L007-0069 kills Staphylococcus aureus in high resistant phenotypes.

Staphylococcus aureus, a common gram-positive pathogenic bacterium, is a main cause of hospital infection. The prevalence rate of methicillin-resistant S. aureus (MRSA) has made its treatment difficult in recent decades. Moreover, S. aureus in the highly tolerant format of biofilm or persister often renders infections refractory. Thus, developing new active compounds against resistant S. aureus is urgently needed. In this study, by a high-throughput screening assay, we identified a small molecule, L007-0069, that exhibited strong and effective bactericidal activity against S. aureus and its high resistance patterns, such as biofilms and persisters, with a low probability of inducing resistance. By molecular dynamics and fluorescent probe analysis, mechanistic studies revealed that the bactericidal activity of L007-0069 was mainly mediated by membrane disruption and metabolic disorder induction. Furthermore, L007-0069 showed effective anti-MRSA effects in vivo in both a wound infection model and a peritonitis-sepsis model, with no detectable toxicity observed at the therapeutic dosage. In conclusion, L007-0069 has the potential to become an alternative for the treatment of highly resistant S. aureus-related infections.

Retrospective analysis of 217 fatal intoxication autopsy cases from 2009 to 2021: temporal trends in fatal intoxication at Tongji center for medicolegal expertise, Hubei, China.

This retrospective analysis of fatal intoxication case autopsies was performed at Tongji Center for Medicolegal Expertise in Hubei (TCMEH) from 2009 to 2021 to obtain up-to-date information on intoxication cases. The objective was to describe important data about evolving patterns in intoxication occurrences, enhance public safety policies, and assist forensic examiners and police in more efficient handling of such cases. Analyses based on sex, age, topical exposure routes, toxic agents, and mode of death were performed using 217 records of intoxication cases collected from TCMEH as a sample, and the results were compared with reports previously published (from 1999 to 2008) from this institution. Deaths from intoxications occurred at a higher rate in males than in females and were most common among individuals aged 30-39 years. The most frequent method of exposure was oral ingestion. The causative agents of deadly intoxications have changed when compared to the data from the previous 10 years. For instance, deaths from amphetamine overdoses are becoming more prevalent gradually, whereas deaths due to carbon monoxide and rodenticide intoxication have declined dramatically. In 72 cases, pesticides continued to be the most frequent intoxication cause. A total of 60.4% of the deaths were accidental exposure. Men died from accidents at a higher rate than women, although women were more likely to commit suicide. Particular focus is needed on the use of succinylcholine, cyanide, and paraquat in homicides.

Study on antibacterial effect of halicin (SU3327) against Enterococcus faecalis and Enterococcus faecium.

Enterococci are important pathogens of nosocomial infections and are increasingly difficult to treat due to their intrinsic and acquired resistance to a range of antibiotics. Therefore, there is an urgent need to develop novel antibacterial agents, while drug repurposing is a promising approach to address this issue. Our study aimed to determine the antimicrobial efficacy of halicin against enterococci and found that the minimum inhibitory concentrations (MIC) of halicin against different strains of Enterococcus faecalis and Enterococcus faecium ranged from 4 to 8 µg/ml. In addition, the synergistic antibacterial effect between halicin and doxycycline (DOX) against Enterococcus was observed through the checkerboard method, and it was observed that halicin and DOX could significantly synergistically inhibit biofilm formation and eradicate preformed biofilms at sub-MICs. Moreover, the electron microscope results revealed that halicin could also disrupt the bacterial cell membrane at high concentrations. Furthermore, it is also confirmed that the combination of halicin and DOX has no significant cytotoxic effect on erythrocytes and other human-derived cells. In addition, the mouse subcutaneous model and H&E staining showed that the combination of halicin and DOX could effectively reduce the bacterial load and inflammatory infiltration without obvious side effects. In nutshell, these results demonstrate the potential of halicin in combination with DOX as a novel therapy against infections by Enterococcus.

