CT perfusion for predicting intracranial atherosclerotic middle cerebral artery occlusion.

Backgrounds and purpose: Identifying the underlying cause of acute middle cerebral artery occlusion (MCAO) as intracranial atherosclerotic stenosis (ICAS) or embolism is essential for determining the optimal treatment strategy before endovascular thrombectomy. We aimed to evaluate whether baseline computed tomography perfusion (CTP) characteristics could differentiate ICAS-related MCAO from embolic MCAO. Methods: We conducted a retrospective analysis of the clinical and baseline CTP data from patients who underwent endovascular thrombectomy for acute MCAO between January 2018 and December 2022. Core volume growth rate was defined as core volume on CTP divided by onset to CTP time. Multivariate logistic analysis was utilized to identify independent predictors for ICAS-related acute MCAO, and the diagnostic performance of these predictors was evaluated using receiver operating characteristic curve analysis. Results: Among the 97 patients included (median age, 71 years; 60% male), 31 (32%) were diagnosed with ICAS-related MCAO, and 66 (68%) had embolism-related MCAO. The ICAS group was younger (p = 0.002), had a higher proportion of males (p = 0.04) and smokers (p = 0.001), a lower prevalence of atrial fibrillation (AF) (p < 0.001), lower NIHSS score at admission (p = 0.04), smaller core volume (p < 0.001), slower core volume growth rate (p < 0.001), and more frequent core located deep in the brain (p < 0.001) compared to the embolism group. Multivariate logistic analysis identified core volume growth rate (aOR 0.46, 95% CI 0.26-0.83, p = 0.01) as an independent predictor of ICAS-related MCAO. A cutoff value of 2.5 mL/h for core volume growth rate in predicting ICAS-related MCAO was determined from the receiver operating characteristic curve analysis, with a sensitivity of 81%, specificity of 80%, positive predictive value of 66%, and negative predictive value of 90%. Conclusion: Slow core volume growth rate identified on baseline CTP can predict ICAS-related MCAO. Further prospective studies are warranted to confirm and validate these findings.

Enterocytozoon bieneusi in Wild Rats and Shrews from Zhejiang Province, China: Occurrence, Genetic Characterization, and Potential for Zoonotic Transmission.

Globally, Enterocytozoon bieneusi has been detected in humans and various animal hosts. Wild rats and shrews have the potential to act as carriers of E. bieneusi, facilitating the parasite's transmission to humans and domestic animals. We aimed to investigate the prevalence of E. bieneusi in 652 wild rats and shrews from Zhejiang Province, China, by amplifying the internal transcribed spacer (ITS) region of rDNA through polymerase chain reaction (PCR). To determine animal species, we amplified the Cytochrome b (Cyt-b) gene in their fecal DNA using PCR. Furthermore, we determined the genotype of E. bieneusi by amplifying the ITS region of rDNA through PCR. Genetic traits and zoonotic potential were evaluated using similarity and phylogenetic analyses. Suncus murinus (n = 282) and five rat species, Rattus losea (n = 18), Apodemus agrarius (n = 36), Rattus tanezumi (n = 86), Rattus norvegicus (n = 155), and Niviventer niviventer (n = 75), were identified. The average infection rate of E. bieneusi was 14.1% (92/652) with 18.1% (51/282) in S. murinus and 11.1% (41/370) in rats (27.8% in R. losea, 22.2% in A. agrarius, 10.5% in R. tanezumi, 8.4% in R. norvegicus, and 8.0% in N. niviventer). Thirty-three genotypes were identified, including 16 known genotypes. The most commonly known genotypes were HNR-VI (n = 47) and Peru11 (n = 6). Type IV, KIN-1, SHW7, and HNPL-II were each found in two samples, while Macaque4, CH5, K, Henan-III, Henan-V, HNP-II, HNPL-I, HNPL-III, HNHZ-II, and HNHZ-III were each found in one sample. Additionally, 17 novel genotypes were discovered: WZR-VIII (n = 5), WZR-I to WZR-VII, WZR-IX to WZR-XII, and WZSH-I to WZSH-V (n = 1 each). Those 33 genotypes were divided into three groups: Group 1 (n = 25), Group 2 (n = 3), and Group 13 (n = 5). The initial report underscores the extensive occurrence and notable genetic diversity of E. bieneusi in wild rats and shrews from Zhejiang province, China. These results suggest that these animals play a pivotal role in the transmission of E. bieneusi. Furthermore, animals carrying the zoonotic genotypes of E. bieneusi pose a serious threat to residents.

