Approximately 60% of colorectal cancer (CRC) patients exhibit TP53 mutations, which are strongly associated with tumor progression, chemotherapy resistance, and an unfavorable prognosis. However, targeting p53 has historically been challenging, and currently, there are no approved p53-based therapeutics for clinical use worldwide. In this study, we discovered that ubiquitin carboxyl terminal hydrolase L3 (UCHL3) plays a crucial role in high-level glycolysis, enhanced stem-like properties, and 5-fluorouracil (5-FU) chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilize α-enolase (ENO1) protein. Notably, we identified a newly Food and Drug Administration (FDA)-approved drug, pacritinib, that potently suppresses UCHL3 expression by blocking the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway in TP53-mutant CRC. Furthermore, Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC. Our findings suggest that targeting the JAK2-STAT3-UCHL3-ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC. Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.

Objective To observe the effects of Huatan Quyu Decoction on cognitive function and the expressions of GABA and VILIP-1 in brain tissue of rats with cerebral small vessel disease;To discuss its mechanism for treatment on cerebral small vessel disease.Methods Totally 48 male SD rats were randomly divided into blank group,model group,Huatan Quyu Decoction low-and high-dosage groups,with 12 rats in each group.Except for the blank group,a rat model of cerebral small vessel disease was prepared by in vitro injection of homologous microemboli.Huatan Quyu Decoction low-and high-dosage groups were given Huatan Quyu Decoction 1.25 and 2.5 g/kg by gavage,the blank group and model group were gavage with equal amounts of distilled water for 28 consecutive days.Morris water maze experiment was conducted on day 1,7,14,and 28 after administration to evaluate the learning and memory abilities of rats,HE staining was used to observe pathological changes in hippocampal tissue,and immunohistochemical staining was used to detect the expressions of GABA and VILIP-1 proteins in brain tissue.Results Compared with the blank group,the escape latency of Morris water maze experiment in model group significantly prolonged(P<0.05),and the number of crossing platforms was significantly reduced(P<0.05);the arrangement of hippocampal tissue cells was disordered,gaps widen,and nuclei atrophy and necrosis,the GABA expression in brain tissue significantly decreased(P<0.05),while the VILIP-1 expression significantly increased(P<0.05).Compared with the model group,the escape latency of Morris water maze experiment in the Huatan Quyu Decoction low-and high-dosage groups significantly shortened(P<0.05)on day 7,14,and 28 of administration,and the number of crossing platforms significantly increased(P<0.05),GABA expression significantly increased(P<0.05),while VILIP-1 expression significantly decreased(P<0.05).Compared with the Huatan Quyu Decoction low-dosage group,the escape latency of Morris water maze experiment in Huatan Quyu Decoction high-dosage group decreased at various time points,and the number of crossing platforms increase,the pathological damage of hippocampal tissue was reduced,the expression of GABA in brain tissue increased,and the expression of VILIP-1 decreased,with statistical significance(P<0.05).Conclusion Huatan Quyu Decoction can increase the expression of GABA in brain tissue and inhibit the expression of VILIP-1,thereby improve the cognitive function of rats with cerebrovascular disease.

This article reported a survived case of amniotic band syndrome (ABS) following fetal reduction by radiofrequency ablation. The woman conceived monochorionic diamniotic twin pregnancy spontaneously. Prenatal ultrasound at 24 weeks of gestation indicated twin-twin transfusion syndrome (stage Ⅲ), and radiofrequency ablation for fetal reduction was successfully performed after formal consent. At 28 +6 weeks, ultrasound reexamination revealed significant edema in the left foot of the fetus, with banding around the ankle, as well as the strangulation mark and narrowing rings. Fetal ABS (ⅡB stage) was diagnosed after multidisciplinary consultation. An immediate emergency cesarean section was performed and a live male baby was born. A thin amniotic band could be seen wrapping around the left ankle of the newborn for several rounds, with obvious strangulation marks about 1 cm deep into the skin, and significant edema on the dorsum and sole of the foot, and the submalleolus area. The amniotic band was released at once, and the edema faded gradually after surgery. After a follow-up of 28 days, the lower limbs of the newborn became normal.

Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.
Humans ; Metformin/pharmacokinetics* ; Diabetes Mellitus, Type 2/metabolism* ; Hypoglycemic Agents/pharmacology* ; AMP-Activated Protein Kinases/metabolism* ; Aging

Objective:To explore the consistency of peripheral whole blood and venous serum procalcitonin (PCT) levels, and the value of peripheral whole blood PCT in evaluating pediatric bacterial infection.Methods:This multicenter cross-sectional parallel control study was conducted in 11 children′s hospital. All the 1 898 patients older than 28 days admitted to these hospitals from March 2018 to February 2019 had their peripheral whole blood and venous serum PCT detected simultaneously with unified equipment, reagent and method. According to the venous serum PCT level, the patients were stratified to subgroups. Analysis of variance and chi-square test were used to compare the demographic characteristics among groups. And the correlation between the peripheral blood and venous serum PCT level was investigated by quantitative Pearson correlation analysis.The PCT resultes were also converted into ranked data to further test the consistency between the two sampling methods by Spearman′s rank correlation test. Furthermore, the ranked data were converted into binary data to evaluate the consistency and investigate the best cut-off of peripheral blood PCT level in predicting bacterial infection.Results:A total of 1 898 valid samples were included (1 098 males, 800 females),age 27.4(12.2,56.7) months. There was a good correlation between PCT values of peripheral whole blood and venous serum ( r=0.97 , P<0.01). The linear regression equation was PCT?venous serum=0.135+0.929×PCT peripheral whole blood. However, when stratified to 5 levels, PCT results showed diverse and unsatisfied consistency between the two sampling methods ( r=0.51-0.92, all P<0.01). But after PCT was converted to ordinal categorical variables, the stratified analysis showed that the coincidence rate of the measured values by the two sampling methods in each boundary area was 84.9%-97.1%. The dichotomous variables also showed a good consistency (coincidence rate 96.8%-99.3%, Youden index 0.82-0.89). According to the severity of disease, the serum PCT value was classified into 4 intervals（<0.5、0.5-<2.0、2.0-<10.0、≥10.0 μg/L）, and the peripheral blood PCT value also showed a good predictive value (AUC value was 0.991 2-0.997 9). The optimal cut points of peripheral whole blood PCT value 0.5、1.0、2.0、10.0 μg/L corresponding to venous serum PCT values were 0.395, 0.595, 1.175 and 3.545 μg/L, respectively. Conclusions:There is a good correlation between peripheral whole blood PCT value and the venous serum PCT value, which means that the peripheral whole blood PCT could facilitate the identification of infection and clinical severity. Besides, the sampling of peripheral whole blood is simple and easy to repeat.

Objective To explore the status of emotional-social loneliness including emotional isolation,social isolation,emotional and social loneliness in patients with acute cerebral infraction,and to analyze the related factors.Methods A total of 122 patients with acute cerebral infraction admitted to the neurology department of 5 third-grade class-A hospitals from Jan.2017 to Oct.2017 were enrolled.Data was collected by self-reported questionnaires including patients' general data and the emotional-social loneliness questionnaire data.Results Among 122 patients with acute cerebral infraction,emotional isolation,social isolation,emotional loneliness and social loneliness were found in 48 cases(39.3％),60 cases(49.2％),40 cases(32.8％)and 36 cases(29.5％),respectively.The total average score for emotional isolation,social isolation,emotional loneliness and social loneliness were 8.3 ± 5.2,8.6 ± 5.1,7.5 ± 6.1,and 7.4 ± 5.5,respectively.The scores for emotional-social loneliness were associated with education level,monthly family income,occupations and the emotion state before disease,and were not associated with gender,marriage status and stroke history.Conclusions The prevalence of emotional-social loneliness is high in patients with acute cerebral infraction.Especially careful attention should be paid to patients with higher education level and retired with monthly family income ≥5 000 RMB.

