Using machine learning to predict the bleeding risk for patients with cardiac valve replacement treated with warfarin in hospitalized.

BACKGROUND: Distinguishing warfarin-related bleeding risk at the bedside remains challenging. Studies indicate that warfarin therapy should be suspended when international normalized ratio (INR) ≥ 4.5, or it may sharply increase the risk of bleeding. We aim to develop and validate a model to predict the high bleeding risk in valve replacement patients during hospitalization. METHOD: Cardiac valve replacement patients from January 2016 to December 2021 across Nanjing First Hospital were collected. Five different machine-learning (ML) models were used to establish the prediction model. High bleeding risk was an INR ≥4.5. The area under the receiver operating characteristic curve (AUC) was used for evaluating the prediction performance of different models. The SHapley Additive exPlanations (SHAP) was used for interpreting the model. We also compared ML with ATRIA score and ORBIT score. RESULTS: A total of 2376 patients were finally enrolled in this model, 131 (5.5%) of whom experienced the high bleeding risk after anticoagulation therapy of warfarin during hospitalization. The extreme gradient boosting (XGBoost) exhibited the best overall prediction performance (AUC: 0.882, confidence interval [CI] 0.817-0.946, Brier score, 0.158) compared to other prediction models. It also shows superior performance compared with ATRIA score and ORBIT score. The top 5 most influential features in XGBoost model were platelet, thyroid stimulation hormone, body surface area, serum creatinine and white blood cell. CONCLUSION: A model for predicting high bleeding risk in valve replacement patients who treated with warfarin during hospitalization was successfully developed by using machine learning, which may well assist clinicians to identify patients at high risk of bleeding and allow timely adjust therapeutic strategies in evaluating individual patient.

METTL3-dependent N6-methyladenosine modification is involved in berberine-mediated neuroprotection in ischemic stroke by enhancing the stability of NEAT1 in astrocytes.

Ischemic stroke (IS) is one of the principal causes of disability and death worldwide. Berberine (BBR), derived from the traditional Chinese herbal medicine Huang Lian, has been reported to inhibit the progression of stroke, but the specific mechanism whereby BBR modulates the progression of ischemic stroke remains unclear. N6-methyladenosine (m6A) modification is the most typical epigenetic modification of mRNA post-transcriptional modifications, among which METTL3 is the most common methylation transferase. During the study, the middle cerebral artery occlusion/reperfusion (MCAO/R) was established in mice, and the mice primary astrocytes and neurons induced by oxygen-glucose deprivation/reoxygenation (OGD/R) was simulated in vitro. Level of LncNEAT1, miR-377-3p was detected via RT-qPCR. The levels of Nampt and METTL3 were measured by Western blot. CCK8 and LDH assay was performed to detect cell viability. Here, we found that berberine alleviates MCAO/R-induced ischemic injury and up-regulates the expression of Nampt in astrocytes, miR-377-3p inhibits the expression of Nampt in astrocytes after OGD/R, thus promoting neuronal injury. NEAT1 binds to miR-377-3p in OGD/R astrocytes and plays a neuronal protective role as a ceRNA. METTL3 can enhance NEAT1 stability in OGD/R astrocytes by modulating m6A modification of NEAT1. Taken together, our results demonstrate that berberine exerts neuroprotective effects via the m6A methyltransferase METTL3, which regulates the NEAT1/miR-377-3p/Nampt axis in mouse astrocytes to ameliorate cerebral ischemia/reperfusion (I/R) injury.

Solar CO2 Reduction Enabled by Cascade Hole Migration.

Solar-powered photocatalytic conversion of CO2 to hydrocarbon fuels represents an emerging approach to solving the greenhouse effect. However, low charge separation efficiency, deficiency of surface catalytic active sites, and sluggish charge-transfer kinetics, together with the complicated reaction pathway, concurrently hinder the CO2 reduction. Herein, we show the rational construction of transition metal chalcogenides (TMCs) heterostructure CO2 reduction photosystems, wherein the TMC substrate is tightly integrated with amorphous oxygen-containing cobalt sulfide (CoSOH) by a solid non-conjugated polymer, i.e., poly(vinyl alcohol) (PVA), to customize the unidirectional charge-transfer pathway. In this well-defined multilayered nanoarchitecture, the PVA interim layer intercalated between TMCs and CoSOH acts as a hole-relaying mediator and meanwhile boosts CO2 adsorption capacity, while CoSOH functions as a terminal hole-collecting reservoir, stimulating the charge transport kinetics and boosting the charge separation over TMCs. This peculiar interface configuration and charge transport characteristics endow TMC/PVA/CoSOH heterostructures with significantly enhanced visible-light-driven photoactivity and CO2 conversion. Based on the intermediates probed during the photocatalytic CO2 reduction reaction, the photocatalytic mechanism was determined. Our work would inspire sparkling ideas to mediate the charge transfer over semiconductor for solar carbon neutral conversion.

