Safety, tolerability, pharmacokinetics, and pharmacodynamics of a soluble guanylate cyclase stimulator, HEC95468, in healthy volunteers: a randomized, double-blinded, placebo-controlled phase 1 trial.

Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and pharmacodynamic profile of HEC95468, a soluble guanylate cyclase (sGC) stimulator, in healthy volunteers. Sixty-two, eighteen, and forty-eight participants were enrolled in the single ascending dose (SAD) study, the food effect (FE) study, and the multiple ascending dose (MAD) study, respectively. The study conforms to good clinical practice and the Declaration of Helsinki. Overall, HEC95468 was safe and tolerable; a higher proportion of HEC95468-treated participants reported mild headaches, dizziness, decreased blood pressure, increased heart rate, and gastrointestinal-related treatment-emergent adverse events (TEAEs), similar to the sGC stimulators riociguat and vericiguat. In terms of pharmacokinetic parameters, the maximum observed plasma concentration (Cmax) and the area under the concentration-time curve (AUC0-t) were dose-proportional over the dose range. Moderate accumulation was observed after multiple administrations of HEC95468. Systolic blood pressure (SBP) and diastolic blood pressure decreased, while 3',5'-cyclic guanosine monophosphate (cGMP) concentration in plasma increased and heart rate was induced. Vasoactive hormones (renin, angiotensin II, and norepinephrine) in plasma were compensatorily elevated after oral administration. These data supported further clinical trials of HEC95468 in the treatment of heart failure and pulmonary arterial hypertension. Systematic Review Registration: http://www.chinadrugtrials.org.cn, identifier CTR20210064.

Safety, tolerability, and pharmacokinetics of fluoropezil (DC20), a novel acetylcholinesterase inhibitor: A phase I study in healthy young and elderly Chinese subjects.

The present study evaluated the safety, tolerability, and pharmacokinetics of fluoropezil (DC20), a novel acetylcholinesterase inhibitor under development for the treatment of Alzheimer's disease (AD) in otherwise healthy young and elderly Chinese subjects. The study of young subjects included the multiple ascending dose (MAD) arm (2 and 6 mg, N = 24) and the food effect arm (4 mg, N = 12) and was followed by the study of elderly subjects who were given (2 and 4 mg, N = 11). The noncompartmental analysis method was used to determine the pharmacokinetic parameters. The pharmacokinetics of fed versus fasted dose administration in the same subjects was assessed by 90% confidence interval. In the MAD arm, the accumulation ratios of DC20 in vivo were 2.29 and 2.15, respectively. In the food effect arm, compared with fasting administration, an area under the concentration-time curve from zero to t after a standard and high-fat diet orally administered slightly increased by about 19% and 29%, and the time to maximum concentration (Tmax ) was delayed by around 1 h. For elderly study subjects, Tmax was 1.5 and 1.25 h, and terminal half-life (t1/2 ) was 77.1 and 74.2 h, respectively. There were no serious adverse events (AEs), whereas gastrointestinal reactions were the most common AEs associated with the study drug. We predicted the safety risks of DC20 in the clinical treatment of AD, which were well-tolerated by the healthy young and elderly subjects. The elimination of DC20 from the body was slower in elderly subjects than in young subjects. This study was approved by the Center for Drug Evaluation, National Medical Products Administration (CTR20181428, CTR20190664, CTR20191878, and CTR20192724).

Effect of a high-fat meal on the relative bioavailability of HMPL-689 in Chinese healthy volunteers.