Toremifene, an Alternative Adjuvant Endocrine Therapy, Is Better Than Tamoxifen in Breast Cancer Patients with CYP2D6*10 Mutant Genotypes / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Tamoxifen showed individual differences in efficacy under different CYP2D6*10 genotypes. Our study evaluated the prognosis of tamoxifen or toremifene in hormone receptor (HR)–positive breast cancer patients under different genotypes. @*Materials and Methods@#CYP2D6*10 genotypes of HR-positive breast cancer patients were determined by Sanger sequencing, and all the patients were divided into tamoxifen group or toremifene group. @*Results@#A total of 268 patients with HR-positive breast cancer were studied. The median follow-up time was 72.0 months (range, 5.0 to 88.0 months). Of these, 88 (32.9%), 114 (42.5%), and 66 (24.6%) patients had C/C, C/T, and T/T genotypes, respectively. Among patients who received tamoxifen (n=176), the 5-year disease-free survival (DFS) rate in patients with C/C and C/T genotype was better than that in patients with T/T genotype, and the difference was statistically significant (p < 0.001 and p=0.030, respectively). In patients receiving toremifene, CYP2D6*10 genotype was not significantly associated with DFS (p=0.325). Regardless of genotypes, the 5-year DFS rate was higher in patients treated with toremifene than in patients with tamoxifen (91.3% vs. 80.0%, p=0.011). Compared with tamoxifen, toremifene remained an independent prognostic marker of DFS in multivariate analysis (hazard ratio, 0.422; p=0.021). For all the 180 patients with CYP2D6*10 C/T and T/T genotypes, the 5-year DFS rate was significantly higher in the toremifene group than in the tamoxifen group (90.8% vs. 70.1%, p=0.003). @*Conclusion@#Toremifene may be an alternative adjuvant endocrine therapy for patients with CYP2D6*10 mutant genotypes.

Preliminary study on high throughput screening small molecules targeting Gram-negative bacilli outer membrane protein BamA / 中华检验医学杂志

Objective:High-throughput screening to obtain small molecular compounds against Gram-negative bacilli by targeting BamA outer membrane protein.Methods:The sybyl-X2.1 software was used to perform high-throughput virtual screening of small molecular compounds in Chemdiv compound library based on the molecular docking. The top 150 hits by high-throughput screening were re-screened through in vitro biological experiments. The top 4 small molecules with obvious antibacterial activity were selected for in-depth molecular docking analysis, and the small molecule 8308-0401 with the highest docking score was selected for further experiments. The antibacterial effect of 8308-0401 combined with rifampicin was tested by checkerboard assay. Finally, the affinity between 8308-0401 and BamA was tested by plasma surface resonance assay. Results:The docking score of the top 150 hits calculated by high-throughput virtual screening had a mean value of 5.63. In vitro biological experiments showed that small molecules 8308-0401, 8365-1335, C066-2507 and L582-0346 exhibited strong antibacterial activity. Among those molecules, 8308-0401 showed the highest molecular docking score, and synergistic antibacterial activity against both types of strains and clinical isolates when combined with rifampicin. 8308-0401 has a strong affinity to BamA with binding a constant of 182 μmol/L. Conclusion:The small molecule 8308-0401 exerts antibacterial activity against Gram negative bacilli by targeting the outer membrane protein BamA.

Analysis of clinical features of 40 cases with asthma-chronic obstructive pulmonary overlap syndrome / 中国基层医药

