Abstract Palbociclib, a CDK4/6 inhibitor, plays a crucial role in the treatment of HR+ breast cancer. However, resistance to palbociclib is a significant concern that merits further investigation. Our investigation identifies TMEM45A as a potential driver of palbociclib resistance and its association with increased cellular glycolysis. We demonstrate that TMEM45A is highly expressed in palbociclib-resistant breast cancer (BRCA) cells, correlating with enhanced tumor progression. Silencing TMEM45A enhances sensitivity to palbociclib, promotes cell cycle arrest and apoptosis, and inhibits the proliferation of BRCA cells. Moreover, attenuation of TMEM45A expression reduces cancer aggressiveness by decreasing the expression of EMT and glycolysis-related proteins. Subsequent gene set enrichment analysis (GSEA) confirms that TMEM45A activates the AKT/mTOR signaling pathway, which is integral to cell cycle progression and glycolysis. In a cell line-derived xenograft (CDX) mouse model, TMEM45A knockdown significantly restores sensitivity to palbociclib and suppresses tumor growth. Additionally, the use of engineered exosomes loaded with siRNA targeting TMEM45A presents a promising strategy for enhancing CDK4/6 inhibitor sensitivity without observable toxic side effects in a patient-derived xenograft (PDX) model. Collectively, our findings suggest that TMEM45A may be a therapeutic target for overcoming palbociclib resistance, and exosomal siRNA delivery could be a viable strategy for precision medicine in HR+ breast cancer.
It remains controversial whether patients with Stage II colorectal cancer would benefit from adjuvant chemotherapy after radical resection. The aim of this study was to establish two mathematical models to identify the suitable patients for adjuvant chemotherapy.The current study comprised of two steps. In the first step, 353 patients with Stage II colorectal cancer who underwent surgical procedures at the Third Affiliated Hospital of Sun Yat-sen University between June 2006 and December 2015 were entered and followed up for 6-120 months. Their clinical data were collected and enrolled into the database. We established two mathematical models by univariate and multivariate Cox regression analysis to identify the target patients; in the second step, 230 patients under the same standard between January 2012 and December 2016 were entered and followed up for 3-62 months to verify the two models' validation.In the first step, totally 340 surgical patients with Stage II colorectal cancer were finally enrolled in this study. Statistical analysis showed that tumor differentiation (TD) (P < 0.001), lymphovascular invasion (LVI) (P < 0.001), uncertain or positive margins (UPM) (P < 0.001), and fewer lymph nodes (LNs) (<12) retrieved (P < 0.001) were correlated with the overall survival (OS) and disease free survival (DFS). We obtained two models: (1) OS risk score = 1.116 × TD + 2.202 × LVI + 3.676 × UPM + 1.438 × LN - 0.493; (2) DFS risk score = 0.789 × TD + 2.074 × LVI + 3.183 × UPM + 1.329 × LN - 0.432. According to the models and cutoff points [(0.07, 1.33) and (-0.04, 1.30), respectively], patients can be divided into three groups: low-risk, moderate-risk, and high-risk. Moreover, the high-risk group patients could benefit from adjuvant chemotherapy. In the second step, totally 221 patients were finally used to verify the models' validation. The results proved that the models were accurate and feasible (P< 0.05).According to the predictive models, patients with Stage II colorectal cancer in the high-risk group are strongly recommended for adjuvant chemotherapy, thus facilitating the individualized and precise treatment.
To explore the safety, feasibility, and clinical curative effect of endoscopy-assisted laparoscopic resections for gastric gastrointestinal stromal tumors (GISTs).We retrospectively compared the general condition of 41 GIST patients undergoing endoscopy-assisted laparoscopic resections (n = 41, combined group) with those undergoing traditional open gastrectomy (n = 43, open surgery group).All patients survived during the surgery. The average operation time of the combined group and the open surgery group was 90 ± 40 minutes and 120 ± 60 minutes, respectively, and no significant difference (P = .088) was observed. Bleeding volume during operation was significantly lower [(50 ± 20 versus 150 ± 40) mL, P < .001] and recovery time of the gastrointestinal function was significantly shorter in the combined group [(2.02 ± 0.99) days versus (3.02 ± 1) days, P < .001]. No statistical difference was found in the postoperative complications (5% versus 12%, P = .442) or GIST recurrence (2.44% versus 2.33%, P = 1.000) between the two groups. Follow-up visit showed no death.For GIST patients who attempted to receive gastrectomy, endoscopy-assisted laparoscopic resections showed advantages on the operation time, bleeding volume, and recovery time and are suggested as a better alternative for GISTs.
