Prognostic analysis of cT1-3N1M0 breast cancer patients who have responded to neoadjuvant therapy undergoing various axillary surgery and breast surgery based on propensity score matching and competitive risk model.

Background: Sentinel lymph node biopsy (SLNB) in breast cancer patients with positive clinical axillary lymph nodes (cN1+) remains a topic of controversy. The aim of this study is to assess the influence of various axillary and breast surgery approaches on the survival of cN1+ breast cancer patients who have responded positively to neoadjuvant therapy (NAT). Methods: Patients diagnosed with pathologically confirmed invasive ductal carcinoma of breast between 2010 and 2020 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. To mitigate confounding bias, propensity score matching (PSM) analysis was employed. Prognostic factors for both overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated through COX regression risk analysis. Survival curves were generated using the Kaplan-Meier method. Furthermore, cumulative incidence and independent prognostic factors were assessed using a competing risk model. Results: The PSM analysis matched 4,890 patients. Overall survival (OS) and BCSS were slightly worse in the axillary lymph node dissection (ALND) group (HR = 1.10, 95% CI 0.91-1.31, p = 0.322 vs. HR = 1.06, 95% CI 0.87-1.29, p = 0.545). The mastectomy (MAST) group exhibited significantly worse OS and BCSS outcomes (HR = 1.25, 95% CI 1.04-1.50, p = 0.018 vs. HR = 1.37, 95% CI 1.12-1.68, p = 0.002). The combination of different axillary and breast surgery did not significantly affect OS (p = 0.083) but did have a significant impact on BCSS (p = 0.019). Competing risk model analysis revealed no significant difference in the cumulative incidence of breast cancer-specific death (BCSD) in the axillary surgery group (Grey's test, p = 0.232), but it showed a higher cumulative incidence of BCSD in the MAST group (Grey's test, p = 0.001). Multivariate analysis demonstrated that age ≥ 70 years, black race, T3 stage, ER-negative expression, HER2-negative expression, and MAST were independent prognostic risk factors for both OS and BCSS (all p < 0.05). Conclusion: For cN1+ breast cancer patients who respond positive to NAT, the optimal surgical approach is combining breast-conserving surgery (BCS) with SLNB. This procedure improves quality of life and long-term survival outcomes.

Development of a difficulty scoring system for laparoscopic pancreatoduodenectomy in the initial stage of the learning curve: a retrospective cohort study.

BACKGROUND: It remains uncertain how surgeons can safely pass the learning curve of laparoscopic pancreatoduodenectomy (LPD) without potentially harming patients. We aimed to develop a difficulty scoring system (DSS) to select an appropriate patient for surgeons. MATERIALS AND METHODS: A total of 773 elective pancreatoduodenectomy surgeries between July 2014 and December 2019, including 346 LPD and 427 open pancreatoduodenectomy cases, were included. A 10-level DSS for LPD was developed, and an additional 77 consecutive LPD surgeries which could provide information of the learning stage I of LPD externally validated its performance between December 2019 and December 2021. RESULTS: The incidences of postoperative complications (Clavien-Dindo≥III) gradually decreased from the learning curve stage I-III (20.00, 10.94, 5.79%, P =0.008, respectively). The DSS consisted of the following independent risk factors: (1) tumor location, (2) vascular resection and reconstruction, (3) learning curve stage, (4) prognostic nutritional index, (5) tumor size, and (6) benign or malignant tumor. The weighted Cohen's κ statistic of concordance between the reviewer's and calculated difficulty score index was 0.873. The C -statistics of DSS for postoperative complication (Clavien-Dindo≥III) were 0.818 in the learning curve stage I. The patients with DSS<5 had lower postoperative complications (Clavien-Dindo≥III) than those with DSS≥5 (4.35-41.18%, P =0.004) in the training cohort and had a lower postoperative pancreatic fistula (19.23-57.14%, P =0.0352), delayed gastric emptying (19.23-71.43%, P =0.001), and bile leakage rate (0.00-21.43%, P =0.0368) in validation cohort in the learning curve stage I. CONCLUSION: We developed and validated a difficulty score model for patient selection, which could facilitate the stepwise adoption of LPD for surgeons at different stages of the learning curve.