The aim of this study was to investigate the effect of a high-fat meal on the single-dose pharmacokinetics (PK) and tolerability of HMPL-689 in Chinese healthy volunteers. In this study, 34 eligible male volunteers received a single 30-mg dose of HMPL-689 capsules following an overnight fast or a high-fat breakfast prior to dosing. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety and tolerability were assessed throughout the study. Total 32 healthy male volunteers were completed in the study. The GMRs of AUC0-t , AUC0-∞ , and Cmax and their 90% CIs were 1.12 (1.09, 1.15), 1.12 (1.09, 1.15), and 0.64 (0.58, 0.70), respectively, in healthy male subjects after oral administration of HMPL-689 following intake of a high-fat diet versus under fasting state. The 90% CI of Cmax GMR fell outside the acceptable equivalent range (0.8-1.25). In addition, the median Tmax of HMPL-689 was 1.0 and 4.0 h under the fasting and the fed conditions. The study indicated that intake of a high-fat diet had an impact on the in vivo PK profile of HMPL-689 in healthy Chinese male subjects, which could obviously reduce the oral absorption rate of HMPL-689 and had little effect on the extent of oral absorption (AUC).

Effect of food on the single-dose pharmacokinetics and tolerability of savolitinib in Chinese healthy volunteers.

The aim of this study was to investigate the effect of a high-fat and high-calorie meal on the single-dose pharmacokinetics (PK) and tolerability of savolitinib. The study included two phases: safety run-in phase and food effect assessment phase. In the safety run-in phase, 9 healthy male volunteers were divided into three groups to be administered a single oral dose of savolitinib tablets at 200, 400, and 600 mg. In the food effect assessment phase, 16 healthy male volunteers received a single 600 mg dose of savolitinib tablets following an overnight fast or a high-fat and high-calorie breakfast prior to dosing. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety and tolerability were assessed throughout the study by clinical assessments and adverse events (AEs). A total of 25 healthy male volunteers were enrolled in the study, including 9 in the safety run-in phase and 16 in the food effect assessment phase. In the food effect assessment phase, the geometric mean ratios (90% confidence interval) for savolitinib dosed under the fed condition compared with that dosed under the fasting condition were 102.7% (84.9%, 124.2%) and 117.1% (103.9%, 131.9%) for Cmax and AUC0-inf of savolitinib, respectively. The Tmax was delayed significantly (p = 0.023) under fed condition. The most common AEs possibly related to the study drug were dizziness, nausea, and emesis. The study indicated that a high-fat and high-calorie meal has no clinically relevant impact on the PK and bioavailability of savolitinib in healthy male volunteers.

Dopamine receptor D2 is correlated with gastric cancer prognosis.

It has been reported previously that a dopamine receptor D2 (DRD2) antagonist was able to induce cancer cell apoptosis and that DRD2 was expressed at high levels in pituitary adenomas. However, the expression of DRD2 in gastric cancer and its correlation with the prognosis of patients with gastric cancer remain to be elucidated. In the present study, the expression of DRD2 in 84 paired gastric cancer tissues and respective adjacent non-cancerous tissues were detected using an immunohistochemical assay. The correlation between the expression of DRD2 and the with survival durations of the patients with gastric cancer was analyzed using Kaplan-Meier analysis. In addition, online resources were utilized to further analyze the correlation between the mRNA expression level of DRD2 and prognosis. The effect of the DRD2 antagonist, thioridazine, on the proliferation of the AGS gastric cancer cells was determined. The results of the present study showed that the percentage of gastric cancer cases with a high expression level of DRD2 (51.2%) was higher, compared with that of cases with a low expression level of DRD2 (39.3%). Patients with a higher expression of DRD2 had shorter survival durations. The online database analysis revealed that the expression of DRD2 was also inversely correlated with the prognosis of patients with gastric cancer. Furthermore, the DRD2 antagonist, thioridazine, inhibited the growth of AGS gastric cancer cells. In conclusion, as the expression of DRD2 was negatively correlated with survival durations in patients with gastric cancer, it may be considered as a prognosis marker in the future. Developing DRD2 antagonists may assist in increasing the efficiency of cancer therapy.

CLIC1 overexpression is associated with poor prognosis in gallbladder cancer.