A Physiologically Based Pharmacokinetic Approach to Recommend an Individual Dose of Tacrolimus in Adult Heart Transplant Recipients.

Tacrolimus is the principal immunosuppressive drug which is administered after heart transplantation. Managing tacrolimus therapy is challenging due to a narrow therapeutic index and wide pharmacokinetic (PK) variability. We aimed to establish a physiologically based pharmacokinetic (PBPK) model of tacrolimus in adult heart transplant recipients to optimize dose regimens in clinical practice. A 15-compartment full-PBPK model (Simbiology® Simulator, version 5.8.2) was developed using clinical observations from 115 heart transplant recipients. This study detected 20 genotypes associated with tacrolimus metabolism. CYP3A5*3 (rs776746), CYP3A4*18B (rs2242480), and IL-10 G-1082A (rs1800896) were identified as significant genetic covariates in tacrolimus pharmacokinetics. The PBPK model was evaluated using goodness-of-fit (GOF) and external evaluation. The predicted peak blood concentration (Cmax) and area under the drug concentration-time curve (AUC) were all within a two-fold value of the observations (fold error of 0.68-1.22 for Cmax and 0.72-1.16 for AUC). The patients with the CYP3A5*3/*3 genotype had a 1.60-fold increase in predicted AUC compared to the patients with the CYP3A5*1 allele, and the ratio of the AUC with voriconazole to alone was 5.80 when using the PBPK model. Based on the simulation results, the tacrolimus dosing regimen after heart transplantation was optimized. This is the first PBPK model used to predict the PK of tacrolimus in adult heart transplant recipients, and it can serve as a starting point for research on immunosuppressive drug therapy in heart transplant patients.

Self-Transformation of Atomically Precise Alloy Nanoclusters to Plasmonic Alloy Nanocrystals: Evaluating Photosensitization in Solar Water Oxidation.

Atomically precise alloy nanoclusters (NCs) inherit the advantages of homometal NC counterparts such as atomic stacking fashion, quantum confinement effect, and enriched catalytic active sites and simultaneously possess the advantageous physicochemical properties such as significantly enhanced photostability, ideal photosensitization efficiency, and favorable energy band structure. Nevertheless, elucidation of the roles of alloy NCs and alloy nanocrystals (NYs) in boosting solar water oxidation has so far not yet been reported owing to the deficiency of applicable alloy NC photosystems. Herein, utilizing the generic thermal-induced self-transformation of alloy NCs to alloy NYs, we comprehensively explore the photosensitization properties of glutathione (GSH)-capped alloy NCs (AgxAu1-x@GSH and CuxAu1-x@GSH) and the corresponding alloy NY (AgAu and CuAu) counterparts in solar water oxidation reaction. The results imply that photoelectrons of alloy NCs surpass the hot electrons over plasmonic alloy NYs in stimulating the PEC water oxidation reaction. The photoelectrons of alloy NCs demonstrate lower interfacial charge-transfer resistance, longer carrier lifetime, and a more enhanced photosensitization effect with respect to the plasmonic alloy NYs, contributing to the significantly boosted photoelectrochemical water oxidation activities. Moreover, we found that our result is universal.

Maneuvering the Directional Charge Flow for Photoredox Organic Conversion.

