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.

Objective:To investigate the clinical characteristics and independent predictors of progression-free survival (PFS)in patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma in the real world.Methods:This was a retrospective observational study.The clinical data of 74 EGFR mutation-positive lung adenocarcinoma patients who visited the Geriatric Oncology Department of the Fisrt Affiliated Hospital of Nanjing Medical University from January 2020 to March 2025 were retrospectively collected.Retrospective analysis was performed on baseline clinical characteristics(gender, age, smoking history, stage, etc.), EGFR mutation types, and treatment follow-up data(PFS, treatment regimens). Descriptive statistics were used to summarize the baseline clinical characteristics of the patients.The distribution differences in clinical characteristics between the elderly group and the non-elderly group were compared.Kaplan-Meier survival curves were plotted with Log-rank test, and the Cox proportional hazards model was used to screen for independent prognostic factors.Results:The incidence of comorbidities in the elderly group(48.78%, 20/41)was significantly higher than that in the non-elderly group(24.24%, 8/33), with a statistically significant difference( χ2=4.681, P=0.031). No statistically significant differences were observed between groups in other variables[gender, stage, presence of multiple metastases, smoking history, Eastern cooperative oncology group (ECOG)score, treatment regimens, mutation types](all P>0.05). The median PFS (mPFS)in the elderly group was significantly shorter than that in the non-elderly group(18.20 months vs.26.78 months, Log-rank χ2=3.930, P=0.047). No significant differences in mPFS were found among gender, stage, presence of multiple metastases, smoking history, comorbidity status, ECOG score, treatment regimens, EGFR mutation types or types of tyrosine kinase inhibitor(TKI)(all P>0.05). Multivariate Cox regression further confirmed that advanced age(≥65 years)is an independent predictor of shortened PFS( HR=2.67, 95% CI: 1.04~6.85, P=0.041). The overall incidence of TKI treatment-related adverse reactions was 40.58%(28/69), with a grade ≥3 adverse event rate of 11.59%(8/69). Common adverse reactions included rash, oral mucositis, and diarrhea.The incidence of TKI-related adverse reactions in the elderly group(17/39, 43.59%)was higher than that in the non-elderly group(11/30, 36.67%), but the difference was not statistically significant( χ2=1.038, P=0.196). Conclusions:Age is an independent predictor of PFS in patients with EGFR-mutant lung adenocarcinoma, and its effect is not interfered with by comorbidities or mutation subtypes.

Objective:To investigate the clinical characteristics and independent predictors of progression-free survival (PFS)in patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma in the real world.Methods:This was a retrospective observational study.The clinical data of 74 EGFR mutation-positive lung adenocarcinoma patients who visited the Geriatric Oncology Department of the Fisrt Affiliated Hospital of Nanjing Medical University from January 2020 to March 2025 were retrospectively collected.Retrospective analysis was performed on baseline clinical characteristics(gender, age, smoking history, stage, etc.), EGFR mutation types, and treatment follow-up data(PFS, treatment regimens). Descriptive statistics were used to summarize the baseline clinical characteristics of the patients.The distribution differences in clinical characteristics between the elderly group and the non-elderly group were compared.Kaplan-Meier survival curves were plotted with Log-rank test, and the Cox proportional hazards model was used to screen for independent prognostic factors.Results:The incidence of comorbidities in the elderly group(48.78%, 20/41)was significantly higher than that in the non-elderly group(24.24%, 8/33), with a statistically significant difference( χ2=4.681, P=0.031). No statistically significant differences were observed between groups in other variables[gender, stage, presence of multiple metastases, smoking history, Eastern cooperative oncology group (ECOG)score, treatment regimens, mutation types](all P>0.05). The median PFS (mPFS)in the elderly group was significantly shorter than that in the non-elderly group(18.20 months vs.26.78 months, Log-rank χ2=3.930, P=0.047). No significant differences in mPFS were found among gender, stage, presence of multiple metastases, smoking history, comorbidity status, ECOG score, treatment regimens, EGFR mutation types or types of tyrosine kinase inhibitor(TKI)(all P>0.05). Multivariate Cox regression further confirmed that advanced age(≥65 years)is an independent predictor of shortened PFS( HR=2.67, 95% CI: 1.04~6.85, P=0.041). The overall incidence of TKI treatment-related adverse reactions was 40.58%(28/69), with a grade ≥3 adverse event rate of 11.59%(8/69). Common adverse reactions included rash, oral mucositis, and diarrhea.The incidence of TKI-related adverse reactions in the elderly group(17/39, 43.59%)was higher than that in the non-elderly group(11/30, 36.67%), but the difference was not statistically significant( χ2=1.038, P=0.196). Conclusions:Age is an independent predictor of PFS in patients with EGFR-mutant lung adenocarcinoma, and its effect is not interfered with by comorbidities or mutation subtypes.