Calycosin-7-glucoside promotes mitochondria-mediated apoptosis in hepatocellular carcinoma by targeting thioredoxin 1 to regulate oxidative stress.

Thioredoxin1 (TRX1) is a key protein that regulates redox and is considered to be a key target for cancer therapy. Flavonoids have been proven to have good antioxidant and anticancer activities. This study aimed to investigate whether the flavonoid calycosin-7-glucoside (CG) exerts an anti-hepatocellular carcinoma (HCC) role by targeting TRX1. Different doses of CG were used to treat HCC cell lines Huh-7 and HepG2 to calculate the IC50. On this basis, the effects of low, medium and high doses of CG on cell viability, apoptosis, oxidative stress and TRX1 expression of HCC cells were investigated in vitro. Also, HepG2 xenograft mice were used to evaluate the role of CG on HCC growth in vivo. The binding mode of CG and TRX1 was explored by molecular docking. Then si-TRX1 was used to further discover the effects of TRX1 on CG inhibition of HCC. Results found that CG dose-dependent decreased the proliferation activity of Huh-7 and HepG2 cells, induced apoptosis, significantly activated oxidative stress and inhibited TRX1 expression. In vivo experiments also showed that CG dose-dependent regulated oxidative stress and TRX1 expression, and promoted the expression of apoptotic proteins to inhibit HCC growth. Molecular docking confirmed that CG had a good binding effect with TRX1. Intervention with TRX1 significantly inhibited the proliferation of HCC cells, promoted apoptosis, and further promoted the effect of CG on the activity of HCC cells. In addition, CG significantly increased ROS production, reduced mitochondrial membrane potential, regulated the expression of Bax, Bcl-2 and cleaved-caspase-3, and activated mitochondria-mediated apoptosis. And si-TRX1 enhanced the effects of CG on mitochondrial function and apoptosis of HCC, suggesting that TRX1 participated in the inhibitory effect of CG on mitochondria-mediated apoptosis of HCC. In conclusion, CG exerts anti-HCC activity by targeting TRX1 to regulate oxidative stress and promote mitochondria-mediated apoptosis.

Cytotoxic phenyl polyketides from Hypericum curvisepalum N. Robson.

(±)-Hypecurvone A (1) and B (2), two new undescribed phenyl polyketides, along with seven known analogues (3-9) were isolated from the whole plant of Hypericum curvisepalum. Chiral separation of 1 and 2 yielded two pairs of enantiomers 1a/1b and 2a/2b, respectively. The structures of these compounds were elucidated by extensive spectroscopic analyses and ECD spectra simulations. All isolates exhibited moderate cytotoxicity against human hepatocellular carcinoma SMMC-7721 cells, and compound 3 also showed weak cytotoxicity toward MGC-803 cells. The cytotoxicity of these compounds was found to be related to enhanced mitochondria-mediated apoptosis and inhibition of the G2/M phase of the cell cycle.

Hypoxia activated HGF expression in pancreatic stellate cells confers resistance of pancreatic cancer cells to EGFR inhibition.