Transition-metal chalcogenide quantum dots (TMC QDs) show great promise in artificial photosynthesis for excellent light-harvesting capability. Nonetheless, TMC QDs have limitations of ultrafast charge recombination rate, sluggish carrier migration kinetics, and generic photocorrosion, retarding their widespread applications. To solve these obstacles, herein, we demonstrate the stimulation of charge migration over TMC QDs with the aid of nonconjugated insulating polymer and graphene (GR) for a versatile photoredox selective organic transformation. To this end, an ultrathin insulating polymer layer, i.e., poly(allylamine hydrochloride) (PAH), grafted on the GR framework, is electrostatically intercalated at the interface of TMCs QDs and the GR framework via a self-assembly for constructing TMC QDs/PAH/GR three-dimensional spatially multilayered heterostructures. In this well-defined nanoarchitecture, TMC QDs function as a light-harvesting antenna, GR as a terminal electron reservoir, and PAH as an intermediate interfacial charge relay mediator. We ascertain that the ultrathin PAH interim layer unexpectedly fosters the photoelectron migration from TMCs QDs to the GR framework in a tunable fashion, boosting the charge separation of TMCs QDs and resulting in significantly improved photoactivities toward anaerobic reduction of aromatic nitro compounds to amino derivatives and oxidation of alcohols to aldehydes under visible light. Photoredox catalysis mechanisms of such TMC QDs/PAH/GR photosystems are elucidated, and the active species in these photoredox organic conversion reactions are comprehensively determined. Our work would open new frontiers to finely modulate the charge transport of TMCs QDs via nonconjugated insulating polymers for solar energy conversion.

A single-center, randomized, controlled study on the efficacy of niacinamide-containing body emollients combined with cleansing gel in the treatment of mild atopic dermatitis.

OBJECTIVE: To observe the effect of niacinamide-containing body emollients combined with a cleansing gel on the clinical symptoms of mild atopic dermatitis (AD) in adults. METHODS: From July 2022 to January 2023, adults with mild AD were enrolled at Huashan Hospital Affiliated to Fudan University using single-center, randomized and placebo-controlled methods. They were divided into three groups: the control group, treatment group 1 (T1) receiving niacinamide-containing body emollients alone, and treatment group 2 (T2) receiving emollients plus niacinamide-containing cleansing gel. All patients were orally administered 10 mg of ebastine tablets daily. AD severity (SCORAD score), peak pruritus numeric rating scale (PP-NRS), patient-oriented measure of eczema (POEM), dermatological quality of life index (DLQI) score, transepidermal water loss (TEWL), and stratum corneum water content (SCWC) were measured by the same dermatologist at days 0, 7, 14, and 28. RESULTS: A total of 122 patients were enrolled, including 38 in the control group, 42 in the T1 group and 42 in the T2 group. There were no obvious adverse reactions at the end of the study and the clinical scores and stratum corneum barrier of all the groups improved significantly relative to baseline. The SCORAD, PP-NRS, DLQI, TEWL and SCWC scores in T1 group (12.43 ± 3, 3.3 ± 0.9, 7.1 ± 2.33, 17.1 ± 9.12, 67.2 ± 21.46, seperately) and T2 group (11.17 ± 3.26, 3 ± 1.3, 6.5 ± 2.11, 16.3 ± 9.12, 69.4 ± 24.52, seperately) were significantly improved than the control group(15.1 ± 3.64, 4.3 ± 1.7, 9.5 ± 2.46, 21.2 ± 9.47, 52.7 ± 22.43, seperately) at the endpoint of the study, while compared the POEM scores, only T2 group showed the difference with control group (5.2 ± 1.4 vs. 6 ± 1.6). The epidermal barrier parameters of TEWL and SCWC in the T2 group (17.57 ± 5.24, 66.46 ± 21.38, seperately) were significantly better than that of the T1 (19.96 ± 4.45, 56.45 ± 20.48, seperately) and control group(21.89 ± 7.03, 51.56 ± 16.58, seperately) on the 14th day of follow-up. CONCLUSION: The use of niacinamide-containing body emollients can significantly improve the clinical symptoms, quality of life, and skin barrier function in patients with mild AD. The addition of niacinamide-containing cleansing gel can also affect the clinical efficacy at certain time points.

Salvianolic acid B ameliorates retinal deficits in an early-stage Alzheimer's disease mouse model through downregulating BACE1 and Aß generation.