The chloride intracellular channel 1 (CLIC1) gene family is a recently identified class of Cl channel proteins. Although CLIC1 involvement is well established in some cancers such as gastric cancer and colon cancer, its expression pattern in gallbladder cancer (GBC) remains unknown. The aim of our study was to investigate the expression of CLIC1 in relation to progression and prognosis of GBC. Eight fresh gallbladder cancers paired with adjacent non-tumour tissues were quantified using real-time PCR and Western blot. Tissue samples from resected gallbladder cancer (n = 75) and cholelithiasis (n = 75) were evaluated for CLIC1 expression by immunohistochemical staining. Their expression was correlated with different clinicopathological parameters. CLIC1 expression was significantly higher (62.7 %) in gallbladder cancer than in cholelithiasis (21.3 %, p < 0.001). CLIC1 levels were associated with the histological grade, TNM stage and perineural invasion (p < 0.05), but not with patient age, sex, lymph node metastasis or gallbladder stones (p > 0.05). Univariate Kaplan-Meier analysis showed that a positive CLIC1 expression was associated with a decreased overall survival (p < 0.001). Multivariate Cox regression analysis showed that CLIC1 expression and histological grade were independent risk factors for overall survival. Therefore, the expression of CLIC1 is closely related to the progression of GBC and may be used as an effective marker for predicting the prognosis of this disease.

Three-step method for systematic lymphadenectomy in gastric cancer surgery using the 'curettage and aspiration dissection technique' with Peng's multifunctional operative dissector.

BACKGROUND: Gastric cancer is one of the most common malignancies and is a leading cause of cancer death worldwide. Surgery is the most effective and successful method of treatment for gastric cancer, and systematic lymph node (LN) dissection is unquestionably the most effective procedure for treating LN metastases of gastric cancer. Systematic lymphadenectomy is the most important part of curative resection, but lymphadenectomy is also the most difficult procedure in gastric cancer surgery. The aim of this study is to report our three-step method for lymphadenectomy in gastric cancer. METHODS: In this study, the lymph node stations and groups were defined according to the 13th edition of the Japanese Classification for Gastric Carcinoma. The authors' novel, simplified method consists of three steps: (1) the Kocher maneuver and dissection of the greater omentum together with the anterior sheet of the mesocolon, (2) dissection of the lesser omentum, and (3) lymphadenectomy following the main vessels. We primarily used Peng's multifunctional operative dissector, which combines four different functions (cutting, separating, aspirating and coagulating). Our systematic lymphadenectomy included three steps, and the main procedure started from right to left and in the caudal to cranial direction. RESULTS: A total of 830 consecutive patients underwent our three-step-method systematic lymphadenectomy in advanced gastric cancer surgery. The mean operation time was 146 minutes, and the mean blood loss was 248 ml. The median postoperative hospital stay was 10.9±4.8 days. The median number of examined LN was 31.6 (range 17 to 72) per patient, and the median number of metastatic LN was 5.6 (range 0 to 42) per patient. The overall incidence of postoperative complications was 10.6%, and the rate of hospital death was 0.9%. The overall three-year survival rate was 52.6%. CONCLUSIONS: Our three-step method for lymphadenectomy is easy to perform and is a useful procedure for gastric cancer surgery.

Yes-associated protein 1 (YAP1) promotes human gallbladder tumor growth via activation of the AXL/MAPK pathway.

The transcriptional coactivator Yes-associated protein 1 (YAP1), a key regulator of cell proliferation and organ size in vertebrates, has been implicated in various malignancies. However, little is known about the expression and biological function of YAP1 in human gallbladder cancer (GBC). In this study we examined the clinical significance and biological functions of YAP1 in GBC and found that nuclear YAP1 and its target gene AXL were overexpressed in GBC tissues. We also observed a significant correlation between high YAP1 and AXL expression levels and worse prognosis. The depletion of YAP1 using lentivirus shRNAs significantly inhibited cell proliferation by inducing cell cycle arrest in S phase in concordance with the decrease of CDK2, CDC25A, and cyclin A, and resulted in increased cell apoptosis and invasive repression in GBC cell lines in vitro. Furthermore, knockdown of YAP1 also inhibited tumor growth in vivo. Additionally, we demonstrated that the activation of the AXL/MAPK pathway was involved in the oncogenic functions of YAP1 in GBC. These results demonstrated that YAP1 is a putative oncogene and represents a prognostic marker and potentially a novel therapeutic target for GBC.

