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 systematically evaluate the accuracy of computer navigation technique in the positioning of bone tunnel location of anterior cruciate ligament reconstruction(ACLR) and its effect on post-operative functional recovery.Methods The controlled trials of computer navigation-assisted ACLR in the da-tabases of Cochrane Library,PubMed,Embase,CNKI,Wanfang and VIP Database were retrieved.The retriev-al time limit was from the establishment of the database to August 2023.According to the inclusion and exclu-sion criteria,the NoteExpress V3.0 software was used to screen the literatures,the Cochrane risk bias assess-ment tool was used to evaluate the quality of the included literatures,and the RevMan5.4 software was used for conducting the meta analysis.Results A total of 10 trials involving 705 patients were included,including 354 cases in the navigation group and 351 cases in the conventional group.The meta analysis results showed that compared with the conventional group,the location positioning of bone tunnel in the navigation group was significantly improved[in femoral side (MD=5.59,95％CI:1.21-9.97,P=0.01) and tibial side (MD=1.32,95％CI:0.20-2.43,P=0.02).However there were no statistically significant differences in the IKDC scores (MD=1.76,95％CI:-0.17 to 3.70,P=0.07),Lysholm scores (MD=0.49,95％CI:-0.16 to 1.14,P=0.14),Tegner scores (MD=-0.08,95％CI:-0.35 to 0.20,P=0.58),KT-1000 anterior shift dis-tance (MD=0.01,95％CI:-0.49 to 0.52,P=0.96),the positive rate of Lachman test (RD=-0.01,95％CI:-0.09 to 0.07,P=0.75) and the positive rate of axial shift test (RD=-0.09,95％CI:-0.22 to 0.04,P=0.20).Conclusion The computer navigation technology is conducive to elevate the accuracy of tibial and femoral tunnel positioning in ACLR,but could not improve the postoperative functional recovery of the pa-tients.

Objective To evaluate the intraoperative and postoperative effects of new type and modified probe in fractured lacrimal duct anastomosis.Methods Forty-nine patients with lower canalicular laceration were included in this study.The operation comparison was performed between the modified probe in a manner of synchronousintubation and the traditional pigtail probe.The differences of intraoperative effects were observed,and the clinical effects were assessed at postoperative 3,12 months.Results The average intubation time was (10.05±1.51) min in the observation group and (32.30±4.70) min in the control group,the difference was statistically significant (t=23.63,P＜0.01),the average whole operation time was (32.91 ± 3.98) min in the Observation group and (53.74± 5.48) min in the control group,the difference was staustically significant (t=15.71,P＜0.01).The rates of anatomic and functional success were 100.0％ (22 cases) and 90.9％ (20 cases) in the observation group,which were significantly higher than 70.4％ (19 cased) and 59.3％ (16 cases) in the control group,the difference was statistically significant (x2 =5.77,P＜0.05;x2 =6.23,P＜0.05).The punctal dilator was used by 18 times in the observation group and by 13 times in the control group,the difference was statistically significant (x2=5.91,P＜0.05),nevertheless no punctal incision was used.The rates of anatomic and functional success detected at 3 postoperative months,intraoperative once success and final success rates and postoperative complications showed no statistically significant differences(P＞0.05).Conclusion The modified probe provides a synchronous intubation new type operation mode,which simplifies the operation procedure,increases the operative success rate and partially reduces the occurrence of postoperative complications.

Objective To evaluate the effect of phacoemulsification on the corneal endothelium and thickness of diabetic cataract patients.Methods Cataract surgery of phacoemulsification with intraocular lens implantation was performed on together 348 eyes of 348 patients,including 96 eyes of 96 patients suffered from type 2 diabetes (diabetic group) and 252 eyes of 252 patients suffered from senile cataract (elderly group).Then,tear break-up time,basal tear secretion,corneal endothelial density and central corneal thickness were detected before surgery and 1 week,4 weeks and 8 weeks after surgery.Results There were significant difference in tear break-up time,basal tear secretion,corneal endothelial density and central corneal thickness before surgery and 1 week,4 weeks and 8 weeks after surgery between the two groups (all P ＜0.05).There were significant difference in corneal endothelial density (all P ＜ 0.05),but there was no significant difference in tear break-up time,basal tear secretion and central corneal thickness before and after surgery in the elderly group (all P ＞ 0.05).Intergroup comparison of tear break-up time,basal tear secretion,corneal endothelial density and central corneal thickness were significantly different before and after operation (all P ＜ 0.05).Conclusion Cataract surgery of phacoemulsification can achieve satisfying outcomes and it is crucial to protect the corneal endothelium and ocular surfacetissue intraoperatively and postoperatively for the patient with diabetic cataract.