Alzheimer's disease (AD) is a neurodegenerative disease with subtle onset, early diagnosis remains challenging. Accumulating evidence suggests that the emergence of retinal damage in AD precedes cognitive impairment, and may serve as a critical indicator for early diagnosis and disease progression. Salvianolic acid B (Sal B), a bioactive compound isolated from the traditional Chinese medicinal herb Salvia miltiorrhiza, has been shown promise in treating neurodegenerative diseases, such as AD and Parkinson's disease. In this study we investigated the therapeutic effects of Sal B on retinopathy in early-stage AD. One-month-old transgenic mice carrying five familial AD mutations (5×FAD) were treated with Sal B (20 mg·kg-1·d-1, i.g.) for 3 months. At the end of treatment, retinal function and structure were assessed, cognitive function was evaluated in Morris water maze test. We showed that 4-month-old 5×FAD mice displayed distinct structural and functional deficits in the retinas, which were significantly ameliorated by Sal B treatment. In contrast, untreated, 4-month-old 5×FAD mice did not exhibit cognitive impairment compared to wild-type mice. In SH-SY5Y-APP751 cells, we demonstrated that Sal B (10 µM) significantly decreased BACE1 expression and sorting into the Golgi apparatus, thereby reducing Aß generation by inhibiting the ß-cleavage of APP. Moreover, we found that Sal B effectively attenuated microglial activation and the associated inflammatory cytokine release induced by Aß plaque deposition in the retinas of 5×FAD mice. Taken together, our results demonstrate that functional impairments in the retina occur before cognitive decline, suggesting that the retina is a valuable reference for early diagnosis of AD. Sal B ameliorates retinal deficits by regulating APP processing and Aß generation in early AD, which is a potential therapeutic intervention for early AD treatment.

Amelioration of olfactory dysfunction in a mouse model of Parkinson's disease via enhancing GABAergic signaling.

BACKGROUND: Olfactory dysfunction is among the earliest non-motor symptoms of Parkinson's disease (PD). As the foremost pathological hallmark, α-synuclein initiates the pathology in the olfactory pathway at the early stage of PD, particularly in the olfactory epithelium (OE) and olfactory bulb (OB). However, the local neural microcircuit mechanisms underlying olfactory dysfunction between OE and OB in early PD remain unknown. RESULTS: We observed that odor detection and discrimination were impaired in 6-month-old SNCA-A53T mice, while their motor ability remained unaffected. It was confirmed that α-synuclein increased and accumulated in OB but not in OE. Notably, the hyperactivity of mitral/tufted cells and the excitation/inhibition imbalance in OB were found in 6-month-old SNCA-A53T mice, which was attributed to the impaired GABAergic transmission and aberrant expression of GABA transporter 1 and vesicular GABA transporter in OB. We further showed that tiagabine, a potent and selective GABA reuptake inhibitor, could reverse the impaired olfactory function and GABAergic signaling in OB of SNCA-A53T mice. CONCLUSIONS: Taken together, our findings demonstrate potential synaptic mechanisms of local neural microcircuit underlying olfactory dysfunction at the early stage of PD. These results highlight the critical role of aberrant GABAergic signaling of OB in early diagnosis and provide a potential therapeutic strategy for early-stage PD.

Interpretable Machine Learning Model Predicting Early Neurological Deterioration in Ischemic Stroke Patients Treated with Mechanical Thrombectomy: A Retrospective Study.

Early neurologic deterioration (END) is a common and feared complication for acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT). This study aimed to develop an interpretable machine learning (ML) model for individualized prediction to predict END in AIS patients treated with MT. The retrospective cohort of AIS patients who underwent MT was from two hospitals. ML methods applied include logistic regression (LR), random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGBoost). The area under the receiver operating characteristic curve (AUC) was the main evaluation metric used. We also used Shapley Additive Explanation (SHAP) and Local Interpretable Model-Agnostic Explanations (LIME) to interpret the result of the prediction model. A total of 985 patients were enrolled in this study, and the development of END was noted in 157 patients (15.9%). Among the used models, XGBoost had the highest prediction power (AUC = 0.826, 95% CI 0.781-0.871). The Delong test and calibration curve indicated that XGBoost significantly surpassed those of the other models in prediction. In addition, the AUC in the validating set was 0.846, which showed a good performance of the XGBoost. The SHAP method revealed that blood glucose was the most important predictor variable. The constructed interpretable ML model can be used to predict the risk probability of END after MT in AIS patients. It may help clinical decision making in the perioperative period of AIS patients treated with MT.