Bufalin induces cell cycle arrest and apoptosis in gallbladder carcinoma cells.

Bufalin, a major digoxin-like immunoreactive component of the Chinese medicine Chan Su, has been shown to exert a potential for anticancer activity against various human cancer cell lines in vitro. However, no detailed studies have so far been reported on its action on human gallbladder carcinoma cells. In this study, bufalin remarkably inhibited growth in human gallbladder cancer cells by decreasing cell proliferation, inducing cell cycle arrest and apoptosis in a dose-dependent manner. Bufalin also disrupted the mitochondrial membrane potential (ΔΨm) and regulated the expression of cell cycle and apoptosis regulatory molecules. Activation of caspase-9 and the subsequent activation of caspase-3 indicated that bufalin may be inducing mitochondria apoptosis pathways. Intraperitoneal injection of bufalin for 3 weeks significantly inhibited the growth of gallbladder carcinoma (GBC-SD) xenografts in athymic nude mice. Taken together, the results indicate that bufalin may be a potential agent for the treatment of gallbladder cancer.

Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway.

Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis.

Effects of oxymatrine on the apoptosis and proliferation of gallbladder cancer cells.

Gallbladder carcinoma is the most common malignancy of the biliary tract and is associated with a very poor outcome. The aim of the present study was to investigate the effects of oxymatrine (OM) on gallbladder cancer cells and the possible mechanism of its effects. The effects of OM on the proliferation of gallbladder cancer cells (GBC-SD and SGC-996) were investigated using cell counting kit-8 and colony formation assays. Annexin V/propidium iodide double staining was performed to investigate whether OM could induce apoptosis in gallbladder cancer cells. The mitochondrial membrane potential (ΔΨm) and expression of apoptosis-associated proteins were evaluated to identify a mechanism for the effects of OM. In addition, the RNA expression of relevant genes was measured by qRT-PCR using the SYBR Green method. Finally, a subcutaneous implantation model was used to verify the effects of OM on tumor growth in vivo. We found that OM inhibited the proliferation of gallbladder cancer cells. In addition, Annexin V/propidium iodide double staining showed that OM induced apoptosis after 48 h and the ΔΨm decreased in a dose-dependent manner after OM treatment. Moreover, the activation of caspase-3 and Bax and downregulation of Bcl-2 and nuclear factor κB were observed in OM-treated cells. Finally, OM potently inhibited in-vivo tumor growth following subcutaneous inoculation of SGC-996 cells in nude mice. In conclusion, OM treatment reduced proliferation and induced apoptosis in gallbladder cancer cells, which suggests that this drug may serve as a novel candidate for adjuvant treatment in patients with gallbladder cancer.

[Relationship between mesenchymal stem cells and liver cancer recurrence after liver transplantation in mice].

OBJECTIVE: To explore the relationship between mesenchymal stem cells (MSCs) and liver cancer recurrence after liver transplantation in mice. METHODS: The recurrent murine model of hepatocellular carcinoma (HCC) after liver transplantation was established by transplanting tumor cells of hind paw pads. MSCs labeled with green fluorescent protein (GFP) were injected into the marrow cavity of 615 mice after successful modeling. And the proliferation of MSCs in marrow cavity was observed under stereoscopic fluorescence microscope. MSCs labeled with red fluorescent protein (RFP) were injected into tail vein of mice during tumor dissection. The migration of GFP and RFP- labeled MSCs were tracked before and after tumor recurrence. After recurrence, the mice were sacrificed and the recurrent lesions harvested for conforming pathological type by biopsy. RESULTS: The rate of success modeling was 37.5%. Both gross morphology and pathological examination corresponded to typical HCC manifestations. Thirty mice were detected by GFP/RFP fluorescence for a recurrence of HCC. The outcomes were GFP+RFP (n = 4), GFP (n = 1) and neither (n = 25). CONCLUSIONS: The presence of MSCs in host may be one of important reasons for recurrent HCC after liver transplantation.It helps to support the traditional view of residual tumor cells mediating the relapse and metastasis of HCC.

