Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation. In this study, we identify ubiquitin-specific protease 2 (USP2) as a novel deubiquitinating enzyme of KRAS in multiple myeloma (MM). Specifically, we demonstrate that gambogic acid (GA) forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket, inhibiting its deubiquitinating activity. Inactivation or knockdown of USP2 leads to the degradation of KRAS, resulting in the suppression of MM cell proliferation in vitro and in vivo. Conversely, overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells. Furthermore, elevated USP2 levels may be associated with poorer prognoses in MM patients. These findings highlight the potential of the USP2/KRAS axis as a therapeutic target in MM, suggesting that strategically inducing KRAS degradation via USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.

Objective:To investigate the predictive value of STAF (score for the targeting of atrial fibrillation) score for paroxysmal atrial fibrillation (PAF) in patients with recurrent acute ischemic stroke.Methods:Consecutive patients with recurrent acute ischemic stroke hospitalized in the Department of Neurology, Huizhou Municipal Central Hospital from January 2014 to January 2020 were enrolled retrospectively. All patients were divided into a sinus rhythm (SR) group and a PAF group. PAF was defined as no PAF during the last stroke hospitalization or after discharge, and PAF was found by routine ECG, ambulatory ECG or long-term ECG monitoring after this recurrent acute ischemic stroke. Multivariate logistic regression analysis was used to evaluate the independent related factors of PAF in patients with recurrent acute ischemic stroke. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of STAF for PAF in patients with recurrent acute ischemic stroke. Results:A total of 234 patients with recurrent acute ischemic stroke were enrolled, including 174 males (74.4%), aged 67.15±10.63 years, and 199 (85.0%) in the SR group and 35 (15.0%) in the PAF group. Univariate analysis showed that the proportion of patients in age >62 years old (94.3% vs. 63.8%; χ2=12.777, P<0.001) and left atrial enlargement (54.3% vs. 11.1%; χ2=40.379, P<0.001) of the PAF group was significantly higher than those of the SR group. Multivariate logistic regression analysis showed that age (odd ratio [ OR] 1.071, 95% confidence interval [ CI] 1.028-1.114; P=0.001) or age >62 years ( OR 17.512, 95% CI 2.881-106.453; P=0.002), left atrial enlargement ( OR 17.511, 95% CI 6.298-48.687; P<0.001), absence of vascular etiology ( OR 8.562, 95% CI 2.534-28.923; P=0.001), STAF score ( OR 2.715, 95% CI 1.969-3.744; P<0.001) and STAF score ≥5 ( OR 12.714, 95% CI 5.636-28.681; P<0.001) were independently associated with PAF. ROC curve analysis showed that the area under the curve of STAF for predicting PAF in patients with recurrent acute ischemic stroke was 0.848 (95% CI 0.779-0.917), and the sensitivity and specificity of STAF ≥5 for predicting PAF were 58.1% and 89.4%, respectively; the area under the curve for predicting PAF in patients with recurrent ischemic stroke of undetermined cause was 0.809 (95% CI 0.663-0.956), and the sensitivity and specificity of STAF ≥5 for predicting PAF were 53.8% and 91.3%, respectively. Conclusions:PAF is likely to exist in patients with recurrent acute ischemic stroke and aged >62 years, left atrial enlargement and absence of vascular etiology. STAF has medium predictive value for PAF in patients with recurrent acute ischemic stroke, but the sensitivity is not high.

Sex reversal, representing extraordinary sexual plasticity during the life cycle, not only triggers reproduction in animals but also affects reproductive and endocrine system-related diseases and cancers in humans. Sex reversal has been broadly reported in animals; however, an integrated resource hub of sex reversal information is still lacking. Here, we constructed a comprehensive database named ASER (Animal Sex Reversal) by integrating sex reversal-related data of 18 species from teleostei to mammalia. We systematically collected 40,018 published papers and mined the sex reversal-associated genes (SRGs), including their regulatory networks, from 1611 core papers. We annotated homologous genes and computed conservation scores for whole genomes across the 18 species. Furthermore, we collected available RNA-seq datasets and investigated the expression dynamics of SRGs during sex reversal or sex determination processes. In addition, we manually annotated 550 in situ hybridization (ISH), fluorescence in situ hybridization (FISH), and im-munohistochemistry (IHC) images of SRGs from the literature and described their spatial expression in the gonads. Collectively, ASER provides a unique and integrated resource for researchers to query and reuse organized data to explore the mechanisms and applications of SRGs in animal breeding and human health. The ASER database is publicly available at http://aser.ihb.ac.cn/.