OBJECTIVE: To evaluate the intervening effect of nutritional health education on the dietary intake on hightemperature operation steel workers.METHODS: A total of 301 workers engaged in high-temperature operation in a steel enterprise in Tangshan City were selected as study objects by cluster sampling method.They were randomly divided into control group(149 cases) and intervention group(152 cases) by random sampling method.After a baseline dietary intake survey,the intervention group received nutritional health education for 3 months,and no intervention was given to control group.RESULTS: Before the intervention,only the intake of egg,grease and energy were up to the standard.Most of the other foods,water intake during the work break and the intake of essential nutrients were not up to the standard.After the intervention,the intake of cereals,vegetables,fruits,dairy and milk,beans,livestock,fish and shrimp,salt,protein,Vit B1,Vit B2,Vit C,kalium,sodium and water intake during the work break were improved compared with control group(P<0.05).After intervention,the ratio of energy supply of meal during work in the intervention group was higher than that of control group(67.8% vs 55.0%,P<0.05).CONCLUSION: The intervention of nutritional health education can effectively improve the status of dietary intake in high-temperature operation steel workers.

Objective To investigate the clinical distribution and change in antimicrobial resistance of Acinetobact-er baumannii (A.baumannii)from a hospital between 2011 and 2013,so as to provide guidance for clinical treat-ment.Methods Sources and antimicrobial susceptibility testing results of A.baumannii from a hospital were ana-lyzed statistically.Results A total of 14 705 bacterial isolates were isolated in 2011 —2013,13.59%(n=1 999)of which were A.baumannii isolates,the percentage of A.baumannii in isolated pathogens in 3 years was 12.74%, 13.05%,and 14.85% respectively,which showed a rising trend (χ2 =9.458,P =0.002).The main specimen was sputum (n = 1 541 ,77.09%),bacteria were mainly isolated from patients in respiratory disease department (21 .71 %),surgical intensive care unit (16.26%),and emergency intensive care unit (8.26%).Antimicrobial re-sistance rates of A.baumannii increased year by year(all P <0.05);multidrug-resistant and extensively drug-resist-ant A.baumannii also increased year by year (all P <0.001).Conclusion Isolation rate and antimicrobial resistance rate of A.baumannii strains increase year by year,multidrug-resistant and extensively drug-resistant A.baumannii strains are obvious,which should be paid more attention in clinical department.

Purpose To discuss the feasibility of evaluating left ventricular systolic function in patients with acute anterior myocardial infarction (AAMI) with three-dimensional speckle tracking imaging (3D-STI). Materials and Methods Thirty AAMI patients were examined with 3D-STI technique in terms of left ventricular longitudinal strain (LS), radial strain (RS), circumferential strain (CS), area strain (AS), global longitudinal strain (GLS), global riadial strain (GRS), global circumferential strain (GCS) and global area strain (GAS). The results were compared with those of 30 healthy persons and the strain values in normal segments of those AAMI patients. The threshold, sensibility and specificity of those parameters in diagnosing myocardial infarction were analyzed. Results Compared with healthy group, LS reduced in 12 out of 17 segments (12/17), RS reduced in 10/17, CS in 9/17 and AS in 11/17;they mainly focused in the base segment, middle and apex of anterior wall, the base segment and the middle of anterior septal, the apex of aboral septal, and the middle segment, apex of the lateral wall. The GLS, GRS, GCS and GAS were all lower than those in healthy group (differences with statistic signiifcance:P<0.05). In AAMI patient, LS, RS, CS and AS in the infarcted segments were lower compared with those in the normal segments (differences with statistic signiifcance:P<0.05). ROC curve analysis showed that the sensitivity of LS, RS, CS and AS were 89.2%, 79.0%, 77.9%, 85.3%, respectively in the diagnosis of myocardial infarction, and the speciifcity were 65.8%, 71.0%, 66.9%and 92.3%, respectively. The sensitivity of the GLS, GRS, GCS and GAS were 91.2%, 74.0%, 68.9%, 85.3%, respectively in the diagnosis of myocardial infarction, and the speciifcity were 69.8%, 71.0%, 76.9%and 93.3%, respectively. Conclusion 3D-STI can detect the strain values of LV segments efficiently and accurately so as to discriminate normal and infracted segments, which provides a reliable measurement to evaluate the extent of the infarction of the patients with acute anterior wall myocardial infarction.

A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC50, 2.28-117.86 micromol x L(-1) for AChE and 1.67-125 micromol x L(-1) for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Abeta aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 micromol x L(-1).