Effect of Several Naja atra Antivenom Injection Methods on the Rabbit Model of Naja naja atra Bite Poisoning.

Snakebite is a global public health concern, which often occurs in tropical and subtropical underdeveloped areas, but it is often neglected. In the southern China, Naja naja atra (Chinese cobra) is a common venomous snake that causes swelling and necrosis of local tissues, even amputation and death. Currently, the main therapy is the administration of Naja atra antivenom, which greatly reduces mortality. However, the antivenom is not particularly effective in the improvement of local tissue necrosis. Clinically, antivenom is mainly administered intravenously. We speculated that the method of injection influences the efficacy of antivenom. In this study, the rabbit model was used to explore the effects of different antivenom injection methods on systemic and local poisoning symptoms. If topical injection of antivenom contributes to ameliorate tissue necrosis, then we need to reconsider the use of Naja atra antivenom.

Astrocytes-derived exosomes pre-treated by berberine inhibit neuroinflammation after stroke via miR-182-5p/Rac1 pathway.

BACKGROUND: Our previous studies have shown that berberine can improve the nerve function deficits in ischemic stroke by inhibiting inflammation. The cellular communication between astrocytes and neurons via exosomes might affect neurological function after ischemic stroke, which plays a vital role in the therapy of ischemic stroke. OBJECTIVE: The present study focused on the effects of exosomes released from astrocytes induced by the glucose and oxygen deprivation model with berberine pretreatment (BBR-exos) treatment for ischemic stroke and its regulatory mechanism. METHODS: Oxygen-glucose-deprivation/Reoxygenation (OGD/R)-treated primary cells were used to mimic cerebral ischemia/reperfusion conditions in vitro. With the treatment of BBR-exos and exosomes released from primary astrocytes induced by the glucose and oxygen deprivation model (OGD/R-exos), the cell viability was detected. C57BL/6J mice were used to establish middle cerebral artery occlusion/reperfusion (MCAO/R) model. The anti-neuroinflammation effects of BBR-exos and OGD/R-exos were evaluated. Subsequently, the key miRNA in BBR-exos was identified by exosomal miRNA sequencing and cell validation. miR-182-5p mimic and inhibitors were provided to verify the effects in inflammation. Finally, the binding sites between miR-182-5p and Rac1 were predicted online and verified by using a dual-luciferase reporter assay. RESULTS: BBR-exos and OGD/R-exos both improved the decreased activity of OGD/R-induced neurons, and decreased the expression of IL-1ß, IL-6 and TNF-α (all P ＜ 0.05), which reduced neuronal injury and inhibited neuroinflammation in Vitro. And BBR-exos showed better effects (P ＜ 0.05). The same effect has been verified in vivo experiments: BBR-exos and OGD/R-exos both reduced cerebral ischemic injury and inhibited neuroinflammation in MCAO/R mice (all P ＜ 0.05). Likewise, BBR-exos showed better effects (P ＜ 0.05). The exosomal miRNA sequencing results showed that miR-182-5p was highly expressed in BBR-exos and inhibited neuroinflammation by targeting Rac1 (P ＜ 0.05). CONCLUSION: BBR-exos can carry miR-182-5p to injured neurons and inhibit the expression of Rac1, which could inhibit neuroinflammation and improved brain injury after ischemic stroke.

Comprehensive Evaluation of Metabolism and the Contribution of the Hepatic First-Pass Effect in the Bioavailability of Glabridin in Rats.

Glabridin is a bioactive isoflavan, which has a wide range of biological properties and is widely used in the market of health products and dietary supplements. However, the transformation pathway of glabridin in vivo is unclear, and the bioavailability is controversial among different studies. Therefore, a new HPLC-Q-TOF method was developed to analyze and identify the prototype and metabolites of glabridin in rats. A total of 63 compounds were identified, including hydroxylation, demethylation, acetylation, demethylation to carboxylation, glucuronidation, and sulfate conjugation, and 43 of which were new metabolites that had not been reported. Additionally, our study verified that the oral bioavailability of glabridin was 6.63 ± 2.29% in rats. Furthermore, we found that the hepatic first-pass effect was 62.12 ± 15.7% for glabridin. These results indicated that a high hepatic first-pass effect and extensive metabolism of glabridin in vivo may lead to its limited oral bioavailability.