Objective:To investigate the clinical characteristics and outcomes in patients with wake-up stroke.Methods:From January 2019 to December 2019, consecutive patients with acute ischemic stroke admitted to the Department of Neurology, Huizhou Municipal Central Hospital were enrolled retrospectively. The modified Rankin Scale was used to evaluate the outcome of patients at 90 d after the onset. 0 to 2 was defined as a good outcome, and >2 was defined as a poor outcome. Multivariate logistic regression analysis was used to determine the factors affecting the poor outcome of patients with wake-up stroke. Results:A total of 356 patients with acute ischemic stroke were enrolled, including 97 (27.2%) wake-up stroke, and 259 (72.8%) non-wake-up stroke. The National Institutes of Health Stroke Scale (NIHSS) score at admission and the proportion of patients with atrial fibrillation, moderate to severe stroke and cardiogenic embolism in the wake-up stroke group were significantly higher than those of the non-wake-up stroke group, and the proportion of patients with small artery occlusion was significantly lower than that in the non-wake-up stroke group (all P<0.05). Moreover, the proportion of patients with poor outcome in the wake-up stroke group was significantly higher than that in the non-wake-up stroke group (36.1% vs. 24.7%; χ2=4.546, P=0.033). In the wake-up stroke group, 62 patients (63.9%) had a good outcome, and 35 (36.1%) had a poor outcome. The NIHSS score at admission and the proportion of patients with atrial fibrillation and moderate to severe stroke in the subgroup with poor outcome were significantly higher than those in the subgroup with good outcome, and the proportion of patients receiving intravenous thrombolysis and mechanical thrombectomy was significantly lower than those in the good outcome subgroup (all P<0.05). Multivariate logistic regression analysis showed that moderate to severe stroke (odds ratio [ OR] 6.674, 95% confidence interval [ CI] 2.223-20.034; P=0.001) was independently associated with the poor outcome in patients with wake-up stroke, while intravenous thrombolysis ( OR 0.102, 95% CI 0.017-0.630; P=0.014) and endovascular mechanical thrombectomy ( OR 0.108, 95% CI 0.023-0.506; P=0.005) were independently associated with the good outcome of patients with wake-up stroke. Conclusions:In patients with wake-up stroke, the proportion of cardioembolism is higher, the clinical symptoms are more serious and the incidence of poor outcome is higher. The severity of stroke at admission is associated with poor short-term outcome, and intravenous thrombolysis and endovascular mechanical thrombectomy can improve the outcome in patients with wake-up stroke.

Objective　We established a model by using microfluidic chip that is a horizontal side by side diffusion system through microporous separating three adjacent channels in a triple-culture using neurons,astrocytes,and bEnd.3.Methods　(1)In the in vitro microphysiological system of neurovascular unit,we identified the seed density,seed time,seed sequence and seed method.(2)We adopt the repeated measures data of ANOVA to see whether there is significant difference in the viability when the three cell types are tri-cultured and separately mono-cultured.Results　(1) In the novel in vitro NVU model,the seed density of the neurons,astrocytes and bEnd.3 is 5×10^6~10×10^6 /ml,3×10^5~8×10^5个/ml and 1×10^5~5×10^5/ml.The seed sequence is from neurons to astrocytes to bEnd.3.The seed time is that after the previous seeded cells enter the exponential phase,the next cells will be seeded.(2)We adopt the repeated measures data of ANOVA to see whether there is significant difference in the viability when the three cell types are tri-cultured and separately mono-cultured.Conclusion　In this study,neurons,astrocytes and bEnd.3 were tri-cultured by using microfluidic chip.In this tri-culture model,these three kinds of cells have high cell viability.

Early anticoagulation with conventional anticoagulants (such as heparin, low-molecular- weight heparin or warfarin) has no benefit in preventing recurrence of stroke in ischemic stroke patients with atrial fibrillation. Non-vitamin K oral anticoagulants (NOACs) has the same or better anticoagulant effect and much lower incidence of intracranial hemorrhage than warfarin, and it works on the same day. Although it has been available for less than 10 years, it has a tendency to replace warfarin. This article reviews the research progress in the prevention of early recurrence with NOACs in ischemic stroke patients with atrial fibrillation.

