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 compare the efficacy of inverted triangular and equilateral triangular cannulated screw internal fixation (CSIF) in the treatment of femoral neck fracture (FNF) in young and middle-aged patients.Methods:A retrospective cohort study was conducted to analyze the clinical data of 52 patients with FNF admitted to Qingdao Central Hospital of Rehabilitation University from January 2020 to January 2022, including 18 males and 34 females, aged 28-60 years [(45.7±9.3)years]. Based on the Garden classification, the fractures were classified as type I in 11 patients, type II in 34, and type III in 7. According to Pauwels classification, the fractures were classified as type I in 33 patients, type II in 13, and type III in 6. Among them, 28 patients received inverted triangular CSIF (inverted triangle group) and 24 received equilateral triangular CSIF (equilateral triangle group). Before surgery and at 3 months after surgery, nuclear medicine three-phase bone scan and bone tomography imaging were performed to evaluate the proximal blood supply recovery in the fractured sites in the two groups. The Harris hip joint function scores before surgery, at 1 day, 3 months after surgery, and at the last follow-up, the posterior tilt angles of the femoral head before surgery and at 3 months after surgery, and the fracture nonunion rate and ischemic necrosis rate of the femoral head at the last follow-up were compared between the two groups.Results:All the patients were followed up for 18-30 months [(24.2±5.6)months]. Before surgery, the fracture of both groups showed extensive blood supply defects at the proximal end. At 3 months after surgery, the excellent and good rate of the proximal blood supply recovery in the inverted triangle group was 92.9% (26/28), significantly higher than 70.8% (17/24) in the equilateral triangle group ( P<0.05). The Harris hip joint function scores before surgery were (44.1±4.1)points and (43.5±5.1)points in the inverted triangle group and equilateral triangle group ( P>0.05). At 1 day, 3 months after surgery, and at the last follow-up, the Harris hip joint function scores in the inverted triangle group were (71.7±3.6)points, (87.0±3.6)points, and (88.7±2.6)points respectively, higher than those in the equilateral triangle group [(65.0±5.4)points, (80.5±5.2)points, and (82.6±4.0)points] ( P<0.05). In both groups, there were no significant differences between the Harris hip joint function scores at the last follow-up and those at 3 months after surgery ( P>0.05), which were all higher than those at 1 day after surgery ( P<0.05). The posterior tilt angles of the femoral head were (16.9±4.4)° and (16.8±5.0)° in the inverted triangle group and equilateral triangle group preoperatively ( P>0.05). At 3 months after surgery, the posterior tilt angles of the inverted femoral head were (8.9±1.9)° and (9.0±1.8)° in the inverted triangle group and equilateral triangle group ( P>0.05). The posterior tilt angles of the femoral head at 3 months after surgery were lower than those before surgery in both groups ( P<0.05). At the last follow-up, there were no statistically significant differences in the fracture nonunion rate and ischemic necrosis rate of the femoral head between the two groups ( P>0.05). Conclusion:Compared with equilateral triangle CSIF, inverted triangle CSIF achieves better recovery of the proximal blood supply and hip joint function in the treatment of femoral neck fracture in young and middle-aged patients.

Objective:To compare the efficacy of inverted triangular and equilateral triangular cannulated screw internal fixation (CSIF) in the treatment of femoral neck fracture (FNF) in young and middle-aged patients.Methods:A retrospective cohort study was conducted to analyze the clinical data of 52 patients with FNF admitted to Qingdao Central Hospital of Rehabilitation University from January 2020 to January 2022, including 18 males and 34 females, aged 28-60 years [(45.7±9.3)years]. Based on the Garden classification, the fractures were classified as type I in 11 patients, type II in 34, and type III in 7. According to Pauwels classification, the fractures were classified as type I in 33 patients, type II in 13, and type III in 6. Among them, 28 patients received inverted triangular CSIF (inverted triangle group) and 24 received equilateral triangular CSIF (equilateral triangle group). Before surgery and at 3 months after surgery, nuclear medicine three-phase bone scan and bone tomography imaging were performed to evaluate the proximal blood supply recovery in the fractured sites in the two groups. The Harris hip joint function scores before surgery, at 1 day, 3 months after surgery, and at the last follow-up, the posterior tilt angles of the femoral head before surgery and at 3 months after surgery, and the fracture nonunion rate and ischemic necrosis rate of the femoral head at the last follow-up were compared between the two groups.Results:All the patients were followed up for 18-30 months [(24.2±5.6)months]. Before surgery, the fracture of both groups showed extensive blood supply defects at the proximal end. At 3 months after surgery, the excellent and good rate of the proximal blood supply recovery in the inverted triangle group was 92.9% (26/28), significantly higher than 70.8% (17/24) in the equilateral triangle group ( P<0.05). The Harris hip joint function scores before surgery were (44.1±4.1)points and (43.5±5.1)points in the inverted triangle group and equilateral triangle group ( P>0.05). At 1 day, 3 months after surgery, and at the last follow-up, the Harris hip joint function scores in the inverted triangle group were (71.7±3.6)points, (87.0±3.6)points, and (88.7±2.6)points respectively, higher than those in the equilateral triangle group [(65.0±5.4)points, (80.5±5.2)points, and (82.6±4.0)points] ( P<0.05). In both groups, there were no significant differences between the Harris hip joint function scores at the last follow-up and those at 3 months after surgery ( P>0.05), which were all higher than those at 1 day after surgery ( P<0.05). The posterior tilt angles of the femoral head were (16.9±4.4)° and (16.8±5.0)° in the inverted triangle group and equilateral triangle group preoperatively ( P>0.05). At 3 months after surgery, the posterior tilt angles of the inverted femoral head were (8.9±1.9)° and (9.0±1.8)° in the inverted triangle group and equilateral triangle group ( P>0.05). The posterior tilt angles of the femoral head at 3 months after surgery were lower than those before surgery in both groups ( P<0.05). At the last follow-up, there were no statistically significant differences in the fracture nonunion rate and ischemic necrosis rate of the femoral head between the two groups ( P>0.05). Conclusion:Compared with equilateral triangle CSIF, inverted triangle CSIF achieves better recovery of the proximal blood supply and hip joint function in the treatment of femoral neck fracture in young and middle-aged patients.