Berberine Mediates the Production of Butyrate to Ameliorate Cerebral Ischemia via the Gut Microbiota in Mice.

Ischemic stroke (IS) is a vascular disease group concomitant with high morbidity and mortality. Berberine is a bioactive substance and it has been known to improve stroke, but its mechanism is yet to be proven. Mice were fed with BBR for 14 days. Then, the mice were made into MCAO/R models. Neurological score, infarct volume, neuronal damage and markers associated with inflammation were detected. We tested the changes in intestinal flora in model mice after BBR administration using 16SrRNA sequencing. Chromatography-mass spectrometry was used to detect butyrate chemically. Tissue immunofluorescence was used to detect the changes in the microglia and astroglia in the mice brains. Our findings suggest that berberine improves stroke outcomes by modulating the gut microbiota. Specifically, after MCAO/R mice were given berberine, the beneficial bacteria producing butyric acid increased significantly, and the mice also had significantly higher levels of butyric acid. The administration of butyric acid and an inhibitor of butyric acid synthesis, heptanoyl-CoA, showed that butyric acid improved the stroke outcomes in the model mice. In addition, butyric acid could inhibit the activation of the microglia and astrocytes in the brains of model mice, thereby inhibiting the generation of pro-inflammatory factors IL-6, IL-1ß and TNF-α as well as improving stroke outcomes. Our results suggest that berberine may improve stroke outcomes by modulating the gut flora to increase the abundance of butyric acid. These findings elucidate the mechanisms by which berberine improves stroke outcomes and provide some basis for clinical treatment.

Astrocyte-derived exosomal nicotinamide phosphoribosyltransferase (Nampt) ameliorates ischemic stroke injury by targeting AMPK/mTOR signaling to induce autophagy.

Acute ischemic stroke (AIS) is a global cerebrovascular disease with high disability and mortality, which has no effective therapy. Studies have demonstrated that astrocyte-derived exosomes (ADEXs) provided neuroprotection in experimental stroke models. Nevertheless, the role of exosomes derived from oxygen-glucose-deprivation/reoxygenation-stimulated astrocytes (OGD/R-stimulated astrocytes; OGD/R-ADEXs) in AIS remains largely unknown. Here, we found that OGD/R-ADEXs significantly reduced OGD/R-induced neuronal death and promoted neuronal autophagy. These effects were reversed when astrocytes were pretreated with GW4869, an exosome secretion inhibitor, or when hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) was knocked down. Neuroprotection was also observed during treatment with OGD/R-ADEXs in vivo. Further studies showed that Nampt, played a vital effect in the regulation of autophagy, was significantly increased in OGD/R-ADEXs. Knockdown of Nampt in astrocytes abolished the above-mentioned effects of OGD/R-ADEXs. Mechanistically, Nampt increased autophagy and decreased cell death by modulating AMPK/mTOR signaling, which recognized as a key signaling pathway of autophagy after AIS. Collectively, these results showed that Nampt released by OGD/R-ADEXs ameliorated acute ischemic stroke during neuronal injury by targeting AMPK/mTOR signaling to induce autophagy. Our study revealed a new key factor in the secretion of exosomes by OGD/R astrocytes, which regulated autophagy and induced neuroprotection in a mouse stroke model.

The diagnostic and prognostic value of the miR-17-92 cluster in hepatocellular carcinoma: A meta-analysis.