BACKGROUND: Epidermal growth factor receptor (EGFR) is an essential target for cancer treatment. However, EGFR inhibitor erlotinib showed limited clinical benefit in pancreatic cancer therapy. Here, we showed the underlying mechanism of tumor microenvironment suppressing the sensitivity of EGFR inhibitor through the pancreatic stellate cell (PSC). METHODS: The expression of alpha-smooth muscle actin (α-SMA) and hypoxia marker in human pancreatic cancer tissues were detected by immunohistochemistry, and their correlation with overall survival was evaluated. Human immortalized PSC was constructed and used to investigate the potential effect on pancreatic cancer cell lines in hypoxia and normoxia. Luciferase reporter assay and Chromatin immunoprecipitation were performed to explore the potential mechanisms in vitro. The combined inhibition of EGFR and Met was evaluated in an orthotopic xenograft mouse model of pancreatic cancer. FINDINGS: We found that high expression levels of α-SMA and hypoxia markers are associated with poor prognosis of pancreatic cancer patients. Mechanistically, we demonstrated that hypoxia induced the expression and secretion of HGF in PSC via transcription factor HIF-1α. PSC-derived HGF activates Met, the HGF receptor, suppressing the sensitivity of pancreatic cancer cells to EGFR inhibitor in a KRAS-independent manner by activating the PI3K-AKT pathway. Furthermore, we found that the combination of EGFR inhibitor and Met inhibitor significantly suppressed tumor growth in an orthotopic xenograft mouse model. INTERPRETATION: Our study revealed a previously uncharacterized HIF1α-HGF-Met-PI3K-AKT signaling axis between PSC and cancer cells and indicated that EGFR inhibition plus Met inhibition might be a promising strategy for pancreatic cancer treatment. FUNDING: This study was supported by The National Natural Science Foundation of China.

Prognostic validity of the American joint committee on cancer eighth edition staging system for well-differentiated pancreatic neuroendocrine tumors.

BACKGROUND: The American Joint Committee on Cancer (AJCC) made improvements for staging pancreatic neuroendocrine tumors (pNETs) in its 8th Edition; however, multicenter studies were not included. METHODS: We collected multicenter datasets (n = 1,086, between 2004 and 2018) to validate the value of AJCC 8 and other coexisting staging systems through univariate and multivariate analysis for well-differentiated (G1/G2) pNETs. RESULTS: Compared to other coexisting staging systems, AJCC 7 only included 12 (1.1%) patients with stage III tumors. Patients with European Neuroendocrine Tumor Society (ENETS) stage IIB disease had a higher risk of death than patients with stage IIIA (hazard ratio [HR]: 4.376 vs. 4.322). For the modified ENETS staging system, patients with stage IIB disease had a higher risk of death than patients with stage III (HR: 6.078 vs. 5.341). According to AJCC 8, the proportions of patients with stage I, II, III, and IV were 25.7%, 40.3%, 23.6%, and 10.4%, respectively. As the stage advanced, the median survival time decreased (NA, 144.7, 100.8, 72.0 months, respectively), and the risk of death increased (HR: II = 3.145, III = 5.925, and IV = 8.762). CONCLUSION: These findings suggest that AJCC 8 had a more reasonable proportional distribution and the risk of death was better correlated with disease stage.

Development and Validation of a Nomogram to Predict Survival in Pancreatic Head Ductal Adenocarcinoma After Pancreaticoduodenectomy.

BACKGROUND: Pancreatic head ductal adenocarcinoma (PHDAC) patients with the same tumor-node-metastasis (TNM) stage may share different outcomes after pancreaticoduodenectomy (PD). Therefore, a novel method to identify patients with poor prognosis after PD is urgently needed. We aimed to develop a nomogram to estimate survival in PHDAC after PD. METHODS: To estimate survival after PD, a nomogram was developed using the Tongji Pancreatic cancer cohort comprising 355 PHDAC patients who underwent PD. The nomogram was validated under the same conditions in another cohort (N = 161) from the National Taiwan University Hospital. Prognostic factors were assessed using LASSO and multivariate Cox regression models. The nomogram was internally validated using bootstrap resampling and then externally validated. Performance was assessed using concordance index (c-index) and calibration curve. Clinical utility was evaluated using decision curve analysis (DCA), X-tile program, and Kaplan-Meier curve in both training and validation cohorts. RESULTS: Overall, the median follow-up duration was 32.17 months, with 199 deaths (64.82%) in the training cohort. Variables included in the nomogram were age, preoperative CA 19-9 levels, adjuvant chemotherapy, Tongji classification, T stage, N stage, and differentiation degree. Harrell's c-indices in the internal and external validation cohorts were 0.79 (95% confidence interval [CI], 0.76-0.82) and 0.83 (95% CI, 0.78-0.87), respectively, which were higher than those in other staging systems. DCA showed better clinical utility. CONCLUSION: The nomogram was better than TNM stage and Tongji classification in predicting PHDAC patients' prognosis and may improve prognosis-based selection of patients who would benefit from PD.