Objective To analyze the clinical characteristics of patients with asthma-chronic obstructive pulmonary overlap syndrome (ACOS).Methods From January 2015 to December 2017,40 patients with ACOS,40 patients with asthma and 40 patients with chronic obstructive pulmonary disease (COPD) in Zhoushan Hospital were collected.The general information,laboratory test indicators,lung function test indicators and FEV1 mutation after bronchodilator test were compared among the three groups.Results There were statistically significant differences in age[(45.36 ±5.27) vs.(54.45 ±4.69) vs.(67.57 ±5.18),F=9.334,P=0.004],the proportion of smoking patients (92.50％ vs.75.00％ vs.60.00％,x2 =11.550,P =0.003),and the proportion of family history of asthma (7.50％ vs.20.00％ vs.30.00％,x2 =6.562,P =0.038) among the patients with ACOS,asthma and COPD.The percentage of eosinophils in peripheral blood [(8.46 ± 0.94) ％ vs.(6.13 ± 0.78) ％ vs.(3.75 ±0.45) ％,F =11.626,P =0.001] and the serum IgE levels [(353.41 ± 45.74) IU/mL vs.(252.65 ± 30.45) IU/ mL vs.(155.26 ± 22.77) IU/mL,F =7.605,P =0.001] were decreased in turn,the differences were statistically significant.The FEV1/FVC％ and FEV1％ pred in the ACOS group were lower than those in the asthma group [(54.26 ± 6.86) ％ vs.(72.43 ± 8.52) ％,t =10.506,P =0.001 and (50.35 ± 6.22) ％ vs.(62.60 ± 7.52) ％,t =7.939,P =0.001],however,there were no significant differences compared with the COPD group [(54.26 ± 6.86)％ vs.(53.88 ±7.25)％,t =0.241,P =0.810 and (50.35 ±6.22)％ vs.(50.56 ±6.46)％,t =0.148,P =0.883].The proportion of small airway dysfunction in the ACOS group was higher than that in the asthma group (82.50％ vs.57.50％,x2 =5.952,P =0.015),however,there was no statistically significant difference compared with COPD group(82.50％ vs.85.00％,x2 =0.092,P =0.762).The RV/TLC％ in the ACOS group was higher than that in the asthma group [(46.71 ± 5.31) ％ vs.(32.46 ± 4.52) ％,t =12.924,P =0.001],however,there was no statistically significant difference compared with the COPD group [(46.71 ± 5.31)％ vs.(46.92 ± 5.75)％,t =0.170,P =0.866].The DLCO％ in the ACOS group was lower than that in the asthma group [(64.37 ±4.66) ％ vs (82.62 ± 4.53) ％,t =17.760,P =0.001],but higher than that of the COPD group [(64.37 ± 4.66) ％ vs.(51.25 ± 4.35) ％,t =13.017,P =0.001].After bronchodilator test,the FEV1 mutation rate of the ACOS group was higher than that of the COPD group [(20.86 ± 2.05) ％ vs.(6.52 ± 0.55) ％,t =42.730,P =0.001],but there was no statistically significant difference compared with the asthma group [(20.86 ± 2.05)％ vs.(21.13 ±2.14)％,t =0.576,P=0.566].Conclusion Compared with asthma patients,the age of ACOS patients is older,the percentage of peripheral blood eosinophils and the level of serum IgE are lower,the pulmonary ventilation function is lower,the airway dysfunction is more significant,the residual volume is more significant,the lung diffuse function is lower,acidic granulocyte airway inflammation is mild.But compared with patients with COPD,the age of ACOS patients is younger,the percentage of peripheral blood eosinophils and serum IgE levels are higher,the lung diffuse function is higher,and acidic granulocyte airway inflammation is heavier.

Analysis of clinical features of 40 cases with asthma-chronic obstructive pulmonary overlap syndrome / 中国基层医药