Objective To investigate the risk factors of intracranial hemorrhagic (ICH) transformation within 14-days in acute cerebral infarction with non-valvular atrial fibrillation (NVAF) patients. Methods CT and/or MRI scans of the head were conducted within 14 days on patients with NVAF acute cerebral infarction who admitted to the Department of Neurology, Huizhou Municipal Central Hospital between January 2015 to March 2018. The baseline scan data were reviewed to determine whether ICH conversion occurred. Comparable risk assessment were based on stratification scores using HAS-BLED, ASPECTS, and pc-ASPECTS. Results There were 150 cases of acute cerebral infarction with NVAF, 126 patients were eligible for the analysis, with an ICH conversion rate of 27.0% (34/126). The following four risk factors were statistically significant among the ICH and non-ICH transformation groups: ①systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg post-cerebral infarction, ②Severe cerebral infarction, progressing stroke, ③ASPECTS (pc-ASPECTS) score ≤7 points, and ④ HAS-BLED score ≥3 points (P<0.05). Conclusion Approximately 1/3 of NVAF acute cerebral infarction patients experience an ICH transformation within 14 days of their episode. The following indicators are independent risk factors of ICH transformation: SBP >160mmHg or DBP >100mmHg after cerebral infarction, severe cerebral infarction, progressing stroke, ASPECTS (pc-ASPECTS)≤7 points, and HAS-BLED score≥3 points.

Objective To find out whether inpatients with acute ischaemic stroke and atrial fibrillation (AF) have higher rate of renal dysfunction than without AF,and analyze risk factors associated with renal dysfunction.Method 374 patients with acute ischaemic stroke and AF were enrolled,which cases have complete data.500 patients were randomly selected as the non-AF group.To compare the prevalence of renal dysfunction [eGFR ＜ 60 mL/(min· 1.73 m2)] of two groups.Non-conditional Logistic regression analysis was used to detemmine the factors associated with renal dysfunction.Results 374 patients in AF group,114 (30.5％) were renal dysfunction;500 patients in non-AF group,75 (15％) were renal dysfunction (P =0.000,OR =2.485).The eGFR of AF and non-AF group was (77.75 ± 39.89) mL/(min· 1.73 m2) and (96.93±39.14) mL/(min · 1.73 m2).In Logis tic regression analysis,heart dysfunction (OR =2.057),hypertension (OR =1.826),diabetes (OR =1.897),hypevuricemia (OR =3.161) were found to be associated with renal dysfunction.Conclusions Adult patients with acute ischaemic stroke and AF have a higher rate of renal dysfunction than acute ischaemic stroke without AF.Heart dysfunction,hypertension,diabetes,hyperuricemia were factors associated with renal dysfunction.

Objectives The aim of this study was to study the relationship between silent cerebral ischemia (SCI) and mild cognitive impairment(MCI)in inpatients with nonvalvula atrial fibrillation (NAF) and those with sinus rhythm (SR) older than sixty. Methods Ninety-eight inpatients were enrolled from November 2014 to November 2015 in Hui?zhou Municipal Central Hospital: 45 patients with NAF and 53 with SR. All general clinical data was collected. The Montreal Cognitive Assessment (MoCA) and brain MRI were used to assess the cognitive performance of patients within 1 weeks of admission. Results The MoCA scores were lower in patients with NAF than in those with SR[16(10,20) vs. 20 (15,23),P=0.006]. At least one foci of SCI was present in patients 80%with NAF and 52.8%with SR (NAF vs. SR, P=0.018).The rates of SCIs in the cortex/subcortex were higher in the NAF group than in the SR group (25.2%vs. 12.4%, P=0.017). Multivariate analysis showed that MoCA score were related to the degree of education in NAF patients and were related to age and education level in SR patients. Conclusions NAF is an independent risk factor for cognitive impair?ment in NAF patient and associated with the SCI present. Educational level is a factor affecting the cognitive function with elderly patients.

Objective To explore the diagnostic value of serum thyroglobulin antibody (TGAb),thyroid microsomal antibody (TMAb)and thyroid peroxidase antibody (TPOAb)in au-toimmune thyroid disease (AITD).Methods 100 patients with thyroid dysfunction were divided into hyperthyroidism group and hypothyroidism group according to the levels of serum triiodothy-ronine (T3),thyroxine (T4)and thyroid stimulating hormone (TSH),50 cases in each group.An-other 50 patients with normal thyroid function were collected and designed as control group.5 mL venous blood was collected,and the serum was separated.The levels of TGAb,TMAb,TPOAb, T3,T4 and TSH were detected by radioimmunoassay in each group,positive rates of TGAb,TMAb and TPOAb were observed,and the serum levels of positive TGAb,TMAb and TPOAb were com-pared among all the groups.Results The positive rate of serum TPOAb was significantly higher than those of TGAb and TMAb in hyperthyroidism group and hypothyroidism group.The positive rates of serum TGAb,TMAb and TPOAb in hyperthyroidism and hypothyroidism groups were sig-nificantly higher than the control group,and those in hypothyroidism group were higher than hy-perthyroidism group.The levels of serum TGAb,TMAb and TPOAb in hyperthyroidism group and hypothyroidism group were significantly higher than the control group,and those in hypothyroidism group were obviously higher than hyperthyroidism group.Conclusion TPOAb shows an important significance in diagnosing AITD,which provides an important evidence for AITD diagnosis, treatment and prognosis.