Polymeric Drug Delivery System Based on Pluronics for Cancer Treatment.

Pluronic polymers (pluronics) are a unique class of synthetic triblock copolymers containing hydrophobic polypropylene oxide (PPO) and hydrophilic polyethylene oxide (PEO) arranged in the PEO-PPO-PEO manner. Due to their excellent biocompatibility and amphiphilic properties, pluronics are an ideal and promising biological material, which is widely used in drug delivery, disease diagnosis, and treatment, among other applications. Through self-assembly or in combination with other materials, pluronics can form nano carriers with different morphologies, representing a kind of multifunctional pharmaceutical excipients. In recent years, the utilization of pluronic-based multi-functional drug carriers in tumor treatment has become widespread, and various responsive drug carriers are designed according to the characteristics of the tumor microenvironment, resulting in major progress in tumor therapy. This review introduces the specific role of pluronic-based polymer drug delivery systems in tumor therapy, focusing on their physical and chemical properties as well as the design aspects of pluronic polymers. Finally, using newer literature reports, this review provides insights into the future potential and challenges posed by different pluronic-based polymer drug delivery systems in tumor therapy.

New staging classification for pancreatic neuroendocrine neoplasms combining TNM stage and WHO grade classification [].

AJCC TNM stage and WHO grade (G) are two widely used staging systems to guide clinical management for pancreatic neuroendocrine neoplasms (panNENs), based on clinical staging and pathological grading information, respectively. We proposed to integrate TNM stage and G grade into one staging system (TNMG) and to evaluate its clinical application as a prognostic indicator for panNENs. Accordingly, 5254 patients diagnosed with panNENs were used to evaluate and to validate the applicability of TNMG to panNENs. The predictive accuracy of TNMG system was compared with that of each separate staging/grading system. We found that TNM stage and G grade were independent risk factors for survival in both the Surveillance, Epidemiology, and End Result (SEER) and multicenter series. The interaction effect between TNM stage and G grade was significant. Twelve subgroups combining the TNM stage and G grade were proposed in the TNMG stage, which were classified into five stages TNMG. According to the TNMG staging classification in the SEER series, the estimated median survival for stages I, II, III, IV, and V were 203, 174, 112, 61, and 8 months, respectively. The predictive accuracy of TNMG stage was higher than that of TNM stage and G grade used independently. The TNMG stage classification was more accurate in predicting panNEN patient's prognosis than either the TNM stage or G grade.

Impact of Percutaneous Transhepatic Biliary Drainage on Clinical Outcomes of Patients with Malignant Obstructive Jaundice Undergoing Laparoscopic Pancreaticoduodenectomy.