Objective To explore the comparative application of phase and diaphragmatic navigation in three-dimensional magnetic resonance cholangiopancreatography(3D-MRCP)thin-layer scanning in elderly patients.Methods A total of 180 elderly patients were scanned by phase and diaphragmatic navigation via Siemens Aera1.5T superconducting MR scanner.The acquired images were reconstructed by 3D reconstruction.The anatomical structure,image quality and disease diagnosis were compared between the phase and diaphragmatic navigation groups.Results In liver of anatomy,the liver of primary bile duct,the superior,middle and inferior extrahepatic bile duct and the gallbladder could be well displayed,and the difference was not statistically significant between the two groups(P＞0.05).The display of pancreatic duct and the liver of secondary bile duct of diaphragmatic navigation was significantly better than those of phase navigation(P＜0.05).In terms of image quality,the excellent rate of diaphragmatic navigation was significantly higher than that of phase navigation,and the difference was statistically significant(P＜0.05).There were no statistically significant differences in the detection rate of pancreatobiliary system diseases,the diagnostic rate of cholelithiasis,common bile duct stones,common bile duct dilatation and pancreatic duct dilatation between the two groups(P＞0.05).Conclusion Diaphragmatic navigation is signifi-cantly better than phase navigation in the display of the anatomical structure of the pancreatic duct,the liver of secondary bile duct,and the excellent rate of image quality.Diaphragmatic navigation is more suitable for thin-layer 3D-MRCP scanning in elderly patients.

Objective To comprehensively analyze the clinical outcomes of total cavopulmonary connection (TCPC) in the treatment of functional single ventricle combined with heterotaxy syndrome (HS). Methods A retrospective analysis was conducted on the patients with functional single ventricle and HS who underwent TCPC (a HS group) in Guangdong Provincial People's Hospital between 2004 and 2021. The analysis focused on postoperative complications, long-term survival rates, and identifying factors associated with patient survival. Early and late postoperative outcomes were compared with matched non-HS patients (a non-HS group). Results Before propensity score matching, 55 patients were collected in the HS group, including 42 males and 13 females, with a median age of 6.0 (4.2, 11.8) years and a median weight of 17.0 (14.2, 28.8) kg. Among the patients, there were 53 patients of right atrial isomerism and 2 patients of left atrial isomerism. Eight patients underwent TCPC in one stage. TCPC procedures included extracardiac conduit (n=39), intracardiac-extracardiac conduit (n=14), and direct cavopulmonary connection (n=2). Postoperative complications included infections in 27 patients, liver function damage in 19 patients, and acute kidney injury in 11 patients. There were 5 early deaths. The median follow-up time was 94.7 (64.3, 129.8) months. The 1-year, 5-year, and 10-year survival rates were 87.2%, 85.3%, and 74.3%, respectively. After propensity score matching, there were 45 patients in the HS group and 81 patients in the non-HS group. Compared to the non-HS group, those with HS had longer surgical and mechanical ventilation time, higher infection rates (P<0.05), and a 12.9% lower 10-year survival rate. Multivariate Cox regression analysis identified asplenia was a risk factor for mortality (HR=8.98, 95%CI 1.86-43.34, P=0.006). Conclusion Compared to non-HS patients, patients with HS have lower survival rates after TCPC, and asplenia is an independent risk factor for the survival of these patients.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood-brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).