Objective To investigate the effect of Wnt1 on the expression of Cyclin D1 in human corneal epithelial cells and its related molecular mechanisms. Methods 12 T25 cell culture flasks were cultured after hu-man corneal epithelial cells anabiosis ,culture and continuous passage for 2 times. Culture flasks were divided into 3 groups with 4 culture flasks in each group. Twenty-five ng/mL and 50 ng/mL recombinant human Wnt1 protein were added in two of the groups,and one group without T-cell culture medium(Wnt1)was used as control. Cells cultured in T25 flask were taken from three groups at different time(6 h,24 h,48 h and 72 h). The total number of corneal epithelial cells in each group was calculated. Expression of Cyclin D1 in corneal epithelial cells was de-tected by Western blot. Results The expression of Cyclin D1 protein in the control group decreased gradually from 0 h to 48 h,and reached the lowest level at 48 h and increased at 72 h. Cyclin D1 protein expression in 25 ng/mL group at 6 h after Wnt1 was added was not detected,and Cyclin D1 protein expression in 50 ng/mL group in-creased. The expression of Cyclin D1 protein in 25 ng/mL group and 50 ng/mL group was significantly higher than that in control group at 24 h,48 h and 72 h,reaching the peak at 48 h and decreased at 72 h. Compared with the control group,the growth rate of corneal epithelial cells in 25ng/ml group and 50ng/ml group increased after Wnt1 was added. There was significant difference in 72 h,but no significant difference in 6h,24h and 48h. Conclu-sions The stimulation of Wnt1 protein can enhance the expression of Cyclin D1 in a certain time range,and has a positive correlation with Wnt1 protein. As one of the target genes of Wnt1 signaling pathway,Cyclin D1 may play an important role in the repair of corneal epithelial injury and its cell proliferation and differentiation.

Chimeric antigen receptor T cells (CAR-T), one of the most promising cancer immunotherapy, has attracted much attention in the 57th American Society of Hematology (ASH) annual meeting. CAR-T therapy has obtained significant effect on leukemia and lymphoma and the latest research results are also inspiring in the 57th ASH annual meeting. It is an important task that how to combine CAR-T therapy with the traditional methods of treatment and the immune checkpoint blocking antibodies and small-molecule-targeted drugs to achieve the best effect. This paper will review the progress of CAR-T in the treatment of hematologic malignancies.

With the further study on heterogeneity and molecular mechanism of diffuse large B-cell lymphoma (DLBCL),many novel targeted drugs have been developed,which also showed clinical benefit in early-stage studies.Therapeutic targets for DLBCL mainly include the surface antigens of B lymphocyte,B cell receptor signaling and the cellular microenvironment.Several new clinical trials about targeted therapy for DLBCL had been reported in the 55th ASH annual meeting,and the results were encouraging.The advances in this field will be summarized in this paper based on the new reports in the 55th ASH annual meeting.

Staphylococcus aureus (S. aureus) is an important human pathogen which can cause a chronic condition with a high relapse rate despite the aggressive antimicrobial treatment. Recent studies showed that intracellular pattern recognition receptors (including NOD) in response to bacteria or bacterial products play a proinflammatory role by activating nuclear transcription factor-κB (NF-κB). But how NOD2 mediates the proinflammatory response to S. aureus in mast cells (MCs) is unclear. So, in this study, we attempted to examine the role of NOD2 in inflammatory responses of MCs to S. aureus. P815 cells (a mouse mast cell line) were cultured. Real-time PCR was used to detect the NOD2 mRNA expression in P815 cells during S. aureus infection. The siRNA against NOD2 gene was synthesized and transfected into S. aureus-infected P815 cells. By using the methods of ELISA and flow cytometry, the effects of NOD2 gene silencing on cell phagocytosis, cytokine secretion, NF-κB activation and cell apoptosis of the S. aureus-infected P815 cells were examined. It was found that S. aureus infection could increase the expression of NOD2 mRNA in P815 cells. NOD2 gene interference in P815 cells reduced the number of S. aureus engulfed by P815 cells, the level of cytokines and the activation of NF-κB. In addition, S. aureus could induce the apoptosis of P815 cells, but NOD2 gene silencing did not affect the cell apoptosis rate. Our data suggested that NOD2 plays a key role in pathogen recognition, signal transduction, and NF-κB activation in the inflammatory responses of MCs infected by S. aureus.

