The p21-activated kinase 4 (PAK4), a key regulator of malignancy, is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy. Given the lack of high efficacy PAK4 inhibitors, we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC₅₀ values of 0.38 and 0.50 μmol/L, respectively. This compound directly binds to PAK4 in a non-ATP competitive manner. In the mouse Pan02 model, compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg, accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue. Overall, compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo, thus making it worthy of further exploration.

Microplastics(MPs)are emerging contaminants in aquatic environments characterized by their polar structure,small particle size(Typically less than 5 mm),large surface area,good stability,and resistance to biodegradation.They pose adverse effects on the normal physiological activities of aquatic organisms and can accumulate in biota,including humans.Therefore,there is an urgent need for rapid and accurate quantitative analysis of MPs in water environments.In this study,Raman spectroscopy combined with partial least squares(PLS)was employed for rapid and accurate quantitative analysis of polyethylene(PE)and polystyrene(PS)MPs in real water samples.Initially,33 simulated water samples containing different concentrations of MPs were prepared,and their Raman spectra were collected.Six spectral preprocessing methods(Normalization,multiplicative scatter correction,standard normal variate transformation,first derivative,second derivative,and wavelet transform)were investigated for their impact on the predictive performance of PLS calibration models.Subsequently,three variable selection methods including synergy interval partial least squares(SiPLS),variable importance in projection(VIP)and mutual information(MI)were employed to optimize the input variables of the PLS calibration model.The predictive capability of the PLS calibration model was evaluated and validated using leave-one-out cross-validation.Under the optimal conditions of spectral preprocessing,variable selection,input variables and latent variables,the wavelet transform-partial least squares(WT-PLS)calibration model based on distilled water was established,and the contents of PE and PS in real water samples were predicted with prediction correlation coefficients(R2p)of 0.9540 and 0.8472 for PE and PS,respectively,and prediction errors(Errorp)of 0.0690 and 0.1126,respectively.Furthermore,a mixed sample MI-PLS calibration model was developed,demonstrating the best predictive performance in real water samples(With R2p values of 0.9776 and 0.9755 for PE and PS,respectively,and Errorp values of 0.0360 and 0.0392,respectively).This method provided a novel approach and new methodology for quantitative analysis of MPs and other organic pollutants in real water samples.

Objective To monitor the antifungal resistance of clinical isolates of Candida spp.in the East China region.Methods MALDI-TOF MS or molecular methods were used to re-identify the strains collected from January 2018 to December 2022.Antifungal susceptibility testing was performed using the broth microdilution method.The susceptibility test results were interpreted according to the breakpoints of 2022 Clinical and Laboratory Standards Institute(CLSI)documents M27 M44s-Ed3 and M57s-Ed4.Results A total of 3 026 strains of Candida were collected,65.33％of which were isolated from sterile body sites,mainly from blood(38.86％)and pleural effusion/ascites(10.21％).The predominant species of Candida were Candida albicans(44.51％),followed by Candida parapsilosis complex(19.46％),Candida tropicalis(13.98％),Candida glabrata(10.34％),and other Candida species(0.79％).Candida albicans showed overall high susceptibility rates to the 10 antifungal drugs tested(the lowest rate being 93.62％).Only 2.97％of the strains showed dose-dependent susceptibility(SDD)to fluconazole.Candida parapsilosis complex had a SDD rate of 2.61％and a resistance rate of 9.42％to fluconazole,and susceptibility rates above 90％to other drugs.Candida glabrata had a SDD rate of 92.01％and a resistance rate of 7.99％to fluconazole,resistance rates of 32.27％and 48.24％to posaconazole and voriconazole non-wild-type strains(NWT),respectively,and susceptibility rates above 90％to other drugs.Candida tropicalis had resistance rates of 29.55％and 26.24％to fluconazole and voriconazole,respectively,resistance rates of 76.60％and 21.99％to posaconazole and echinocandins non-wild-type strains(NWT),and a resistance rate of 2.36％to echinocandins.Conclusions The prevalence and species distribution of Candida spp.in the East China region are consistent with previous domestic and international reports.Candida glabrata exhibits certain degree of resistance to fluconazole,while Candida tropicalis demonstrates higher resistance to triazole drugs.Additionally,echinocandins resistance has emerged in Candida albicans,Candida glabrata,Candida tropicalis,and Candida parapsilosis.