The aim of this study was to investigate the effect of preservation of Denonvilliers' fascia (DF) during laparoscopic resection for mid-low rectal cancer on protection of male urogenital function. Whether preservation of DF during TME is effective for protection of urogenital function is largely elusive. Seventy-four cases of male mid-low rectal cancer were included. Radical laparoscopic proctectomy was performed, containing 38 cases of preservation of DF (P-group) and 36 cases of resection of DF (R-group) intraoperatively. Intraoperative electrical nerve stimulation (INS) on pelvic autonomic nerve was performed and intravesical pressure was measured manometrically. Urinary function was evaluated by residual urine volume (RUV), International Prostatic Symptom Score (IPSS), and quality of life (QoL). Sexual function was evaluated using the International Index of Erectile Function (IIEF) scale and ejaculation function classification. Compared with performing INS on the surfaces of prostate and seminal vesicles in the R-group, INS on DF in the P-group exhibited higher increasing intravesical pressure (7.3 ± 1.5 vs 5.9 ± 2.4 cmH2O, P = 0.008). In addtion, the P-group exhibited lower RUV (34.3 ± 27.2 vs 57.1 ± 50.7 mL, P = 0.020), lower IPSS and QoL scores (7 days: 6.1 ± 2.4 vs 9.5 ± 5.9, P = 0.002 and 2.2 ± 1.1 vs 2.9 ± 1.1, P = 0.005; 1 month: 5.1 ± 2.4 vs 6.6 ± 2.2, P = 0.006 and 1.6 ± 0.7 vs 2.1 ± 0.6, P = 0.003, respectively), higher IIEF score (3 months: 10.7 ± 2.1 vs 8.9 ± 2.0, P = 0.000; 6 months: 14.8 ± 2.2 vs 12.9 ± 2.2, P = 0.001) and lower incidence of ejaculation dysfunction (3 months: 28.9% vs 52.8%, P = 0.037; 6 months: 18.4% vs 44.4%, P = 0.016) postoperatively. Preservation of DF during laparoscopic resection for selective male mid-low rectal cancer is effective for protection of urogenital function.
Although some studies described the characteristics of colon cancer stem cells (CSCs) and the role of endothelial progenitor cells (EPCs) in neovascularization, it is still controversial whether an interaction exists or not between CSCs and EPCs. In the present study, HCT116 and HT29 sphere models, which are known to be the cells enriching CSCs, were established to investigate the roles of this interaction in development and metastasis of colon cancer. Compared with their parental counterparts, spheroid cells demonstrated higher capacity of invasion, higher tumorigenic and metastatic potential. Then the in vitro and in vivo relationship between CSCs and EPCs were studied by using capillary tube formation assay and xenograft models. Our results showed that spheroid cells could promote the proliferation, migration and tube formation of EPCs through secretion of vascular endothelial growth factor (VEGF). Meanwhile, the EPCs could increase tumorigenic capacity of spheroid cells through angiogenesis. Furthermore, higher microvessel density was detected in the area enriching cancer stem cells in human colon cancer tissue. Our findings indicate that spheroid cells possess the characteristics of cancer stem cells, and the coaction of CSCs and EPCs may play an important role in the development of colon cancer.
Objective To investigate the significance and model of laparoscopic training in medical undergraduates.Methods The subjects were 15 doctors proceeding advanced study and 26 medical undergraduates in Grade 2005 and 2006.Among all the subjects,26 students in experimental group and 15 doctors (act as control) participated in laparoscopic training.Statistical analysis of the performance records of theoretical test,laparoscopic skills assessment were performed after training.Questionnaires were filled to assess the course offering using the Dundee Ready Education Environment Measure (DREEM).Results All the trainees finished the training and examination.There were no difference among the two groups in theoretical performance (P ＞ 0.05).Compared to control group,students in experimental group manifested more skillfully,although they had no skills of open surgery.Conclusions Early stage laparoscopic training not only can improve the laparoscopic skill of medical undergraduates,but also can enhance their interest and self-confidence to learning laparoscopic surgery,which is important to the development of minimally invasive surgery.
Key words:
Undergraduate of medicine; Laparoscopic training; Investigation
Background. Simultaneous or delayed surgery for synchronous colorectal liver metastases is performed in the clinic; which method is better is still up for debate. In particular, infectious complications are rarely compared. This study aims to investigate the differences between simultaneous and delayed surgery for synchronous colorectal liver metastases by comparing infectious complications and prognosis. Methods. Firstly, the patients’ information from a single institution’s database was retrospectively analyzed. Then the patients were divided into a simultaneous group and a delayed group according to synchronous colorectal liver metastases. Analyzing the postoperative complications within 30 days, the progression-free survival, and the overall survival in the two groups. Results. The simultaneous group had a higher neo-adjuvant chemotherapy rate (42.0% VS. 16.0% in the delayed group, P<0.05 ) and laparoscopic surgery rate (89.8% VS. 72.0% in the delayed group, P<0.05 ) than the delayed group. Moreover, the simultaneous group had a higher liver-related infection rate (17.0 VS. 0.0% in the delayed group, P<0.05 ). Conclusion. Although there was no difference in survival rate between delayed and simultaneous surgeries, the delayed surgery have fewer liver-related infections compared with the simultaneous surgery in synchronous colorectal liver metastases patients. Delayed surgery could be a better treatment method for synchronous colorectal liver metastases patients.
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