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The problem of off-policy evaluation (OPE) has long been advocated as one of the foremost challenges in reinforcement learning. Gradient-based and emphasis-based temporal-difference (TD) learning algorithms comprise the major part of off-policy TD learning methods. In this work, we investigate the derivation of efficient OPE algorithms from a novel perspective based on the advantages of these two categories. The gradient-based framework is adopted, and the emphatic approach is used to improve convergence performance. We begin by proposing a new analogue of the on-policy objective, called the distribution-correction-based mean square projected Bellman error (DC-MSPBE). The key to the construction of DC-MSPBE is the use of emphatic weightings on the representable subspace of the original MSPBE. Based on this objective function, the emphatic TD with lower-variance gradient correction (ETD-LVC) algorithm is proposed. Under standard off-policy and stochastic approximation conditions, we provide the convergence analysis of the ETD-LVC algorithm in the case of linear function approximation. Further, we generalize the algorithm to nonlinear smooth function approximation. Finally, we empirically demonstrate the improved performance of our ETD-LVC algorithm on off-policy benchmarks. Taken together, we hope that our work can guide the future discovery of a better alternative in the off-policy TD learning algorithm family.

Emphatic temporal-difference (TD) learning (Sutton et al. 2016) is a pioneering off-policy reinforcement learning method involving the use of the followon trace. The recently proposed Gradient Emphasis Learning (GEM, Zhang et al. 2020) algorithm is used to fix the problems of unbounded variance and large emphasis approximation error introduced by the followon trace from the perspective of stochastic approximation. In this paper, we rethink GEM and introduce a novel generalized GEM(β) algorithm to learn the true emphasis. The key to the construction of the generalized GEM(β) algorithm is introducing a tunable hyper-parameter β that is not necessarily the same as the discount factor γ to the GEM operator. We then apply the emphasis estimated by the proposed GEM(β) algorithm to the value estimation gradient and the policy gradient, respectively, yielding the corresponding emphatic TD variant for off-policy evaluation and actor-critic algorithm for off-policy control. Finally, we demonstrate empirically the advantage of the proposed algorithms across a range of problems, for both off-policy evaluation and off-policy control, and for both linear and nonlinear function approximation.

Background. Colon adenocarcinoma (COAD) is a malignancy with a high incidence and is associated with poor quality of life. Dysfunction of circadian clock genes and disruption of normal rhythms are associated with the occurrence and progression of many cancer types. However, studies that systematically describe the prognostic value and immune-related functions of circadian clock genes in COAD are lacking. Methods. Genomic data obtained from The Cancer Genome Atlas (TCGA) database was analyzed for expression level, mutation status, potential biological functions, and prognostic performance of core circadian clock genes in COAD. Their correlations with immune infiltration and TMB/MSI score were analyzed by Spearman’s correlation analysis. Pearson’s correlation analysis was performed to analyze their associations with drug sensitivity. Lasso Cox regression analysis was performed to construct a prognosis signature. Moreover, an mRNA-miRNA-lncRNA regulatory axis was also detected by ceRNA network. Results. In COAD tissues, the mRNA levels of CLOCK, CRY1, and NR1D1 were increased, while the mRNA levels of ARNTL, CRY2, PER1, PER3, and RORA were decreased. We also summarized the relative genetic mutation variation landscape. GO and KEGG pathway analyses demonstrated that these circadian clock genes were primarily correlated with the regulation of circadian rhythms and glucocorticoid receptor signaling pathways. COAD patients with high CRY2, NR1D1, and PER2 expression had worse prognosis. A prognostic model constructed based on the 9 core circadian clock genes predicted the COAD patients’ overall survival with medium to high accuracy. A significant association between prognostic circadian clock genes and immune cell infiltration was found. Moreover, the lncRNA KCNQ1OT1/hsa-miRNA-32-5p/PER2/CRY2 regulatory axis in COAD was also detected through a mRNA-miRNA-lncRNA network. Conclusion. Our results identified CRY2, NR1D1, and PER2 as potential prognostic biomarkers for COAD patients and correlated their expression with immune cell infiltration. The lncRNA KCNQ1OT1/hsa-miRNA-32-5p/PER2/CRY2 regulatory axis was detected in COAD and might play a vital role in the occurrence and progression of COAD.