Objective To explore the efficacy and safety of recombinant human anti-severe acute respiratory syn-drome coronavirus 2(anti-SARS-CoV-2)monoclonal antibody injection(F61 injection)in the treatment of patients with coronavirus disease 2019(COVID-19)combined with renal damage.Methods Patients with COVID-19 and renal damage who visited the PLA General Hospital from January to February 2023 were selected.Subjects were randomly divided into two groups.Control group was treated with conventional anti-COVID-19 therapy,while trial group was treated with conventional anti-COVID-19 therapy combined with F61 injection.A 15-day follow-up was conducted after drug administration.Clinical symptoms,laboratory tests,electrocardiogram,and chest CT of pa-tients were performed to analyze the efficacy and safety of F61 injection.Results Twelve subjects(7 in trial group and 5 in control group)were included in study.Neither group had any clinical progression or death cases.The ave-rage time for negative conversion of nucleic acid of SARS-CoV-2 in control group and trial group were 3.2 days and 1.57 days(P=0.046),respectively.The scores of COVID-19 related target symptom in the trial group on the 3rd and 5th day after medication were both lower than those of the control group(both P＜0.05).According to the clinical staging and World Health Organization 10-point graded disease progression scale,both groups of subjects improved but didn't show statistical differences(P＞0.05).For safety,trial group didn't present any infusion-re-lated adverse event.Subjects in both groups demonstrated varying degrees of elevated blood glucose,elevated urine glucose,elevated urobilinogen,positive urine casts,and cardiac arrhythmia,but the differences were not statistica-lly significant(all P＞0.05).Conclusion F61 injection has initially demonstrated safety and clinical benefit in trea-ting patients with COVID-19 combined with renal damage.As the domestically produced drug,it has good clinical accessibility and may provide more options for clinical practice.

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.
Mice ; Animals ; Alzheimer Disease/pathology* ; Receptor, Nerve Growth Factor ; Amyloid beta-Peptides ; Autoantibodies ; Mice, Transgenic

ObjectiveTo observe the impacts of electroacupuncture （EA） on the expression of hippocampal brain-derived neurotrophic factor （BDNF） and acetylated histone （AcH3） in the rat model of spared nerve injury （SNI）， so as to explore the analgesic and antidepressant effects of EA. MethodsTwenty-four Male SD rats were randomly divided into 4 groups， with 6 in each group. SNI was used to establish the model of pain and depression. All the groups were intervened one week after SNI surgery and persisted 5 weeks. The EA group was treated with EA （2 Hz） for 30 min every other day and imipramine drug group （IMP） group with peritoneal imipramine injection （10 mg/kg） per day. The sham surgery group （SS） and model group （SNI） received the same grasping stimulation. The paw mechanical withdrawal threshold （PWT） test was performed before the SNI surgery， 1， 2， 3， 4， 5， and 6 weeks after surgery， respectively. The forced swimming test （FST） and the sucrose preference test （SPT） were performed 6 weeks after SNI surgery. The Western blot method was employed to detect the expression of BDNF and AcH3 from the rat hippocampal tissue at the end of the behavioral tests. ResultsCompared with the SS group， the SNI group had significantly decreased PWT and sucrose consumption， prolonged FST immobility time （all P<0.01）， down-regulated BDNF and AcH3 expression （P<0.05 & P<0.01） in the hippocampus， which indicated the successful construction of the pain-depression model. Compared with the SNI group， 6 weeks after SNI surgery， the EA and IMP groups had significantly increased PWT and sucrose consumption， and reduced FST immobility time （all P<0.01）； the EA group had up-regulated BDNF and AcH3 expression （both P<0.05） in the hippocampus， the IMP group had up-regulated AcH3 （P<0.05） expression but no difference in BDNF expression. ConclusionEA could relieve pain and depressive behavioral symptoms in SNI rats. And its analgesic and antidepressant mechanisms may relate to the up-regulation of hippocampal AcH3 and BDNF expression.

Objective To investigate the efficacy and safety of stereotactic body radiotherapy(SBRT)combined with camrelizumab and apatinib in treatment of advanced hepatocellular carcinoma(HCC).Methods The clinical data were retrospectively analyzed of 85 patients with advanced HCC treated in the Fifth Affiliated Hospital of Zhengzhou University and People's Hospital of Zhengzhou from January 2019 to September 2021.They were divided into observation group(n=31,SBRT combined with camrelizumab and apatinib)and control group(n=54,treated with camrelizumab and apatinib)according to whether they received SBRT.The propensity score matching(PSM)was used to balance the influence of confounding factors.The objective remission rate(ORR)and disease control rate(DCR)were compared between the two groups.The 6-month overall survival rate,1-year overall survival rate and progression-free survival(PFS)were compared between the two groups by Kaplan-Meier method.The safety of the two groups was evaluated by Common Terminology Criteria for Adverse Events(CTCAE)version 5.0.Results Before PSM,there were significant differences in age(P=0.043),number of extrahepatic metastasis(P=0.028),and previous surgical treatment(P=0.038)between the two groups.After PSM,there was no significant difference in baseline characteristics between the two groups(P>0.05).After PSM,27 cases were included in each groups,and three months after treatment,the ORR in observation group and control group were 66.7%and 29.6%,respectively,showed difference with statistically significant(P=0.006);and the DCR in the both groups were 96.3%and 85.2%respectively,showed no statistically significant difference(P=0.175).There were statistical differences in 6-month overall survival rate(96.3%vs.80.9%,P=0.001),1-year overall survival rate(75.0%vs.61.4%,P=0.034)and median PFS(8 months vs.5 months,P=0.003)between the observation group and control group.Multi-factor Cox regression analysis showed that baseline alpha-fetoprotein(AFP)≥400 ng/ml was an independent risk factor for affecting the survival of patients with advanced HCC(HR>1,P<0.05),while the triple therapy and previous targeted drugs therapy were the protective factors for the survival of patients with advanced HCC(HR<1,P<0.05).In the observation group,4 patients had grade 3 adverse reactions,and the common adverse reactions were dyspepsia(14.8%).One case of grade 3 adverse reactions occurred in control group,and there was no statistically significant difference in the incidence of adverse reactions between the two groups(P=0.639).Conclusion SBRT combined with camrelizumab and apatinib is a safe and effective treatment for advanced HCC with significant clinical effect and controllable adverse reactions.