Preoperative biliary drainage may increase the morbidity and mortality of pancreaticoduodenectomy. Studies on percutaneous transhepatic biliary drainage (PTBD) before laparoscopic pancreaticoduodenectomy (LPD), however, are scarce. The aim of this study was to examine the impact of PTBD on clinical outcomes of patients with malignant obstructive jaundice undergoing LPD. Clinical data of 172 patients who had malignant obstructive jaundice and underwent LPD from 2014 to 2017 in our hospital were retrospectively analyzed. Demographics, catheter-related complications, postoperative complications, and oncological outcomes were collected and analyzed. Propensity score matching was performed to minimize selection bias associated with the comparison of data between patients who underwent PTBD and then LPD (PTBD group), and those given LPD alone (LPD group). The results showed that, in the PTBD group relative to the LPD group, the operating time was significantly shortened (250.28±69.95 vs. 278.58±86.51 min, P=0.0196), the intraoperative blood loss was markedly reduced (271.96±403.47 vs. 429.72±482.47 mL, P=0.022), and overall rates of complications (16.33% vs. 36.49%, P=0.0025) including postoperative haemorrhage (2.04% vs. 12.16%, P=0.0072) and delayed gastric emptying (4.08% vs. 13.51%, P=0.0251) were greatly decreased. The propensity score-matched analysis, with 48 patients enrolled in each group, revealed no statistically significant differences in operating duration (262.71±68.64 vs. 280.25±83.52 min, P=0.264), intraoperative blood loss (290.21±407.71 vs. 373.75±422.33 mL, P=0.327) and delayed gastric emptying (4.17% vs. 12.50%, P=0.1396). PTBD group had lower incidences in overall complications (22.92% vs. 39.58%, P=0.0481) and postoperative haemorrhage (2.08% vs. 12.50%, P=0.0497) than LPD group. In conclusion, patients with malignant obstructive jaundice may benefit from PTBD procedure before LPD in terms of perioperative outcomes.

The ratio of abdominal depth to body mass index is a preoperative predictor of postoperative complications after laparoscopic pancreaticoduodenectomy: a retrospective propensity score matched analysis.

BACKGROUND: Postoperative complication rates after laparoscopic pancreaticoduodenectomy (LPD) remain high despite improvements in perioperative management. Measurements on computed tomography imaging of intra-abdominal tissue have not been thoroughly investigated as predictors of mortality and morbidity following LPD. The aim of this study was to assess whether the ratio of abdominal depth and body mass index (AD/BMI ratio) could predict postoperative complications following LPD. METHODS: We retrospectively analyzed 231 patients who underwent LPD and had a computed tomography scan between 2014 and 2018. Demographic, radiologic, and pathologic data were correlated to the occurrence of postoperative complications. Propensity score matching was performed to minimize selection biases associated with the comparison of retrospective data between the high and low AD/BMI ratio groups. Univariate and multivariate analyses were also performed to assess the risk factors for postoperative complications. RESULTS: Of the 102 patients identified for propensity score matching analysis, 29 patients (28.4%) experienced postoperative complications. Patients with a high AD/BMI ratio had a higher prevalence of overall complications (45.1% vs. 11.8%, P < 0.001), postoperative pancreatic fistula (17.6% vs. 2.00%, P = 0.008), delayed gastric emptying (33.3% vs. 3.90%, P < 0.001), and intra-abdominal abscess (17.6% vs. 0, P = 0.002). In the multivariate analysis, an AD/BMI ratio greater than 2.7 (m3/[kg·103]; OR = 6.16, 95% confidence interval [1.04-36.4], P = 0.045) was the only independent predictive factor of postoperative complications. CONCLUSIONS: The preoperative AD/BMI ratio is a predictor of postoperative complications following LPD.

Prognostic significance of preoperative Naples prognostic score on short- and long-term outcomes after pancreatoduodenectomy for ampullary carcinoma.