397 Background: ASKB589 is a humanized IgG1 monoclonal antibody against Claudin 18.2 (CLDN18.2) with high affinity and enhanced antibody-dependent cellular cytotoxicity activity. We report preliminary safety and efficacy data from an ongoing Phase I/II, first-in-human, dose-escalation and expansion study of ASKB589 in patients (pts) with advanced solid tumors (NCT04632108). Methods: A two-part study was initiated to determine the maximum tolerated dose (MTD), safety and tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ASKB589 as monotherapy (Part A) and in combination with chemotherapy (Part B). Each part used a modified 3 + 3 dose escalation design. Responses were assessed per RECIST 1.1 every 2 cycles (6 weeks). Adverse events (AEs) were graded using CTCAE v5.0. In Part A, pts with heavily pre-treated solid tumors received ASKB589 intravenously (IV) at doses of 0.3, 1, 3, 6, 10,15 or 20mg/kg every 3 weeks (Q3W). In Part B, pts with gastric/gastro-esophageal junction (G/GEJ) cancers received ASKB589 IV at doses of 3, 6, 10 or 15 mg/kg Q3W in combination with capecitabine plus oxaliplatin. Results: As of September 9, 2022, 51 pts received ASKB589 and no drug limiting toxicity (DLT) was observed. In expansion, pts have been enrolled into 6, 10, 15 mg/kg doses. In Part A, 17 pts were enrolled in escalation and 13 in expansion. All pts had metastatic disease, and most (90%) had ≥2 lines of prior therapy. 24 (80%) pts had treatment-related adverse events (TRAEs), the most common being nausea (53%), vomiting (43%), hypoalbuminemia (40%) and loss of appetite (30%). While the majority of TRAEs were grade 1 or 2, 3 pts (10%) had grade 3 events. For the 9 evaluable pts (G/GEJ cancer who received ≥10 mg/kg ASKB589 with at least one post-baseline tumor assessment), 5 pts (45%) had decreases in tumor size (range 1-38% from baseline). 2 pts achieved a partial response (PR) for an objective response rate (ORR) of 22%. In addition, 6 pts had stable disease (SD) for a disease control rate (DCR) of 89%. In Part B, 13 pts were enrolled in escalation and 8 in expansion. These pts were with advanced disease (95% stage IV) and had no prior systemic treatment in this setting. 17 (81%) pts had TRAEs, the most common being nausea (76%), vomiting (66%), hypoalbuminemia (52%), granulocytopenia (38%) and hypoleukemia (33%). While the majority of TRAEs were grade 1 or 2, 8 pts (38%) had grade 3 events. For the 12 evaluable pts (G/GEJ cancer who received ≥6 mg/kg ASKB589 with at least one post-baseline tumor assessment), all had decreases in tumor size (range 6-66% from baseline). 9 pts achieved PR for an ORR of 75%. In addition, 3 pts had SD for a DCR of 100%. The PK profile showed dose-related increases in drug exposure across study doses. Conclusions: ASKB589 showed a manageable safety profile up to doses of 20 mg/kg and promising antitumor activity, both as monotherapy and in combination with chemotherapy. Clinical trial information: NCT04632108 .

Background Long noncoding RNA (lncRNA) TUG1 has been reported to display a pivotal role in the tumorigenesis and malignant progression of various types of cancers, including stomach adenocarcinoma (STAD). However, the contribution of aberrant expression of TUG1 and the mechanism by which it serves as a competing endogenous RNA (ceRNA) in STAD remains largely obscure. Methods The human STAD cell lines (MGC‐803 and AGS), human normal gastric epithelial cell line (GES‐1), human umbilical vein endothelial cells (HUVECs), and human embryonic kidney cells (HEK293T) were purchased and cultured to investigate the roles of TUG1 in STAD. Twenty BALB/c nude mice were purchased to establish a xenograft model to explore the roles of TUG1 in vivo. Results Bioinformatics analysis revealed that TUG1 was upregulated in STAD, of which expression was negatively and positively correlated with miR‐29c‐3p and VEGFA, respectively. Functional analyses indicated that TUG1 functioned as an oncogene to promote malignant behaviors (proliferation, migration, and angiogenesis) of STAD cells; whereas miR‐29c‐3p exerted the opposite role. Mechanistically, the interaction between miR‐29c‐3p with TUG1 and VEGFA was demonstrated. It was observed that miR‐29c‐3p could reverse the TUG1‐induced promotion effect on cell proliferation, migration, and angiogenesis in STAD. Furthermore, TUG1 overexpression promoted STAD cell proliferation, metastasis, and angiogenesis, whereas VEGFA silence restored these effects, both in vitro and in vivo. Conclusion This finding confirmed that lncRNA TUG1 acts as a ceRNA for miR‐29c‐3p to promote tumor progression and angiogenesis by upregulating VEGFA, indicating TUG1 as a therapeutic target in STAD management., TUG1 promotes STAD progression by regulating VEGFA in vitro and in vivo. (A) RT‐qPCR and WB analysis respectively examined the expression of VEGFA. TUG1 overexpression vector was transfected alone or combined with sh‐VEGFA#2 or sh‐NC into MGC‐803 cells. (B) CCK‐8 assay examined cell proliferation. (C) Western blot detected the expression of BMP4, ICAM1, and VCAM1. (E) Angiogenesis assessed by the tube formation of HUVECs. (D) Transwell assay evaluated cell migration ability. (F) The representative photograph, (G) volume, and (H) weight of xenograft tumors. (I) The expression of TUG1 and VEGFA in xenograft tumors by RT‐qPCR. (J) WB analysis detected the protein levels of Ki‐67, BMP4, ICAM1, VCAM1, and CD31 in xenograft tumors.