[Anti-tumor effect of 5-FU-PLLA-CNTs on human gastric carcinoma cell lines in vitro].

OBJECTIVE: To prepare cisPLLAtin-loaded polylactic acid/cnts, and to study the anti-tumor effect of 5-FU-PLLA-CNTs on human gastric carcinoma cell lines(MGC803 and MNK45). METHODS: 5-FU-PLLA-CNTs were prepared with ultrasound emulsification. The morphology of 5-FU-PLLA-CNTs was determined by scanning electron microscope(SEM), and its drug loading and drug release curve in vitro were detected by UV-Vis-NIR spectrophotometer. Cells were divided into experiment, positive control and negative control groups. CCK8 method was used to test the cytotoxic effect of 5-FU-PLLA-CNTs in different concentrations on MGC803 and MNK45 cell proliferation. Flow cytometry was employed to measure the apoptotic rate of MGC803 and MNK45 cells before and after the intervention of 5-FU-PLLA-CNTs. RESULTS: Deep layer film of 5-FU-PLLA-CNTs was successfully established, whose drug-load rate was(4.54±0.43)%, entrapment rate was(21.56±2.36)%. In vitro release test showed release rate within 24 h of 5-FU-PLLA-CNTs was 23.9% in a as lowly increasing manner, and accumulating release rate was 85.3% at day 31. CCk8 experiment revealed, as compared to control group, 5-FU-PLLA-CNTs significantly inhibited the proliferation of two cell lines in dose-dependent and time-dependent manner. The best 5-FU-PLLA-CNTs concentration of inhibition for human gastric cancer cell lines was 1 mg/well. Flow cytometry indicated the apoptotic rate of MGC803 and MNK45 cells in experiment group treated by 1 mg/well 5-FU-PLLA-CNTs significantly increased as compared to negative control group (P<0.05), while the difference was not significant as compared to positive control group (P>0.05). CONCLUSION: The 5-FU-PLLA-CNTs has good drug sustained-release capacity, and can significantly kill and inhibit the proliferation of MGC803 and MNK45 cell lines.

Oridonin induces apoptosis and cell cycle arrest of gallbladder cancer cells via the mitochondrial pathway.

BACKGROUND: Gallbladder cancer is the most frequent malignancy of the bile duct with high aggressive and extremely poor prognosis. The main objective of the paper was to investigate the inhibitory effects of oridonin, a diterpenoid isolated from Rabdosia rubescens, on gallbladder cancer both in vitro and in vivo and to explore the mechanisms underlying oridonin-induced apoptosis and cell cycle arrest. METHODS: The anti-tumor activity of oridonin on SGC996 and NOZ cells was assessed by the MTT and colony forming assays. Cell cycle changes were detected by flow cytometric analysis. Apoptosis was detected by annexin V/PI double-staining and Hoechst 33342 staining assays. Loss of mitochondrial membrane potential was observed by Rhodamine 123 staining. The in vivo efficacy of oridonin was evaluated using a NOZ xenograft model in athymic nude mice. The expression of cell cycle- and apoptosis-related proteins in vitro and in vivo was analyzed by western blot analysis. Activation of caspases (caspase-3, -8 and -9) was measured by caspases activity assay. RESULTS: Oridonin induced potent growth inhibition, S-phase arrest, apoptosis, and colony-forming inhibition in SGC996 and NOZ cells in a dose-dependent manner. Intraperitoneal injection of oridonin (5, 10, or 15 mg/kg) for 3 weeks significantly inhibited the growth of NOZ xenografts in athymic nude mice. We demonstrated that oridonin regulated cell cycle-related proteins in response to S-phase arrest by western blot analysis. In contrast, we observed inhibition of NF-κB nuclear translocation and an increase Bax/Bcl-2 ratio accompanied by activated caspase-3, caspase-9 and PARP-1 cleavage after treatment with oridonin, which indicate that the mitochondrial pathway is involved in oridonin-mediated apoptosis. CONCLUSIONS: Oridonin possesses potent anti-gallbladder cancer activities that correlate with regulation of the mitochondrial pathway, which is critical for apoptosis and S-phase arrest. Therefore, oridonin has potential as a novel anti-tumor therapy for the treatment of gallbladder cancer.

Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer.

Thioridazine, an antipsychotic drug, has been reported to induce apoptosis in various types of cancer cells, with specificity on targeting cancer stem cells (CSCs). However, whether it elicits anticancer effects in gastric cancer has never been reported. In the present study, we examined the ability of thioridazine to induce cell death in the gastric cancer cell lines NCI-N87 and AGS, and detected its in vivo tumor inhibition capacity. Thioridazine elicited cytotoxic effects on NCI-N87 and AGS cells in a dose-dependent manner, and inhibited the colony formation abilitiy of the NCI-N87 and AGS cells. Thioridazine treatment induced nuclear fragmentation, increased the proportion of sub-G1 phase cells, and elevated the percentage of Annexin V-positive cells, suggesting the occurrence of apoptosis. Moreover, thioridazine induced gastric cancer cell apoptosis in a caspase-dependent manner, as shown by a decrease in the precursors of casapse-9, caspase-8 and caspase-3, and by the ability of the caspase inhibitor Z-VAD-FMK to reverse the cytotoxic effect of thioridazine. JC-1 staining further revealed that thioridazine induced gastric cancer cell apoptosis via the mitochondrial pathway. In addition, thioridazine pretreatment inhibited the growth of NCI-N87 cell-derived tumors. The present study demonstrated that the antipsychotic drug thioridazine possesses anti-gastric cancer ability through in vitro and in vivo experiments, suggesting thioridazine as a potential drug in gastric cancer therapy.

Baicalin induces apoptosis of gallbladder carcinoma cells in vitro via a mitochondrial-mediated pathway and suppresses tumor growth in vivo.

Baicalin, the main active ingredient in the Scutellaria baicalensis (SB), is prescribed for the treatment of various inflammatory diseases and tumors in clinics in China. In the present study, we evaluated the antitumor activity of baicalin for gallbladder carcinoma and the underlying mechanisms both in vitro and in vivo. Our results indicate that baicalin induced potent growth inhibition, cell cycle arrest, apoptosis and colony-formation inhibition in a dose-dependent manner in vitro. We observed inhibition of NF-κB nuclear translocation, up-regulation of Bax and down-regulation of Bcl-2, as well as increased caspase-3 and caspase-9 expression after baicalin treatment in vitro and in vivo, which indicates that the mitochondrial pathway was involved in baicalin-induced apoptosis. In addition, daily intraperitoneally injection of baicalin (15, 30 and 60 mg/kg) for 21 days significantly inhibited the growth of NOZ cells xenografts in nude mice, which improved the survival of baicalin-treated mice. In summary, baicalin exhibited a significant anti-tumor effect by suppressing cell proliferation, promoting apoptosis, and inducing cell cycle arrest in vitro, and by suppressing tumor growth and improving survival in vivo, which suggested that baicalin represents a novel therapeutic option for gallbladder carcinoma.

Role of polymorphisms of the IGF2 and IGFBP3 genes and risk of gastric carcinoma in China.