BACKGROUND: The aryl hydrocarbon receptor (AhR) is commonly known as an environmental sensor. Polymorphisms in AhR gene have been implicated in susceptibility to cancer. However, the results were controversial. This study was conducted to quantitatively summarize the association between AhR polymorphisms and cancer risk by meta-analysis. METHODS: Relevant reports were searched in four databases (Embase, PubMed, Wanfang, and China National Knowledge Infrastructure). We used pooled odds ratio (OR) and 95% confidence interval (95% CI) to evaluate the strength of the association in both standard and cumulative meta-analysis. Subgroup and sensitivity analysis was also performed, and between-study heterogeneity and publication bias were checked. RESULTS: A total of seventeen studies referring to three AhR polymorphisms (rs2066853, rs7796976, and rs2074113) were identified, and 9557 cases and 10038 controls were included. There was no statistically significant association of AhR rs2066853 polymorphism with cancer risk in the overall population, and the negative results were repeated in subgroup analysis by the ethnicity and cancer type. Concerning AhR rs7796976 or rs2074113 polymorphism, no significant correlation was detected. Moreover, these non-significant findings were stable in sensitivity analysis, and the cumulative meta-analysis indicated a trend of no significant link between this three AhR polymorphisms and cancer risk as more data accumulated over time. CONCLUSION This meta-analysis provides evidence that the rs2066853, rs7796976, or rs2074113 polymorphism in AhR gene is not a susceptible predictor of cancer. Further clinical and functional investigation between AhR polymorphisms and cancer susceptibility are needed.
Basic Helix-Loop-Helix Transcription Factors/genetics* ; Confidence Intervals ; Genetic Predisposition to Disease/epidemiology* ; Humans ; Neoplasms/genetics* ; Odds Ratio ; Polymorphism, Genetic ; Receptors, Aryl Hydrocarbon/genetics*

OBJECTIVE:To study the chemical compositions of n-butabol extract from Solanum lyratum. METHODS:Glucan LH-20 column chromatography,silica gel column chromatography and TLC were adopted to separate and purity the chemical com-positions,physicochemical property and spectral evidence to identify their structures. RESULTS:Totally 10 chemical compositions were separated from n-butabol extract,namely apigenin-7-O-β-D-apiofuanosyl(1→2)-β-D-glucose (1),apigenin-7-O-β-D-glucose (2),adenosine(3),3-methoxy-4-hydroxy-5-[(8′S)-3′-methoxy-4′-hydroxyl-phenyl-alcohol]-E-cinnamic-phenylpropyl alcohol-4-O-β-D-glucoside (4),N-(4-amino-butyl)-3-(3-hydroxy-4-methoxy-phenyl)-E-acrylamide (5),N-(4-amino-butyl)-3-(3-hydroxy-4-me-thoxy-phenyl)-Z-acrylamide (6),resveratrol (7),naringenin (8),quercetin (9) and dioscin (10). CONCLUSIONS:Compound 1-8 are first separated from S. lyratum,the study can lay a foundation for quality evaluation of S. Lyratum.

OBJECTIVETo estimate the value of blastocyst culture for preimplantation genetic diagnosis (PGD).

METHODSDay 3 embryos were biopsied and analyzed with fluorescence in situ hybridization (FISH) technique. Embryos with normal FISH results were cultured into blastocysts, and the ones with better morphology scores were transferred. Fourteen embryos with abnormal FISH results were cultured into blastocysts. Part of the cells taken from the blastocysts were amplified by whole genomic amplification (WGA) and assessed by array-based comparative genomic hybridization (array-CGH) analysis.

RESULTSSix blastocysts with normal FISH results were transferred in 5 cycles. Four healthy babies of 3 cycles were delivered. Another one was a singleton pregnancy but with embryo growth arrest, whose villus karyotype was normal. Fourteen embryos with abnormal FISH results were cultured into blastocysts and analyzed by array-CGH. Six blastocysts were normal by array-CGH.

CONCLUSIONFISH combined with blastocyst culture may further ensure the accuracy of PGD result. Detection at the blastocyst stage can avoid false positive results and mosaic interferences on Day 3 stage and are therefore more authentic.

Adult ; Blastocyst ; cytology ; Comparative Genomic Hybridization ; methods ; Embryo Transfer ; Female ; Genetic Diseases, Inborn ; diagnosis ; embryology ; genetics ; prevention & control ; Humans ; In Situ Hybridization, Fluorescence ; methods ; Male ; Pregnancy ; Preimplantation Diagnosis ; methods

Genome editing is defined as highly-effective and precise modification of cellular genome in a large scale. In recent years, such genome-editing methods have been rapidly developed in the field of industrial strain improvement. The quickly-updating methods thoroughly change the old mode of inefficient genetic modification, which is "one modification, one selection marker, and one target site". Highly-effective modification mode in genome editing have been developed including simultaneous modification of multiplex genes, highly-effective insertion, replacement, and deletion of target genes in the genome scale, cut-paste of a large DNA fragment. These new tools for microbial genome editing will certainly be applied widely, and increase the efficiency of industrial strain improvement, and promote the revolution of traditional fermentation industry and rapid development of novel industrial biotechnology like production of biofuel and biomaterial. The technological principle of these genome-editing methods and their applications were summarized in this review, which can benefit engineering and construction of industrial microorganism.
Biotechnology ; Fermentation ; Genetic Engineering ; methods ; Genome, Microbial ; Industrial Microbiology