Objective:To analyze the effects of exposure to life events and social support levels during different stages of pregnancy on low birth weight in offspring.Methods:From 2021 to 2023, pregnant women in early pregnancy who were registered with health cards in Linping District, Hangzhou City, were recruited and followed up. The Life Events Scale for Pregnant Women (LESPW) and Social Support Rating Scale (SSRS) were used to evaluate the exposure to life events and social support levels of pregnant women in early, middle and late pregnancy, respectively. A generalized linear model was used to analyze the impact and critical period of exposure to prenatal life events and social support levels on the risk of low birth weight in offspring.Results:A total of 3 663 pregnant women with ages M ( Q1, Q3) of 29.18 (26.59, 32.21) years were included in this study. 116 cases (3.17%) of infants with low birth weight were delivered. Generalized linear model analysis showed no correlation between the level of social support in early, middle and late pregnancy and low birth weight in offspring (all P>0.05). The risk of low birth weight in offspring of pregnant women with high exposure to early pregnancy life events was 1.78 times higher than that of the low exposure group ( RR=1.78, 95% CI: 1.13-2.73, P=0.010), and there was no association in the middle and late stages of pregnancy (both P>0.05). Pregnant women with high exposure to early life events and low levels of social support had a 2.08-fold higher risk of low birth weight in their offspring compared to the low exposure group ( RR=2.08, 95% CI: 1.17-6.78, P=0.010), while this situation was not associated with high social support stratification. Conclusion:Exposure to life events during pregnancy has an early window effect on birth weight. Increased exposure to life events during early pregnancy is associated with a higher risk of low birth weight in offspring. This association is more pronounced in pregnant women with low social support.

AIM:To investigate the impact of honokiol(HKL),an activator of silent information regulator 3(SIRT3),on postoperative cognitive dysfunction(POCD)in mice,and to explore the potential mechanisms.METHODS:Ten-month-old male C57/BL6 mice were randomly divided into control(Con)group,surgical(Sur)group and Sur+HKL group(n=10).The mice in Sur+HKL group were intraperitoneally injected with HKL for 7 d before modeling.The mice in Sur and Sur+HKL groups underwent tibial fracture open reduction and internal fixation to establish the POCD model.The assessment of cognitive function was conducted using the open-field test(OFT),novel object recognition test(NORT),Morris water maze test(MWMT),and Y-maze test(YMT).Nissl staining was employed to assess the morphology,struc-ture and vitality of hippocampal and cortical neurons in mice.The protein expression of glutathione peroxidase 4(GPX4),solute carrier family 7 member 11(SLC7A11),acyl coenzyme A synthetase long-chain family member 4(ACSL4),SIRT3 and nuclear factor E2-related factor 2(NRF2)in the mouse hippocampus was detected by Western blot,while im-munofluorescence staining was utilized to determine GPX4 level in mouse neurons.RESULTS:No statistically signifi-cant differences were observed among the groups in terms of total distance moved and central zone exploration during the OFT(P>0.05).However,the results from the NORT and YMT indicated that the mice in Sur group exhibited significant-ly lower recognition indexes,reduced alternation rates(P<0.01),and decreased percentages of entries and crossing time into the new arm after side arm blockade(P<0.01),when compared with Con group.Furthermore,the mice in Sur group demonstrated a slower decrease in latency during the learning period of MWMT,while significantly lower latency,fewer crossing number and lower percentage of time in the target quadrant were observed during the testing period of MWMT(P<0.01).The above indicators were obviously enhanced in Sur+HKL group compared with Sur group(P<0.01).The results of Nissl staining indicated lighter neuronal staining in the hippocampal CA1 region and medial prefrontal cortex in Sur group,accompanied by a significant reduction in the number of Nissl-stained positive neurons(P<0.01).Notably,HKL pretreatment demonstrated a significant improvement in neuronal vitality.Analysis of Western blot revealed that compared with Con group,the expression of SIRT3,GPX4,SLC7A11 and NRF2 in Sur group was significantly reduced,while the expression of ACSL4 was significantly increased(P<0.05).However,these alterations were reversed after treatment with HKL(P<0.05).Immunofluorescence staining of hippocampal neurons corroborated the findings from Western blot analy-sis,demonstrating a notable decrease in GPX4 expression in hippocampal neurons of Sur group,which was significantly restored after HKL pretreatment(P<0.01).CONCLUSION:Treatment with HKL attenuates POCD in mice,potentially through its inhibitory effect on hippocampal neuronal ferroptosis.