Design, Synthesis, and Evaluation of Novel Magnetic Nanoparticles Combined with Thiophene Derivatives for the Removal of Cr(VI) from an Aqueous Solution.

Most heavy metals are harmful to human health and the environment, even at extremely low concentrations. In natural waters, they are usually found only in trace amounts. Researchers are paying great attention to nanotechnology and nanomaterials as viable solutions to the problem of water pollution. This research focuses on the synthesis of organic thiophene derivatives that can be used as grafted ligands on the surface of silica-coated iron oxide nanoparticles to remove Cr(VI) chromium ions from water. The Vilsmeier-Haack reaction allows the formation of aldehyde groups in thiophene derivatives, and the resulting products were characterized by the FT-IR, NMR, and GC-MS. Schiff base is used as a binder between organic compounds and nanoparticles by the reaction of aldehyde groups in thiophene derivatives and amine groups on the surface of coated iron oxide nanoparticles. Schiff base functionalized Fe3O4 composites (MNPs@SiO2-SB-THCA) and (MNPs@SiO2-SB-THCTA) were successfully synthesized by homogeneous and heterogeneous methods and characterized by a combination of FT-IR, transmission electron microscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis. The adsorption studies, kinetic modeling, adsorption isotherms, and thermodynamics of the two materials, MNPs@SiO2-SB-THCA and MNPs@SiO2-SB-THCTA, were investigated for the removal of Cr(VI) from water at room temperature and at 50 mg/L. The high adsorption capacity at pH 6 for MNPs@SiO2-SB-THCTA was 15.53 mg/g, and for MNPs@SiO2-SB-THCA, it was 14.31 mg/g.

Long-term recurrence of ischemic events in patients with intracranial atherosclerotic stenosis stratified by symptoms and pathogenesis.

BACKGROUND: Intracranial atherosclerotic stenosis (ICAS) can cause either transient ischemic attack (TIA) or acute ischemic stroke (AIS). Pathogenesis of ICAS-AIS can be divided into artery-to-artery embolism(A-A), hypoperfusion(HP), and parent-artery atherosclerosis occluding penetrating artery(POPA). However, the prognosis of each type remains uncertain. Our study aimed to investigate potential disparities in the recurrent risk among these four subtypes of symptomatic ICAS. METHODS: From a prospective, single-center cohort study of acute cerebrovascular diseases from January 2017 to November 2021, we recruited 120 ICAS patients and classified them into four groups based on diffusion weighted imaging. Patients were retrospectively followed up for recurrence in December 2022. The primary outcome was recurrent cerebral vascular events (RCVE) in the same territory. RESULTS: Among 120 recruited patients, POPA(33%) was the most common subtype, followed by A-A(32%), HP(29%), and TIA(6%). Cumulative recurrent rate was 31.2% with median months of follow-up as 27(20-45.5). There was no significant difference in the risk of RCVE in the same territory among four subgroups within three months. However, when considering the risk after three months, TIA(57%) had the highest risk of RCVE, followed by A-A(26%), while HP(4%) and POPA(8%) had lower risks (P = 0.001). Cox regression model indicated that symptom and pathogenesis was an independent risk factor for RCVE in long-term prognosis (P = 0.022), after adjusting for a history of hypertension and cerebral infarction. CONCLUSIONS: Distinctive symptoms and pathogenesis of ICAS exhibit varying risks of RCVE in long-term prognosis. The differentiation in recurrent risk may provide valuable insights for guiding secondary prevention strategies.

Predictors of hemodynamic instability during and persistent after carotid artery stenting.

