional studies showed that DPP4 knockdown significantly inhibited metastatic potential of thyroid cancer cells, and vice versa. However, DPP4 inhibitor sitagliptin did not affect the metastatic ability of thyroid cancer cells, indicating that the promoting effect of DPP4 on tumor metastasis was independent of its enzymatic activity. Mechanistically, DPP4 interacted with the α4 and ß1 integrin subunits, and stabilized the formation of integrin α4ß1 complex. DPP4-mediated integrin signal activation promoted the nuclear localization of c-Jun through the FAK/AKT pathway, thereby inducing the transcription of transforming growth factor-beta 1 (TGFB1 coding for protein TGF-ß1). TGF-ß1 then facilitated tumor metastasis by inducing the epithelial-mesenchymal transition. Conclusions: DPP4 promotes thyroid cancer cell metastasis through the integrins/FAK/AKT/c-Jun/TGF-ß1 signaling axis. These findings may have implications for an alternative therapeutic strategy for thyroid cancer.

Collateral Flow in Magnetic Resonance Angiography: Prognostic Value for Vertebrobasilar Stenosis With Stroke Recurrence.

BACKGROUND AND PURPOSE: Intracranial vertebrobasilar atherosclerotic stenosis (IVBAS) is a major cause of posterior circulation stroke. Some patients suffer from stroke recurrence despite receiving medical treatment. This study aimed to determine the prognostic value of a new score for the posterior communicating artery and the P1 segment of the posterior cerebral artery (PCoA-P1) for predicting stroke recurrence in IVBAS. METHODS: We retrospectively enrolled patients with severe IVBAS (70%-99%). According to the number of stroke recurrences, patients were divided into no-recurrence, single-recurrence, and multiple-recurrences groups. We developed a new 5-point grading scale, with the PCoA-P1 score ranging from 0 to 4 based on magnetic resonance angiography, in which primary collaterals were dichotomized into good (2-4 points) and poor (0 or 1 point). Stroke recurrences after the index stroke were recorded. Patients who did not experience stroke recurrence were compared with those who experienced single or multiple stroke recurrences. RESULTS: From January 2012 to December 2019, 176 patients were enrolled, of which 116 (65.9%) had no stroke recurrence, 35 (19.9%) had a single stroke recurrence, and 25 (14.2%) had multiple stroke recurrences. Patients with single stroke recurrence (odds ratio [OR]=4.134, 95% confidence interval [CI]=1.822-9.380, p=0.001) and multiple stroke recurrences (OR=6.894, 95% CI=2.489-19.092, p<0.001) were more likely to have poor primary collaterals than those with no stroke recurrence. CONCLUSIONS: The new PCoA-P1 score appears to provide improve predictions of stroke recurrence in patients with IVBAS.