Staphylococcus aureus (S. aureus) is an important human pathogen which can cause a chronic condition with a high relapse rate despite the aggressive antimicrobial treatment. Recent studies showed that intracellular pattern recognition receptors (including NOD) in response to bacteria or bacterial products play a proinflammatory role by activating nuclear transcription factor-κB (NF-κB). But how NOD2 mediates the proinflammatory response to S. aureus in mast cells (MCs) is unclear. So, in this study, we attempted to examine the role of NOD2 in inflammatory responses of MCs to S. aureus. P815 cells (a mouse mast cell line) were cultured. Real-time PCR was used to detect the NOD2 mRNA expression in P815 cells during S. aureus infection. The siRNA against NOD2 gene was synthesized and transfected into S. aureus-infected P815 cells. By using the methods of ELISA and flow cytometry, the effects of NOD2 gene silencing on cell phagocytosis, cytokine secretion, NF-κB activation and cell apoptosis of the S. aureus-infected P815 cells were examined. It was found that S. aureus infection could increase the expression of NOD2 mRNA in P815 cells. NOD2 gene interference in P815 cells reduced the number of S. aureus engulfed by P815 cells, the level of cytokines and the activation of NF-κB. In addition, S. aureus could induce the apoptosis of P815 cells, but NOD2 gene silencing did not affect the cell apoptosis rate. Our data suggested that NOD2 plays a key role in pathogen recognition, signal transduction, and NF-κB activation in the inflammatory responses of MCs infected by S. aureus.
Animals ; Cell Line ; Cytokines ; immunology ; Inflammation Mediators ; immunology ; Mast Cells ; immunology ; microbiology ; Mice ; NF-kappa B ; immunology ; Nod2 Signaling Adaptor Protein ; immunology ; Staphylococcus aureus ; physiology

Objective To investigate the effect and mechanism of siHybrids technique on inhibiring the efflux pump gene mexB of Pseudomonas aeruginosa PAO1 in vitro. MethodsTargeting the efflux pump gene mexB of Pseudomonas aeruginosa PAO1 ,we designed and synthesized three siHybrids molecule and one negative scamble siHybrids molecule. Pseudomonas aeruginosa PAO1 were intervened by the siHybrids molecules in 50 nmol/L, respectively. And the experiments were made of control groups[blank and scamble (sc) -001]and intervened groups[siHybrids( si ) -001, siHybrids( si ) -002 and siHybrids(si) -003]of Pseudomonas aeruginosa PAO1. The targeting efflux pump gene mexB mRNA expressions of Pseudomonas aeruginosa PAO1, including all groups, were measured by real-time PCR in 12 h and 24 h after interference in vitro. Further, the minimal inhibitory concentration (MIC) of chlormycetinCP, erythrocin( EM ), levofloxacin ( L-OFLX), ceftazidime ( CAZ), meropenem (MER) to those groups were detected by using Mueller-Hinton broth dilution before and after interference. ResultsThe relative mexB mRNA amounts of Pseudomonas aeruginosa PAO1 intervened by different siHybrids were not much more different from each other after 12 h,but the expression of mexB mRNA of the intervened group ( si-001 ,si-002 ,si-003 ) was much lower than control groups after interference for 24 h. The relative mexB mRNA amounts, comparing 12 h with 24 h, we would find the blank control and negative control submit escalating trend. And the intervened control ,three different siHybrids were all with a downward tendency. However, in presence of 50 nmol/L siHybrids, the minimal inhibitory concentration(MIC) of CP, EM, L-OFLX, CAZ, MER to those controls were not much more different before and after interference. Conclusion On level of the mRNA expressions, siHybrids could inhibit the efflux pump gene mexB of Pseudomonas aeruginosa PAO1 in vitro, and within 24 h would be able to function effectively. Further, the effect was time-dependent.