OBJECTIVES: The risk factors for post-carotid artery stenting severe hemodynamic instability remain elusive. This study aimed to identify the predictors of severe hemodynamic instability during and persisted after carotid artery stenting. MATERIALS AND METHODS: Consecutive patients who underwent carotid artery stenting for extracranial carotid artery stenosis at a single-center between September 2018 and July 2021 were retrospectively assessed. The predictive factors of severe hemodynamic instability intraoperation and post-operation were analyzed. RESULTS: Among the 139 patients included, 63 experienced severe hemodynamic instability, with 45 and 18 cases occurring intra and postoperatively, respectively. Persistent was observed in 21 patients. Smoke exposure (odds ratio [OR], 2.38; p=0.039), carotid bifurcation stenosis (OR, 0.91; p=0.018), and large-diameter balloon (>4 mm) dilatation (OR, 11.95; p<0.001) were identified as independent risk factors for hemodynamic instability at any stage of carotid artery stenting. Intraoperatively, large-diameter balloon (>4 mm) dilatation was associated with an increased risk of hemodynamic instability occurrence (OR, 4.67; p=0.01), whereas general anesthesia (OR, 0.19; p=0.001) and a longer distance from the stenosis to the carotid bifurcation (OR, 0.89; p=0.01) were negatively associated with hemodynamic instability. Furthermore, smoking exposure (OR, 3.73; p=0.03), large diameter balloon dilatation (OR, 6.12; p=0.032), distance from stenosis to bifurcation (OR, 0.85; p=0.047) and long-stent (40 mm) implantation (OR, 0.84 [95% confidence interval, 0.74-0.95]; p=0.007) could independently predict persistent hemodynamic instability. CONCLUSION: Patients with a smoking history, lesions near the carotid bulb, or dilatation using a large-diameter balloon were most likely to suffer severe hemodynamic instability. General anesthesia can protect against severe hemodynamic instability only intraoperatively. Long-term stent implantation may reduce persistent hemodynamic instability.

COVID-19 and primary wound healing: A new insights and advance.

With the outbreak and pandemic of coronavirus disease-2019 (COVID-19), a huge number of people died of it. Apart from lung injuries, multiple organs have been confirmed to be impaired. In COVID-19 time, primary wound healing processes always prolong, however, its possible underlying mechanisms are still unclear. Therefore, to overcome this clinical problem, clarifying its underlying mechanisms clearly is necessary and urgently needed. In this review, we summarized that COVID-19 can prolong primary wound healing by inducing excessive inflammation and oxidative stress, disturbing immune system and haematological system, as well as influencing the functions and viability of epidermal stem cells (ESCs). Otherwise, we summarized that the strict control measures of blocking up COVID-19 pandemic can also have side effects on primary wound healing process.

Soil extracellular enzyme stoichiometry reflects microbial metabolic limitations in different desert types of northwestern China.

Soil extracellular enzyme activity (EEA) stoichiometry reflects the dynamic balance between microorganism metabolic demands for resources and nutrient availability. However, variations in metabolic limitations and their driving factors in arid desert areas with oligotrophic environments remain poorly understood. In this study, we investigated sites in different desert types in western China and measured the activities of two C-acquiring enzymes (ß-1,4-glucosidase and ß-D-cellobiohydrolase), two N-acquiring enzymes (ß-1,4-N-acetylglucosaminidase and L-leucine aminopeptidase), and one organic-P-acquiring enzyme (alkaline phosphatase) to quantify and compare the metabolic limitations of soil microorganisms based on their EEA stoichiometry. The ratios of log-transformed C-, N-, and P-acquiring enzyme activities for all deserts combined were 1:1.1:0.9, which is close to the hypothetical global mean EEA stoichiometry (1:1:1). We quantified the microbial nutrient limitation by means of vector analysis using the proportional EEAs, and found that microbial metabolism was co-limited by soil C and N. For different desert types, the microbial N limitation increased in the following order: gravel desert < sand desert < mud desert < salt desert. Overall, the study area's climate explained the largest proportion of the variation in the microbial limitation (17.9 %), followed by soil abiotic factors (6.6 %) and biological factors (5.1 %). Our results confirmed that the EEA stoichiometry method can be used in microbial resource ecology research in a range of desert types, and that the soil microorganisms maintained community-level nutrient element homeostasis by adjusting enzyme production to increase uptake of scarce nutrients even in extremely oligotrophic environments such as deserts.

Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma.

The reinvigoration of anti-tumor T cells in response to immune checkpoint blockade (ICB) therapy is well established. Whether and how ICB therapy manipulates antibody-mediated immune response in cancer environments, however, remains elusive. Using tandem mass spectrometric analysis of modification of immunoglobulin G (IgG) from hepatoma tissues, we identified a role of ICB therapy in catalyzing IgG sialylation in the Fc region. Effector T cells triggered sialylation of IgG via an interferon (IFN)-γ-ST6Gal-I-dependent pathway. DC-SIGN+ macrophages represented the main target cells of sialylated IgG. Upon interacting with sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivated cGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenic immunity. Although enhanced IgG sialylation in tumors predicted improved therapeutic outcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenic T cell immunity after ICB therapy. Thus, targeting antibody-based negative feedback action of ICB therapy has potential for improving efficacy of cancer immunotherapies.

Targeting inflammatory macrophages rebuilds therapeutic efficacy of DOT1L inhibition in hepatocellular carcinoma.

Epigenetic reprogramming is a promising therapeutic strategy for aggressive cancers, but its limitations in vivo remain unclear. Here, we showed, in detailed studies of data regarding 410 patients with human hepatocellular carcinoma (HCC), that increased histone methyltransferase DOT1L triggered epithelial-mesenchymal transition-mediated metastasis and served as a therapeutic target for human HCC. Unexpectedly, although targeting DOT1L in vitro abrogated the invasive potential of hepatoma cells, abrogation of DOT1L signals hardly affected the metastasis of hepatoma in vivo. Macrophages, which constitute the major cellular component of the stroma, abrogated the anti-metastatic effect of DOT1L targeting. Mechanistically, NF-κB signal elicited by macrophage inflammatory response operated via a non-epigenetic machinery to eliminate the therapeutic efficacy of DOT1L targeting. Importantly, therapeutic strategy combining DOT1L-targeted therapy with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited cancer regression. Moreover, we found that the densities of macrophages in HCC determined malignant cell DOT1L-associated clinical outcome of the patients. Our results provide insight into the crosstalk between epigenetic reprogramming and cancer microenvironments and suggest that strategies to influence the functional activities of inflammatory cells may benefit epigenetic reprogramming therapy.

Grazing exclusion is more beneficial for restoring soil organic carbon and nutrient balance than afforestation on degraded sandy land.

Introduction: Vegetation restoration is an effective measure to improve the ecosystem service of degraded sandy land ecosystem. However, it is unclear how vegetation restoration on severely desertified land affect soil organic carbon (SOC) sequestration and nutrients balance. Therefore, this study was designed to clarify the response of SOC, total nitrogen (TN), total phosphorus (TP), and the resulting stoichiometric ratios (C:N:P) to afforestation and grazing exclusion, and to quantify their dynamics over time. Methods: We conducted vegetation community investigation and soil sampling in natural sparse-forest grassland (the climax community stage), afforestation (Pinus sylvestris var. mongolica (40-year, 48-year), Caragana microphylla (20-year, 40-year)), and grazing exclusion (20-year, 40-year) in China's Horqin Sandy Land. Soil C:N:P stoichiometry and its driving factors under different restoration measures were then studied. Results: Afforestation and grazing exclusion significantly (p < 0.05) increased SOC, TN, and TP concentrations. Vegetation restoration significantly increased C:N, C:P, and N:P ratios, indicating that nutrient limitations may occur in the later stages of restoration. The C:N, C:P, and N:P ratios after a 40-year grazing exclusion were closest to those of natural sparse-forest grassland. The N:P under grazing exclusion increased from 3.1 to 4.1 with increasing restoration age (from 20 to 40 years), which was close to the national mean values (4.2). Moreover, afforestation may lead to water deficit in the surface soil. Vegetation restoration is the main factor leading to changes in soil C:N:P stoichiometry, and indirectly affects soil C:N:P stoichiometry by altering soil structure and chemical properties. Conclusion: In terms of ecological stoichiometry, grazing exclusion was more conducive to restore SOC and nutrient balance than afforestation on severely desertified land. Due to the poor soil nutrients, attentions should be paid to the soil nutrients and water conditions in the later stages of vegetation restoration. Those findings can provide valuable information for the restoration of degraded sandy land in semi-arid areas.