Previous studies demonstrated that microRNAs (miRNAs) could serve as biomarkers in various cancers. This meta-analysis aimed to determine the roles of a miR-17-92 cluster in hepatocellular carcinoma (HCC). Here, eligible included studies were searched through PubMed, Embase, and Wan Fang databases up to 1st February 2022. Relevant data were extracted from each eligible study to evaluate the relationship between miRNA-17-92 cluster miRNA expression and the diagnosis and prognosis of HCC. Finally, a total of 21 studies were pooled and included in the meta-analysis, of which four articles were used for diagnostic meta-analysis and eight articles were used for prognostic meta-analysis. The pooled sensitivity, specificity, and diagnostic odds ratios (DOR) of the miR17-92 cluster for diagnosis of HCC were 0.75 [95% confidence interval (CI): 0.64-0.83], 0.73 (95% CI: 0.65-0.79), and 7.87 (95% CI: 5.36-11.54), respectively. Also, the area under the curve (AUC) for the miR-17-92 cluster when diagnosing HCC was 0.79 (95% CI: 0.76-0.83). For prognostic analysis, hazard ratios (HRs) with 95% CIs were extracted from the included studies and pooled HRs were determined to assess the associations. Patients with increased expression of miR17-92 cluster miRNA were associated with poor overall survival (OS) and recurrence-free survival (RFS) (HR=1.86, 95% CI: 1.04-3.33; HR = 4.18, 95% CI: 3.02-5.77, respectively), but not progression-free survival (PFS) (HR = 0.43, 95% CI: 0.25-0.73), while no association of the miR-17-92 cluster high-expression was detected with disease-free survival (DFS) (HR: 0.95, 95% CI: 0.21-4.34). In short, current pieces of evidence suggested that the miR-17-92 cluster may serve as a novel diagnostic and prognostic biomarker for HCC. However, given the limited study number, larger-size, multi-center, and higher-quality studies are indispensable in the future.

Dynamic Prediction of Mechanical Thrombectomy Outcome for Acute Ischemic Stroke Patients Using Machine Learning.

The unfavorable outcome of acute ischemic stroke (AIS) with large vessel occlusion (LVO) is related to clinical factors at multiple time points. However, predictive models used for dynamically predicting unfavorable outcomes using clinically relevant preoperative and postoperative time point variables have not been developed. Our goal was to develop a machine learning (ML) model for the dynamic prediction of unfavorable outcomes. We retrospectively reviewed patients with AIS who underwent a consecutive mechanical thrombectomy (MT) from three centers in China between January 2014 and December 2018. Based on the eXtreme gradient boosting (XGBoost) algorithm, we used clinical characteristics on admission ("Admission" Model) and additional variables regarding intraoperative management and the postoperative National Institute of Health stroke scale (NIHSS) score ("24-Hour" Model, "3-Day" Model and "Discharge" Model). The outcome was an unfavorable outcome at the three-month mark (modified Rankin scale, mRS 3-6: unfavorable). The area under the receiver operating characteristic curve and Brier scores were the main evaluating indexes. The unfavorable outcome at the three-month mark was observed in 156 (62.0%) of 238 patients. These four models had a high accuracy in the range of 75.0% to 87.5% and had a good discrimination with AUC in the range of 0.824 to 0.945 on the testing set. The Brier scores of the four models ranged from 0.122 to 0.083 and showed a good predictive ability on the testing set. This is the first dynamic, preoperative and postoperative predictive model constructed for AIS patients who underwent MT, which is more accurate than the previous prediction model. The preoperative model could be used to predict the clinical outcome before MT and support the decision to perform MT, and the postoperative models would further improve the predictive accuracy of the clinical outcome after MT and timely adjust therapeutic strategies.

Genetic Variation of Inflammatory Genes to Ischemic Stroke Risk in a Chinese Han Population.

BACKGROUND: Inflammation proteins play an important role in stroke occurrence. IL1A, IL1B, PTGS2, MMP2, and MMP9 were the mediators involved in the immune response, and the association of these genetic variations with ischemic stroke (IS) risk was still unclear. METHODS: To investigate the susceptibility of genetic variations of IL1A, IL1B, PTGS2, MMP2, and MMP9 to IS risk, we performed a case-control study involving 299 patients and 300 controls in a Chinese population. Thirteen genetic variations of investigated genes of all participants were genotyped using an improved multiplex ligase detection-reaction technique. RESULTS: No SNP in all genes showed an association with overall IS. However, in subgroup analysis, PTGS2 rs689466 (dominant model: CT vs TT - ORadjusted= 2.51, 95% CI: 1.22-5.16, p = 0.012; co-dominant model: CT/CC vs TT - ORadjusted= 2.53, 95% CI: 1.26-5.07, p = 0.009; additive model - ORadjusted= 2.26, 95% CI: 1.19-4.28, p = 0.013) and rs5275 (dominant model: GG vs AA - ORadjusted= 0.31, 95% CI: 0.12-0.80, p = 0.016; co-dominant model: GA/GG vs AA - ORadjusted= 0.45, 95% CI: 0.21-0.95, p = 0.036; additive model - ORadjusted= 0.60, 95% CI: 0.39-0.92, p = 0.020) were associated with IS type of small-vessel occlusion. CONCLUSION: Our study suggested that PTGS2 rs689466 C and rs5275 A were potentially associated with IS subtype of small-vessel occlusion. Our result should be confirmed with further large sample sized studies.