Objective To explore the difference in gut microbiota composition between patients with obstructive sleep apnea(OSA)and healthy individuals and the role of gut microbiota in the pathogenesis of OSA.Methods Thirty-nine patients with OSA admitted to our hospital between May and December,2022 and 20 healthy individuals were enrolled in this study.Stool samples were collected from all the participants for analysis of microbiome composition using 16S rRNA high-throughput sequencing analysis.The alpha diversity,beta diversity,and species difference were determined between the two groups and marker species analysis and metabolic pathway function prediction analysis were performed.Results The species diversity(Shannon and Simpson)indexes,richness(observed species)and evenness(Pielou)of gut microbiota were significantly lower in OSA patients than in the healthy individuals(P<0.05).The OSA patients had also a significantly lowered community diversity(P<0.05)with different gut microbial communities from those of the healthy individuals shown by increased relative abundance of potentially pathogenic bacteria such as Pseudomonas and Monocytogenes(P<0.05).LEfSe analysis showed that the abundance of 23 species of gut microbiota differed significantly between the two groups and the OSA patients had significant increases in the abundance of Pseudomonas,Meganomonas,and Fusobacterium(P<0.05).The differential marker flora affected host homeostasis.Random Forest and ROC curve analyses confirmed that Pseudomonas could be used as important biomarkers for a differential diagnosis.Metabolic pathway function prediction analysis showed that biosynthesis function had the greatest contribution to maintaining gut microbiota homeostasis,and Pseudomonas affected the occurrence and progression of OSA by participating in aromatic bioamine degradation and ketogluconic acid metabolic pathway.Conclusion OSA patients have obvious gut microbiota disturbances,and Pseudomonas may affect the development of OSA by participating in substance metabolism to serve as the potential target gut bacteria for OSA treatment.

Objective To analyze the pathological types and causes of misdiagnosis of thyroglossal duct cyst(TGDC).Methods The clinical data of 173 patients diagnosed with TGDC before operation in Tangdu Hospital of Air Force Medical University from January 2013 to January 2023 were retrospectively analyzed.Combined with postoperative pathology,a total of 15 patients were found to be misdiagnosed before operation,and the causes of misdiagnosis were summarized.Results The pathological types of 14 misdiagnosed cases in-cluded seven cases of dermoid cyst,three cases of thyroglossal duct papillary carcinoma,one case of accessory thyroid gland,one case of nodular goiter with intracapsular hemorrhage,one case of cervical lymphadenitis and one case of inflammatory nodule.All the 14 patients underwent standard Sistrunk surgery,and regular follow-up after surgery showed no hypothyroidism,recurrence or metastasis.Preoperative static thyroid imaging proved that the neck mass was vago thyroid in one patient,and surgery was not performed to avoid hypothy-roidism or parathyroidism caused by surgery.Conclusion Misdiagnosis of TGDC as other diseases is rare,cli-nicians should raise awareness to avoid the adverse consequences caused by blind operation.

Background Clozapine belongs to atypical antipsychotic drugs that has shown significant efficacy in treating schizophrenia.However,clozapine can induce arrhythmias in patients.Currently,there is a lack of systematic research on the types and incidence of clozapine-induced arrhythmias.Objective To explore the types and incidence of arrhythmias in patients with schizophrenia induced by clozapine through Meta-analysis,so as to provide references for clinical treatment.Methods On October 31,2022,a search was conducted through PubMed,Embase,Cochrane Library and China National Knowledge Infrastructure(CNKI)to collect relevant literature on clozapine-induced arrhythmia in patients with schizophrenia.Joanna Briggs Institute(JBI)was used to evaluate the quality of the included literature.Meta-analysis was conducted using Review Manager 5.4.Results A total of 12 studies were included,involving 42 490 schizophrenia patients taking clozapine.The incidence of arrhythmias caused by clozapine was 23％(95％CI:0.16～0.29).Among them,the incidence of tachycardia was 25％(95％CI:0.15～0.35),atrial arrhythmia was 6％(95％CI:-0.02～0.14),ventricular arrhythmia was 7％(95％CI:-0.02～0.16),conduction block was 2％(95％CI:0～0.04),QTc prolongation was 4％(95％CI:-0.04～0.12)and T-wave changes was 23％(95％CI:0.16～0.30).Conclusion Schizophrenia patients taking clozapine may increase their risk of developing arrhythmia,with tachycardia being the most prevalent.