BACKGROUND: The Naples prognostic score (NPS) is an effective and objective tool to assess the immune-nutritional status of patients with malignant tumors. The aim of this study was to investigate the clinical significance of preoperative NPS on short- and long-term outcomes after pancreatoduodenectomy (PD) for ampullary carcinoma. METHODS: We retrospectively analyzed 404 consecutive patients with ampullary carcinoma who underwent PD between January 2012 and June 2018. Preoperative NPS was calculated from serum albumin and total cholesterol concentrations, and the neutrophil-lymphocyte ratio and lymphocyte-monocyte ratio (LMR). Patients were then divided into three groups according to their NPS. Clinicopathological variables, postoperative outcomes, and survival data were compared between the three groups. Univariate and multivariate Cox analysis of overall survival (OS) and recurrence-free survival (RFS) were also conducted, and time-dependent receiver operating characteristic (ROC) curves were created to evaluate the discriminatory ability of the prognostic scoring systems. RESULTS: Patients with higher NPS had worse prognosis, and significant OS difference (group 0 vs. 1, P=0.02; group 1 vs. 2, P<0.001; group 0 vs. 2, P<0.001) and RFS difference (group 0 vs. 1, P=0.088; group 1 vs. 2, P<0.001; group 0 vs. 2, P<0.001). Multivariate analysis revealed that NPS was an independent significant predictor of OS (grade 2 vs. grade 1 or 0, hazard ratio: 3.067; P<0.001) and RFS (grade 2 vs. grade 1 or 0, hazard ratio: 2.732; P<0.001). The time-dependent receiver operating curve analysis showed that NPS had better prognostic performance for OS and RFS than other prognostic models. Additionally, significant differences in the incidence of postoperative morbidity were observed between the three groups, and the NPS was an independent risk factor of overall postoperative complications (grade 2 vs. grade 1 or 0, odds ratio: 1.692; P=0.02). CONCLUSIONS: The NPS was an independent predictor of overall- and RFS in patients undergoing PD for ampullary carcinoma, and was independently associated with the incidence of postoperative complications.

The impact of laryngeal mask versus other airways on perioperative respiratory adverse events in children: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Increasing studies have shown that the use of laryngeal mask airways (LMAs) improved the perioperative respiratory adverse events (PRAEs) in children. However, the results of some of these studies still remained controversial as their sample sizes were small. A systematic review and meta-analysis was designed to evaluate the impact of LMAs in decreasing PRAEs in children. METHODS: We searched the Cochrane Library, PubMed, EMBASE and Web of Science up to May 29, 2018 to identify relevant randomized controlled trials (RCTs) which analyzed and evaluated the impact of LMAs in decreasing PRAEs in children. Participants were randomly assigned to receive LMAs (the intervention group) or other airways (the control group). We studied PRAEs which included breath apnea, laryngospasm, desaturation, cough, fever, pulmonary rales and pulmonary infection. Risk ratio (RR) with 95% confidence intervals (CIs) were estimated to compare the outcomes of the groups. We also performed subgroup analysis and sensitivity analysis to evaluate the impact of LMAs on further decreasing PRAEs. Two reviewers assessed the trial quality and extracted the data independently. All statistical analyses were performed using the standard statistical procedures provided in the Review Manager 5.2. RESULTS: Twelve RCTs (N = 1577 participants) were identified. Comparing with other airways, significant reduction were found in the overall PRAEs (RR 0.52, 95% CI 0.39-0.70; P < 0.0001), major PRAEs (RR 0.47, 95% CI 0.29-0.79; P = 0.004) as well as minor PRAEs (RR 0.57, 95% CI 0.45-0.74; P < 0.0001) in patients managed with LMAs. When compared with endotracheal tubes (ETTs), LMAs also significantly reduced PRAEs. Further analysis also found that LMAs reduced the incidences of postoperative cough (RR 0.44, 95% CI 0.31-0.63; P < 0.00001), pulmonary rales (RR 0.62, 95% CI 0.44-0.87; P = 0.006) and infections (RR 0.28, 95% CI 0.13-0.61; P = 0.001) in children. CONCLUSIONS: LMAs reduced the incidences of many PRAEs in children and should be used as one of anaesthesia methods for children.

Targeted Codelivery of Docetaxel and Atg7 siRNA for Autophagy Inhibition and Pancreatic Cancer Treatment.