Clostridium butyricum potentially improves inflammation and immunity through alteration of the microbiota and metabolism of gastric cancer patients after gastrectomy.

Background: Gastrectomy is the most effective treatment to improve the clinical survival rate of patients with gastric cancer. However, the pathophysiological changes caused by gastrectomy have seriously affected the postoperative recovery. Methods: In the present trial, Ataining (containing C. butyricum, CGMCC0313.1) was applied in patients after gastrectomy to investigate the effect of C. butyricum on the early postoperative recovery by monitoring the inflammatory immune response with blood indicators, detecting the gut microbiota with high-throughput sequencing, and analyzing the short-chain fatty acids (SCFAs) with targeted metabolomics. This study is registered with the number ChiCTR2000040915. Results: Our outcomes revealed that C. butyricum had significantly reduced the number of Leucocyte (P < 0.001), the percentage of Neutrophil (P < 0.001), the expression of IL-1ß (P < 0.01), IL-6 (P < 0.05), and TNF-α (P < 0.01), while markedly enhanced the immunity indexes (immunoglobulin and lymphocyte) (P < 0.05) and nutrition indexes (albumin and total protein) (P < 0.05). In addition, the use of the C. butyricum greatly enriched the relative abundance of beneficial bacteria Bacteroides, Faecalibacterium and Gemmiger, while the abundance of pathogenic Streptococcus, Desulfovibrio and Actinomyces were markedly decreased at genus level. We also observed significant up-regulation of SCFAs, including acetic acid, propionic acid, butyric acid and isobutyric acid, after C. butyricum administration in patients receiving gastrectomy. Conclusion: Therefore, evidence supported that oral administration of C. butyricum after gastrectomy can reduce early postoperative inflammation, enhance immune ability, restore intestinal microbiota eubiosis, increase intestinal SCFAs, reduce the occurrence of postoperative complications, and ultimately promote the early recovery of the patient. Clinical trial registration: http://www.chictr.org.cn/, identifier (ChiCTR2000040915).

Corrigendum: Impaired Glymphatic Transport Kinetics Following Induced Acute Ischemic Brain Edema in a Mouse pMCAO Model.

[This corrects the article DOI: 10.3389/fneur.2022.860255.].

A Comparison of Different Endovascular Treatment for Vertebral Artery Origin Stenosis.

OBJECTIVE: To compare the safety and efficacy of stenting with drug-eluting stent (DES), stenting with bare mental stent (BMS), and angioplasty alone with drug-coated balloon (DCB) in patients with symptomatic vertebral artery origin stenosis (VAOS) who did not respond to aggressive medical management. METHODS: We performed a retrospective analysis of consecutive patients with symptomatic VAOS who underwent endovascular treatment between December 2018 and November 2021 at our institution. The main outcome compared were technical success, perioperative complications, residual stenosis, stroke recurrence, progression of residual stenosis, and restenosis. RESULTS: A total of 46 patients were included: 29 were stented with DES, 12 were stented with BMS, and 5 received angioplasty alone with DCB. Technical success was achieved in 100%, 100%, and 60%, respectively (P = 0.008). Residual stenosis was 10.8%, 20.2%, and 51.2%, respectively (P < 0.001). Perioperative complications occurred only in 1 case in the DES group (P = 1.00). During a mean follow-up of 14.1 months, stroke recurrence rate was 6.9%, 16.7%, and 0% respectively (P = 0.73). Absolute progression of residual stenosis was 10.1%, 34.9%, and -8.0%, respectively (P < 0.001). Restenosis rate was 6.9%, 50.0%, and 20.0%, respectively (P = 0.007). CONCLUSIONS: In patients with symptomatic VAOS who did not respond to aggressive medical management, stenting with DES shows superiority in the lowering the restenosis rate compared with stenting with BMS. Angioplasty alone with DCB is associated with the slowest progression of stenosis in spite of moderate residual stenosis.