Objective:Based on the needs of advanced nursing practice development, to establish an indicator system of role function of position of oncology genetic nurses suitable for our national condition, and to provide a basis for position establishing of nocology genetic nurses.Methods:Initial indexes were generated through the literature review and semi-structured interviews. From September to December 2022, two rounds of expert consultations and analytic hierarchy process were conducted to establish the evaluation index for role function of position of oncology genetic nurses.Results:A total of 43 experts were included in the study, the response rates of 2 rounds were 93.62%(44/47) and 97.73%(43/44), and the authority coefficients of the experts were 0.821 and 0.853. The Kendall′s coefficients of concordance for the 2 rounds of consultations were 0.100-0.150 (all P<0.01) and 0.101-0.237 (all P<0.01). Finally, the role function system of position for oncology genetic nurses was formed, which consisted of 5 first-level indexes, 17 second-level indexes and 86 third-level indexes. Conclusions:The system of role function of position for oncology genetic nurses is reasonable, scientific and reliable, professional and specific, which can provide a theoretical reference for the development of advanced nursing practice on hereditary oncology in China.

Objective:To investigate the resuscitation effect of sodium bicarbonate Ringer's solution on traumatic hemorrhagic shock in patients.Methods:A randomized controlled trial was conducted on 70 patients with traumatic hemorrhagic shock who were admitted to Yiwu Central Hospital between February 2021 and February 2022. The patients were randomly assigned to a control group ( n = 35) and an observation group ( n = 35) using the random number table method. Both groups received routine treatment. The control group was given adequate resuscitation by intravenous injection of a compound sodium chloride injection, while the observation group received restricted resuscitation with sodium bicarbonate Ringer's solution. Related clinical indicators, coagulation function, lactate levels, hemorheological indicators, and incidence of complications were compared between the two groups. Results:The blood oxygen saturation, shock index, pulse pressure difference, and urine output in the observation group were (76.53 ± 2.56)%, (0.43 ± 0.07), (38.56 ± 6.52) mmHg (1 mmHg = 0.133 kPa), and (35.62 ± 4.21) mL/h, respectively. These values were all superior to those in the control group [(65.32 ± 3.21)%, (1.21 ± 0.13), (23.56 ± 4.23) mmHg, (23.65 ± 5.68) mL/h, t = 16.15, 31.25, 11.42, 10.06, all P < 0.001]. The prothrombin time, fibrinogen, activated partial thromboplastin time, and thrombin time in the observation group were (17.65 ± 0.83) seconds, (1.69 ± 0.89) g/L, (39.68 ± 0.52) seconds, and (17.86 ± 0.74) seconds, respectively. These values were significantly superior to those in the control group [(14.56 ± 0.86) seconds, (1.32 ± 0.23) g/L, (35.26 ± 0.16) seconds, and (16.02 ± 0.05) seconds, t = 15.30, 2.38, 48.06, 14.68, all P < 0.05]. The lactate level in the observation group was significantly lower than that in the control group [(2.24 ± 0.53) mmol/L vs. (2.94 ± 0.78) mmol/L, t = 4.39, P < 0.05]. The platelet cohesion, red blood cell deformability, and blood viscosity in each group were significantly reduced, and these indices in the observation group were superior to those in the control group ( t = 13.71, 5.64, 5.67, all P < 0.001). The incidence of complications in the observation group was significantly lower than that in the control group (8.6% (3/35) vs. 60.0% (21/35), χ2 = 10.08, P < 0.05). Conclusion:Restricted resuscitation with sodium bicarbonate Ringer's solution can improve clinical indicators, coagulation function, and lactate levels in patients with traumatic hemorrhagic shock. It can effectively improve hemodynamic indicators and reduce the incidence of complications. It is worthy of clinical promotion.