As the fourth leading cause of cancer-related deaths worldwide, pancreatic cancer has a higher basal level of autophagy as compared to other epithelial tumors. Recently, increasing evidence suggested that docetaxel (DTX) triggered autophagy in pancreatic cancer cells which promoted cancer cell survival after chemotherapy. Therefore, we constructed an amphiphilic block copolymer that can form micelles to simultaneously codeliver with siAtg7 and DTX for effective inhibition of tumor cells grown in vitro and in vivo. The iRGD peptide internalized on the surface of the vehicle could target to tumors and increase the penetration of vehicle into solid tumors. By downregulating the expression of Atg7 gene, the DTX-induced autophagy was inhibited, which improved the DTX therapeutic outcomes during the treatment of pancreatic cancer.

Reactive oxygen species (ROS)-responsive nanomedicine for RNAi-based cancer therapy.

Although much effort has been dedicated to the development of efficient siRNA delivery for cancer therapy, delivery nanomaterials that can particularly respond to reactive oxygen species (ROS), which are overproduced in the tissue and mitochondria of cancer cells, are still rare for the clinical translation of RNA interference (RNAi)-based therapy. To this end, we developed a ROS-responsive boronic vehicle with a lipid envelope for systemic vascular endothelial growth factor (VEGF) siRNA delivery so as to improve RNAi cancer therapy. We found that the efficiency of siRNA delivery largely relied on the ROS responsiveness of the carrier we have developed to mediate timely siRNA release, the PEG-functionalized lipid layer to shield the surface charge of polyplexes as well as the ability of the phenylboronic moiety to stabilize siRNA. The unique carrier nanostructure provides the efficient systemic transportation of siRNA to the tumor site for effective knockdown of the VEGF, which resulted in a significant antiangiogenesis effect and the effective inhibition of tumor growth in vivo. The current study defines a new systemic delivery strategy for siRNA by cooperatively integrating multifunctional lipid coatings with the ROS-responsive boronic polymer, which may potentially benefit RNAi-based therapy in the dawning era of precision nanomedicine for cancer therapy.

Redox-Activatable ATP-Depleting Micelles with Dual Modulation Characteristics for Multidrug-Resistant Cancer Therapy.

A fast adenosine triphosphate (ATP)-depleting micellar system that is activated by intracellular redox for the codelivery of anticancer drug paclitaxel (PTX) and small interference RNA (siRNA) targeting polo-like kinase1 (PLK1) is developed to address the key challenges of multidrug-resistant (MDR) cancer therapy. The ATP-depleting micelle is self-assembled from a redox-responsive amphiphilic polymer (termed as bPEG-SS-P123-PEI (PSPP)) that is composed of biocompatible branched polyethylene glycol (PEG) with 8 arms (bPEG), ATP-depleting Pluronic P123 (P123), and cationic low molecular weight polyethylenimine (PEI) blocks. Upon critical micelle concentration, the PSPP unimer self-assembles into a well-ordered multilayered nanostructure and is able to load PTX and siRNA targeting PLK1. The cleavage of disulfide linkages at intracellular glutathione-rich reduction milieu not only promotes PTX and siRNA release, but also activates the fast ATP-depletion action that is critical in preventing intracellular PTX efflux by multidrug-resistant cancer cells. The combination of ATP depletion and siRNA inhibition by PSPP micelles is found to provide dual modulations for resensitizing multidrug-resistant cancer cells for PTX treatment. As a result, the codelivery of PTX and PLK1 siRNA exerts a stronger combinational effect against tumor growth in MDR tumor models in vivo. The development of fast ATP-depleting nanomicelle represents an original delivery strategy for the distinctive dual modulation of cancer MDR with spatial and temporal control.

Targeted Co-delivery of PTX and TR3 siRNA by PTP Peptide Modified Dendrimer for the Treatment of Pancreatic Cancer.

A new type of tumor-targeted nanovehicle peptide-conjugated PSPG (PSPGP) is successfully synthesized for co-delivery of paclitaxel (PTX) and TR3 small interfering RNA (siRNA). In vitro and in vivo investigations demonstrate that the redox-responsive PSPGP exhibit enhanced endosomal escape and intracellular degradation, which facilitate PTX and TR3 siRNA release, effectively improving the antitumor efficacy.

mTOR inhibitor AZD8055 inhibits proliferation and induces apoptosis in laryngeal carcinoma.