The lncRNA Malat1 functions as a ceRNA to contribute to berberine-mediated inhibition of HMGB1 by sponging miR-181c-5p in poststroke inflammation.

Long non-coding RNAs (lncRNAs) have been identified as essential mediators in neurological dysfunction. Our previous study shows that berberine (BBR) hampers the nuclear-to-cytosolic translocation of high-mobility group box 1 (HMGB1) in the process of poststroke inflammation. In this study, we explored the role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (Malat1) in the process of BBR-induced inhibition of HMGB1 in ischemic brain. Before the 60-min MCAO surgery, the mice were pretreated with BBR (50 mg· kg-1 per day, ig) for 14 days or ICV injected with specific lentiviral vector or shRNA. We showed that MCAO caused marked increase in the expression Malat1 and HMGB1 in the ipsilateral cortex, which was significantly attenuated by pretreatment with BBR. Knockdown of Malat1 attenuated the inflammatory injury after brain ischemia, whereas overexpression of Malat1 exacerbated ischemic brain inflammation. Overexpression of Malat1 also reversed BBR-induced reduction of HMGB1 and proinflammatory cytokines. The above results suggested a potential correlation between Malat1 and stroke inflammation. Based on informatics analysis we predicted that HMGB1 was a direct downstream target of miR-181c-5p, whereas Malat1 acted as a competitive endogenous RNA (ceRNA) for miR-181c-5p targeted the 3'-UTR of HMGB1 to promote inflammation after ischemic stroke. Knockdown of Malat1 significantly decreased HMGB1 level, which could be abrogated by transfection with miR-181c-5p inhibitors. Taken together, our results demonstrate for the first time that Malat1/miR-181c-5p/HMGB1 axis may be a key pathway of BBR-induced antiinflammation effects in stroke, and they may provide a novel avenue for targeted therapy.

Pre-aggregation of scalp progenitor dermal and epidermal stem cells activates the WNT pathway and promotes hair follicle formation in in vitro and in vivo systems.

BACKGROUND: Billions of dollars are invested annually by pharmaceutical companies in search of new options for treating hair loss conditions; nevertheless, the challenge remains. One major limitation to hair follicle research is the lack of effective and efficient drug screening systems using human cells. Organoids, three-dimensional in vitro structures derived from stem cells, provide new opportunities for studying organ development, tissue regeneration, and disease pathogenesis. The present study focuses on the formation of human hair follicle organoids. METHODS: Scalp-derived dermal progenitor cells mixed with foreskin-derived epidermal stem cells at a 2:1 ratio aggregated in suspension to form hair follicle-like organoids, which were confirmed by immunostaining of hair follicle markers and by molecular dye labeling assays to analyze dermal and epidermal cell organization in those organoids. The hair-forming potential of organoids was examined using an in vivo transplantation assay. RESULTS: Pre-aggregation of dermal and epidermal cells enhanced hair follicle formation in vivo. In vitro pre-aggregation initiated the interactions of epidermal and dermal progenitor cells resulting in activation of the WNT pathway and the formation of pear-shape structures, named type I aggregates. Cell-tracing analysis showed that the dermal and epidermal cells self-assembled into distinct epidermal and dermal compartments. Histologically, the type I aggregates expressed early hair follicle markers, suggesting the hair peg-like phase of hair follicle morphogenesis. The addition of recombinant WNT3a protein to the medium enhanced the formation of these aggregates, and the Wnt effect could be blocked by the WNT inhibitor, IWP2. CONCLUSIONS: In summary, our system supports the rapid formation of a large number of hair follicle organoids (type I aggregates). This system provides a platform for studying epithelial-mesenchymal interactions, for assessing inductive hair stem cells and for screening compounds that support hair follicle regeneration.