BACKGROUND: The insulin-like growth factor signaling pathway plays an important role in the modulation of cell growth and proliferation. The aim of this study was to investigate the role of polymorphisms of the insulin-like growth factor 2 (IGF2) and IGF-binding protein 3 (IGFBP3) genes, which encode key proteins of this pathway, as risk factors for gastric carcinoma (GC). METHODS: A case-control study including 404 histologically confirmed GC patients and 424 healthy controls of the same ethnicity was conducted to retrospectively investigate the genetic polymorphisms of two genes, IGF2+820A>G (rs680) and IGFBP3 A-202C (rs2854744). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using Logistic regression. RESULTS: The IGF2 genetic variants examined contributed to GC risk individually (OR, 1.26; 95% CI, 1.08-1.46). The genotype frequencies of IGFBP3 A-202C were not significantly different between the cancer cases and controls (P > 0.05). Compared to the IGF2 AA genotype, carriers of one variant combined genotype were more pronounced among young subjects (<60 years), male subjects, never smokers, and those with a family history of cancer (OR = 1.36, 95% CI = 1.09-1.72, P < 0.05; OR = 1.61, 95% CI = 1.28-2.08, P < 0.05; OR = 1.46, 95% CI = 1.11-1.98, P < 0.05; OR = 1.53, 95% CI = 0.91-2.6, P < 0.05; respectively). Moreover, when the combined effects of the risk genotypes were investigated, significant associations were detected between highrisk genotypes in IGF2 and IGFBP3 (OR, 2.47; 95% CI, 1.75-3.49). CONCLUSIONS: Our results suggest that polymorphic variants of the IGF2 genes modulate gastric carcinogenesis. Moreover, when the IGF2 and IGFBP3 variants are evaluated together, a greater effect on GC risk is observed.

Evaluation of two inflammation-based prognostic scores in patients with resectable gallbladder carcinoma.

BACKGROUND: Survival after surgery for gallbladder cancer is generally poor. A number of inflammation-based prognostic scores have been established to help predict survival after surgery for several types of cancer. The objective of this study was to analyze and compare the utility of two inflammation-based prognostic scores, the Glasgow prognostic score (GPS) and the neutrophil-to-lymphocyte ratio (NLR), for predicting survival in patients with gallbladder cancer after surgery with curative intent. METHODS: We retrospectively reviewed the medical records of 85 patients with histologically confirmed, resectable gallbladder carcinoma (GBC), who were to receive curative surgery in our department. Univariate and multivariate analyses were performed to evaluate the relationship between the variables to overall survival (OS). RESULTS: A significant difference was detected in OS in patients with low and high GPS and NLR scores. Univariate analyses using clinicopathological characteristics revealed that tumor differentiation; tumor invasion; lymph node metastasis; tumor, node, metastasis classification system stage; positive margin status; combined common bile duct resection; serum levels of C-reactive protein, albumin, carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen, and CA125; white blood cell count; and GPS and NLR were all associated with OS. Among these characteristics, multivariate analysis demonstrated that a high GPS was independently associated with poorer OS, together with tumor invasion, lymph node metastasis, and positive margin status. CONCLUSIONS: GPS is superior to NLR with respect to its prognostic value for patients with GBC after surgery with curative intent. GPS is not only associated with tumor progression but is also an independent marker of poor prognosis.

[Anti-tumor effects of DDP-PLLA-CNTs on human cholangiocarcinoma cell line in vitro].

OBJECTIVE: To explore the antitumor effects of DDP-PLLA-CNTs on human cholangiocarcinoma cell line. METHODS: DDP-PLLA-CNTs were prepared with the method of ultrasound emulsification. The morphology of DDP-PLLA-CNTs was determined by scanning electron microscope (SEM). And its drug loading and drug release curve in vitro was detected by UV-Vis-NIR spectrophotometer. CCK8 was used to test the cytotoxic effects of DDP-PLLA-CNTs at different concentrations on QBC939 cell proliferation.Flow cytometry was employed to measure the changes of apoptotic rate. RESULTS: With excellent controlled-release characteristic of in vitro drug release, DDP-PLLA-CNTs inhibited the proliferation and significantly increased the apoptotic rate of QBC939 cell line. CONCLUSION: DDP-PLLA-CNTs have drug sustained-release characteristics and can significantly inhibit the proliferation of QBC939 cell line.