Objective@#To analyze the clinical characteristics of patients with asthma-chronic obstructive pulmonary overlap syndrome (ACOS).@*Methods@#From January 2015 to December 2017, 40 patients with ACOS, 40 patients with asthma and 40 patients with chronic obstructive pulmonary disease(COPD) in Zhoushan Hospital were collected.The general information, laboratory test indicators, lung function test indicators and FEV1 mutation after bronchodilator test were compared among the three groups.@*Results@#There were statistically significant differences in age[(45.36±5.27) vs. (54.45±4.69) vs. (67.57±5.18), F=9.334, P=0.004], the proportion of smoking patients (92.50% vs. 75.00% vs. 60.00%, χ2=11.550, P=0.003), and the proportion of family history of asthma (7.50% vs. 20.00% vs. 30.00%, χ2=6.562, P=0.038) among the patients with ACOS, asthma and COPD.The percentage of eosinophils in peripheral blood [(8.46±0.94)% vs. (6.13±0.78)% vs. (3.75±0.45)%, F=11.626, P=0.001] and the serum IgE levels [(353.41±45.74)IU/mL vs. (252.65±30.45)IU/mL vs. (155.26±22.77)IU/mL, F=7.605, P=0.001] were decreased in turn, the differences were statistically significant.The FEV1/FVC% and FEV1% pred in the ACOS group were lower than those in the asthma group [(54.26±6.86)% vs. (72.43±8.52)%, t=10.506, P=0.001 and (50.35±6.22)% vs. (62.60±7.52)%, t=7.939, P=0.001], however, there were no significant differences compared with the COPD group[(54.26±6.86)% vs. (53.88±7.25)%, t=0.241, P=0.810 and (50.35±6.22)% vs. (50.56±6.46)%, t=0.148, P=0.883]. The proportion of small airway dysfunction in the ACOS group was higher than that in the asthma group (82.50% vs. 57.50%, χ2=5.952, P=0.015), however, there was no statistically significant difference compared with COPD group(82.50% vs. 85.00%, χ2=0.092, P=0.762). The RV/TLC% in the ACOS group was higher than that in the asthma group [(46.71±5.31)% vs. (32.46±4.52)%, t=12.924, P=0.001], however, there was no statistically significant difference compared with the COPD group [(46.71±5.31)% vs. (46.92±5.75)%, t=0.170, P=0.866]. The DLCO% in the ACOS group was lower than that in the asthma group [(64.37±4.66)% vs (82.62±4.53)%, t=17.760, P=0.001], but higher than that of the COPD group [(64.37±4.66)% vs. (51.25±4.35)%, t=13.017, P=0.001]. After bronchodilator test, the FEV1 mutation rate of the ACOS group was higher than that of the COPD group [(20.86±2.05)% vs. (6.52±0.55)%, t=42.730, P=0.001], but there was no statistically significant difference compared with the asthma group [(20.86±2.05)% vs. (21.13±2.14)%, t=0.576, P=0.566].@*Conclusion@#Compared with asthma patients, the age of ACOS patients is older, the percentage of peripheral blood eosinophils and the level of serum IgE are lower, the pulmonary ventilation function is lower, the airway dysfunction is more significant, the residual volume is more significant, the lung diffuse function is lower, acidic granulocyte airway inflammation is mild.But compared with patients with COPD, the age of ACOS patients is younger, the percentage of peripheral blood eosinophils and serum IgE levels are higher, the lung diffuse function is higher, and acidic granulocyte airway inflammation is heavier.

Clinical analysis of thyroid papillary carcinoma and risk factors of pulmonary metastasis in children / 国际外科学杂志

Objective Investigated the clinical features and risk factors of pulmonary metastasis in children with papillary thyroid carcinoma aiming to provide guide for clinical work.Methods Collected the informations of 40 patients with under the age of 14,who underwent surgery in the Thyroid surgery of the First Affiliated Hospital of ZhengZhou University and confirmed for the papillary thyroid carcinoma by the postoperative pathology.At the same time,excluded studies with history of head and neck malignancy or lyphoma or secondary thyroid cancer,papillary thyroid carcinoma with hyperthyroidism and cases of imcomplete informations.The age of the 40 patients was 3 to 14 years old,12 were boy and 28 were girl.The largest tumor diameter was 7.5 cm,and the smallest was 0.3 cm.Tumor lesions were solitary in 22 cases and multiple lesions were in 18 cases.There were 33 cases of cervical lymph node metastases and 7 cases of no cervical lymph nodes.There were 10 cases of pulmonary metastasis and 30 cases of non-pulmonary metastasis.This research adopted chi-square test and Logistic regression statistical analysis of related risk factors and clinical features,including patients' age,gender,tumor diameter,number of lesions,surgical methods,neck lymph node metastasis,and pulmonary metastasis.Results The positive rate of plumonary metastsis in children with papillary thyroid carcinoma was 25％ (10/40),statistical analysis found that the positive rate of children with lung metastasis (x2 =8.620,P =0.003),tumor diameter over 2 cm (x2 =5.763,P =5.763) and the difference was statistically significant higher.Logistic regression analysis showed that the number of risk factors was multifocal papillary thyroid carcinoma in children lung metastasis (OR =13.058,P =0.028).Conclusions Higher lung metastasis is a clinical feature of thyroid papillary carcinoma in children.The risk of lung metastasis was significantly higher for children with thyroid papillary carcinoma who had multiple lessions.