Anti-seizure medications (ASMs) are the main therapy for epilepsy.There are many kinds of ASMs with complex mechanism of action, so it is difficult for pharmacists to examine prescriptions.This paper put forward some suggestions on the indications, dosage forms/routes of administration, appropriateness of usage and dosage, combined medication and drug interaction, long-term prescription review, individual differences in pathophysiology of children, and drug selection when complicated with common epilepsy, for the reference of doctors and pharmacists.

Objective: To analyze the case characteristics of Chronic obstructive pulmonary disease caused by occupational irritant chemicals (OI-COPD). To provide basis for revising its diagnostic criteria. Methods: From June to December 2021, we investigated the information of OI-COPD patients confirmed by Shandong Institute of Occupational Health and Prevention of Occupational Diseases, Guangxi Zhuang Autonomous Region Institute of Occupational Disease Prevention and Control, Qingdao Central Hospital affiliated to Qingdao University and other diagnostic institutions in the past five years, a total of 41 cases. The basic information of OI-COPD cases, occupational risk factors exposure information, medical history, smoking history and clinical symptoms were analyzed retrospectively. The measurement data were tested for normal distribution, which was described by x±s, and compared between groups by t test; Those who do not conform to the normal distribution are described by the median [M (Q(1), Q(3)) ] and analyzed by nonparametric test; The counting data were expressed in frequency and rate (% ), and the comparison between groups was tested. Results: Of the 41 cases, 33 were male and 8 were female. The age of the patient diagnosed with OI-COPD was (49.5±10.3) years old, and the minimum age was 30 years old; Among them, 8 patients had a definite long-term smoking history (more than 5 years) ; The exposure duration of occupational risk factors was (18.6±10.3) years, of which 3 patients had exposure duration of less than 5 years; The occupational risk factors leading to OI-COPD include acids and acid-forming compounds, bases, aldehydes, nitrogen oxides, chlorine and its compounds, etc. The exposure level of occupational risk factors is related to the degree of COPD airflow restriction (χ(2)=6.17, P <0.05). 18 patients with diagnosis age <50 years old were diagnosed as early-onset COPD. The incidence of respiratory symptoms in the early diagnosis COPD group was lower than that in the non-early diagnosis COPD group, and the FEV1% pred was significantly higher than that in the non-early diagnosis COPD group. The difference was statistically significant (P<0.01 ) . Conclusion: The exposure level of occupational risk factors may be the risk factor affecting the degree of COPD airflow restriction. With the increase of the exposure level of COPD patients, the proportion of respiratory symptoms will also increase accordingly.
Humans ; Male ; Female ; Adult ; Middle Aged ; Retrospective Studies ; China/epidemiology* ; Pulmonary Disease, Chronic Obstructive/diagnosis* ; Lung ; Risk Factors ; Occupational Diseases/diagnosis* ; Occupational Exposure/adverse effects*

Intersphincteric resection (ISR) has been performed as an ultimate sphincter-sparing strategy in selected patients with low rectal cancer. Accumulating evidence suggests that ISR may be an interesting alternative to abdominoperineal resection to avoid a permanent stoma without compromising oncological outcomes. However, bowel dysfunction is a most common consequence of ISR not to be neglected. To date, limited clinical research has reported functional and quality of life outcomes according to patient-reported outcome measures. Also, data concerning management of low anterior resection syndrome are scarce due to lack of quality evidence. Therefore, this review provides an up-to-date summary of systematic assessment (including function, quality of life, manometry and morphology) and bowel rehabilitation for ISR patients. Postoperative anal function is often assessed by a combination of scales, including the Incontinence Assessment Scale, the Gastrointestinal Function Questionnaire, the Specific LARS Assessment Scale and the Faecal Diary. The condition-specific Quality of Life Scale is more appropriate for Quality-of-life measures in fecal incontinence after ISR. Patients' physiological function after ISR can be assessed using water- or high-resolution solid-state anorectal manometry. Anatomical and morphological changes can be assessed using defecography and 3D endorectal ultrasound. Electrical stimulation and biofeedback, pelvic floor exercises, rectal balloon training, transanal irrigation and sacral neuromodulation are all options for post-operative rehabilitation.
Humans ; Rectal Neoplasms/surgery* ; Postoperative Complications ; Anal Canal/surgery* ; Quality of Life ; Organ Sparing Treatments ; Fecal Incontinence