MRI-guided thrombolysis for lenticulostriate artery stroke within 12 h of symptom onset.

Stroke thrombolysis treatment is generally administered within 4.5 h, but a greater time window may be permitted depending upon the ischemic penumbra on neuroimaging. This observational cohort study investigated the outcomes of thrombolysis given within 12 h after symptom onset of lenticulostriate artery stroke. The population comprised 160 patients. Thrombolysis was administered via tissue plasminogen activator, alteplase (TPA). Thrombolysis was indicated by a mismatch between diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI), that is, an acute ischemic lesion on DWI without a corresponding lesion on T2WI. Demographics and medical history were compared with the modified Rankin scale (mRS) score, to reflect outcome. Patients with a favorable clinical outcome (mRS 0-1) had significantly lower hypertension, baseline NIH Stroke Scale (NIHSS) score, and admission systolic/diastolic blood pressure compared with patients with mRS 2-6. Lower admission systolic blood pressure and NIHSS score were significantly associated with favorable outcome. In patients either with IV-TPA within 4.5 h, or between 4.5 and 12 h, lower admission systolic blood pressure and/or NIHSS score similarly independently predict favorable outcome. However, in all groups, the onset-to-treatment time did not significantly influence the outcomes. We conclude that in our cohort higher admission systolic blood pressure and higher baseline NIHSS and not time were associated with poor outcome in patients with magnetic resonance-guided thrombolysis within 12 h of isolated lenticulostriate artery stroke, therefore loosening the traditionally perceived dependency of outcome on time.

[Theoretical basis of ecology for the influence of global change on resources, environment, and ecosystems.] / å ¨çƒå˜åŒ–å¯¹èµ„æºçŽ¯å¢ƒåŠç”Ÿæ€ç³»ç»Ÿå½±å“çš„ç”Ÿæ€å­¦ç†è®ºåŸºç¡€.

With the deepening of global change research, the applied problems such as global change risk and response for social sustainable development, temporal and spatial allocation of resources and environmental elements and impact assessment of ecosystem are becoming a new trend in the research field of global change. Based on the ecological framework, we focused on clarifying the connotations of resources and the environment and their components. Resources refer to all substances consumed by organisms in the process of producing organic matter from inorganic matter and transferring energy and matter among organisms. These include inorganic resources (e.g., solar radiation, CO2, O2, water, and mineral elements) and organic resources (as a source of food for other organisms). In contrast, the environment can not be consumed or depleted by organisms. In addition, we described the components of global change and the associated variations of resources and environmental factors, as well as current research progress on the responses of ecosystem to global change. We scientifically described the processes and mechanisms of global change in terms of their influence on resources, the environment, and ecosystems within a theoretical framework based on ecological principles. Our goal was to provide a strong theoretical foundation for future research on coping with the risks of global change.

Impaired Glymphatic Transport Kinetics Following Induced Acute Ischemic Brain Edema in a Mouse pMCAO Model.

Background: Cerebral edema forms immediately after blood flow interruption in ischemic stroke, which largely increased the death and disability. The glymphatic (glial-lymphatic) pathway is a major regulator of the brain liquid dynamics and homeostasis. This study aimed to investigate the transport kinetics of the glymphatic system after the appearance of ischemic edema. Methods: In this study, a coated filament was attached to the left middle cerebral artery (MCA) of mice to establish a mouse model of permanent middle cerebral artery occlusion with an intact blood-brain barrier (BBB). The glymphatic function was then quantified using contrast-enhanced MRI (11.7T) by employing an injection of gadobenate dimeglumine (BOPTA-Gd) into the cisterna magna of mice. We then evaluated the expression and polarization of aquaporin-4 (AQP4) as a proxy for the physiological state of the glymphatic system. Results: Our results revealed a positive correlation between the signal intensity in T1-weighted images and the corresponding apparent diffusion coefficient (ADC) values in the cortex, striatum, and periventricular zone, suggesting that impaired glymphatic transport kinetics in these regions is correlated to the cytotoxic edema induced by the occlusion of MCA. Furthermore, the increased depolarization of AQP4 in the parenchyma perivascular space (PVS) was consistent with glymphatic failure following the induced early cerebral ischemic edema. Conclusions: Glymphatic transport kinetics were suppressed between the onset of cytotoxic edema and the disruption of the BBB, which correlated with the diminishing ADC values that vary based on edema progression, and is associated with depolarization of AQP4 in the parenchyma PVSs.