The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, against all class I phosphatidylinositol3-kinase (PI3K) and other members of the PI3K-like kinase family. The study was to determine the effect of AZD8055 on proliferation and apoptosis on Hep-2, a human laryngeal cancer cell line and to investigate the underlying mechanism(s) of action. Hep-2 cells were treated with AZD8055 for 24, 48 or 72 h. MTT was used to determine cell proliferation. Rhodamine 123 and TUNEL staining were used to determine mitochondrial membrane potential and cell apoptosis analyzed by fluorescence-activated cell sorting (FACS). Protein expressions were examined by western blotting. Treatment with AZD8055 inhibited proliferation and induced apoptosis in Hep-2 cells in a dose- and time-dependent manner. During the prolonged treatment with AZD8055, AZD8055 inhibits the mammalian target of rapamycin mTOR. Further experiments showed which signaling cascade p-4EBP1 and substrate EIF4E as well as downstream proteins were down regulated. Furthermore, our study showed that the expression profiles of various BH3-only proteins including Bid, Bad, and Bim, apoptosis regulatory protein cleaved caspase3 was up regulated in a time-dependent manner in Hep-2 cells treated with AZD8055. Thus, in vitro, AZD8055 potently inhibits proliferation and induces apoptosis in head and neck squamous cell carcinoma.

Combination of AZD2281 (Olaparib) and GX15-070 (Obatoclax) results in synergistic antitumor activities in preclinical models of pancreatic cancer.

In this study, we explored the antitumor activities of the PARP inhibitor AZD2281 (Olaparib) and the pan-Bcl-2 inhibitor GX15-070 (Obatoclax) in six pancreatic cancer cell lines. While both agents were able to cause growth arrest and limited apoptosis, the combination of the two was able to synergistically cause growth arrest and non-apoptotic cell death. Furthermore, in an in vivo xenograft model, the combination caused substantially increased tumor necrosis compared to either treatment alone. Our results support further investigation of the combination of Bcl-2 and PARP inhibitors for the treatment of pancreatic cancer.

Overexpression of GRIM-19, a mitochondrial respiratory chain complex I protein, suppresses hepatocellular carcinoma growth.

GRIM-19 has been demonstrated as an important regulator for the normal tissue development. Recently, more evidences regarded GRIM-19 as the new tumor suppressor. However, the possible mechanisms underlying GRIM-19 suppressing cancer growth are unclear. In the present study, Paired hepatocellular carcinoma (HCC) and adjacent non-tumor liver tissues were obtained from 54 patients who underwent primary surgical HCC tissue resection. GRIM-19 protein expression in HCC tissues was performed by immunohistochemistry. Cells were transfected by lentiviruses plasmid expressing GRIM-19. RT-PCR and Western blot analyses were performed to confirm the expression of GRIM-19 mRNA or protein. Cell proliferation was assessed by MTT and FCM analyses. Mitochondrial membrane potential and apoptosis were respectively determined by using fluorescence microscopy and FCM analyses. AKT1, pAKT1, cyclinD1, CDK4, PCNA, Bax, Bcl-2, cleaved caspase-9, cleaved caspase-3, and cytochrome C were detected by Western blot and immunofluorescence. GRIM-19 protein expression was markedly lower in HCC than in paired adjacent non-tumor liver tissues. GRIM-19 overexpression in HCC cells significantly induced cell cycle arrest and enhanced apoptosis. We also found that AKT1 expression and phosphorylation were regulated by the expression of GRIM-19. Collectively, our study demonstrated that GRIM-19 overexpression suppressed HCC growth and downregulated AKT1 expression, suggesting that GRIM-19 might play a crucial role in hepatocarcinogenesis through negatively regulating the PI3K/AKT signaling pathway.