A score of non-contrast transthoracic echocardiography to screen patent foramen ovale in patients with embolic stroke of undetermined source.

BACKGROUND: The aim of this study was to develop a screening score system of non-contrast transthoracic echocardiography (TTE) for patent foramen ovale (PFO) in patients with embolic stroke of undetermined source (ESUS). METHODS: We performed a retrospective analysis of 218 consecutive patients with a recent ESUS from 2015 to 2018, who received TTE and transcranial Doppler (TCD) as routine examinations. PFO was diagnosed by the bubble test of TCD. Significant differences of the non-contrast TTE findings and patient characteristics between PFO group and non-PFO group were selected into a score. RESULTS: PFO was diagnosed in 35.8% (78/218) of the patients. Compared with non-PFO group, a larger median aortic root diameter (ARd) (34 mm vs. 32 mm, p = 0.005), a lower median peak E wave velocity (Em) (61.5 cm/s vs. 68 cm/s, p = 0.005) and a lower incidence rate of mitral regurgitation (34.6% vs. 50.7%, p = 0.022) were seen in PFO group. ARd>33 mm and Em < 72 cm/s were the best thresholds to predict PFO in ROC analysis. A four-point score system (MEAD) including TTE criteria (including ARd>33 mm, Em < 72 cm/s and without mitral regurgitation) and no history of diabetes predicted PFO with an area under curve of 0.67 (95%CI 0.57-0.72, p < 0.001). MEAD score ≥ 3 was the best threshold to predict PFO with an accuracy of 0.64 (95% CI 0.57-0.7), a sensitivity of 0.65 (95% CI 0.53-0.75) and a specificity of 0.63 (95% CI 0.55-0.71). CONCLUSION: The MEAD score measured with non-contrast TTE can be used to select patients for bubble test of TCD to increase the diagnostic yield of PFO after ESUS.

Deubiquitylase USP12 induces pro-survival autophagy and bortezomib resistance in multiple myeloma by stabilizing HMGB1.

Despite the establishment of novel therapeutic interventions, multiple myeloma (MM) remains invariably incurable due to development of drug resistance and subsequent relapse, which are attributed to activation of oncogenic pathways such as autophagy. Deubiquitinating enzymes (DUBs) are promising targets to overcome resistance to proteasome inhibitor-based treatment. Ubiquitin-specific protease-12 (USP12) is a DUB with a known prognostic value in several cancers. We found that USP12 protein levels were significantly higher in myeloma patient samples than in non-cancerous human samples. Depletion of USP12 suppressed cell growth and clonogenicity and inhibited autophagy. Mechanistic studies showed that USP12 interacted with, deubiquitylated and stabilized the critical autophagy mediator HMGB1 (high mobility group box-1) protein. Knockdown of USP12 decreased the level of HMGB1 and suppressed HMGB1-mediated autophagy in MM. Furthermore, basal autophagy activity associated with USP12/HMGB1 was elevated in bortezomib (BTZ)-resistant MM cell lines. USP12 depletion, concomitant with a reduced expression of HMGB1, suppressed autophagy and increased the sensitivity of resistant cells to BTZ. Collectively, our findings have identified an important role of the deubiquitylase USP12 in pro-survival autophagy and resultant BTZ resistance in MM by stabilizing HMGB1, suggesting that the USP12/HMGB1 axis might be pursued as a potential diagnostic and therapeutic target in human MM.