Side-to-side jejunoileal bypass with proximal loop ligation (SSJIBL) has significant glucose-lowering and weight-control effects; however, no study has elucidated which segment is most effective in SSJIBL. This study investigated the effect of proximal small intestinal bypass (PSIB), middle small intestinal bypass (MSIB), and distal small intestinal bypass (DSIB) on metabolic improvement in streptozotocin (STZ)-induced diabetic rats.STZ-induced diabetic rats were divided into four groups: PSIB, MSIB, DSIB, and sham-operated. The primary outcome measures were body weight, food intake, fasting blood glucose (FBG) levels, oral glucose tolerance (OGTT), insulin tolerance (ITT), serum insulin, gut hormones, serum lipid profile, and liver function levels.Global body weight in the DSIB group was lower than that in the PSIB group. The global food intake in the PSIB group was lower than that in the MSIB group. The PSIB group had a slightly better glucose-lowering effect than the MSIB and DSIB groups. The PSIB, MSIB, and DSIB groups all had improvement in insulin sensitivity at postoperative week 6. The MSIB group exhibited the best improvement in lipid homeostasis. Serum insulin and leptin levels were higher, and serum ghrelin levels were lower in the operated groups than in the sham group.This study provides experimental evidence that PSIB surgery induces a better glucose-lowering effect than DSIB surgery, and MSIB induced the best improvement in lipid homeostasis, whereas DSIB was even more advantageous in terms of weight control in the STZ-induced diabetic rat model.

Background Repeat hepatectomy plays a key role in recurrent hepatic tumors. However, it is still unknown whether laparoscopic hepatectomy is suitable for recurrent liver cancers. The aim of this meta-analysis is to evaluate the efficacy and feasibility of laparoscopic repeat hepatectomy (LRH) compared with open repeat hepatectomy (ORH). Methods Several databases, including Web of Science, PubMed, The Cochrane Library and Ovid, were retrieved from date of inception to 31st March 2018. All articles comparing LRH and ORH were identified. Tumor characteristics and perioperative outcomes including resection type, operation time, blood loss, transfusion, complications and hospital stay were evaluated. Data were extracted and calculated using random- or fixed-effect models. Results A total of seven non-randomized observational clinical articles including 443 patients were analyzed. LRH was associated with significantly lower blood loss (WMD = −389.09, 95% CI -628.34 to −149.84, P = 0.001), transfusion (OR 0.16, 95% CI 0.03–0.74, P = 0.019) as well as limited hospital stay (WMD = −4.00, 95% CI -6.58 to −1.42, P = 0.002). No statistical difference was found in the field of tumor characteristics and other perioperative outcomes. In the sensitivity analysis of case-match studies, LRH was associated with significant limited hospital stay, but with significant longer operation time. There were 8 (1.8%, range 0–13.3%) cases of conversion in LRH group. Conclusions Based on the results of these limited data, LRH is as feasible and efficient as ORH by expert surgeons in selected patients, whose cancer is resectable at the time of surgery and who have Child-Pugh A or B cirrhosis.

Momordica charantia L. (Cucurbitaceae) is a popular vegetable and traditional folk medicine, that has been used for hundreds of years. In this study, three undescribed cucurbitane-type triterpene glycosides furpyronecucurbitane A, goyaglycoside I and charantagenin F along with nine known compounds were isolated from the immature fruit of Momordica charantia L. Their structures were identified on the basis of extensive 1D, 2D NMR and HRESIMS spectroscopy analysis. All isolated compounds were examined for their anti-hepatic fibrosis activity against murine hepatic stellate cells (t-HSC/Cl-6) and anti-hepatoma activity against two kinds of liver cancer cell lines (HepG2 and Hep3B). Among them, karaviloside III exhibited excellent inhibitory activity against activated t-HSC/Cl-6 cells and cytotoxic activity against Hep3B and HepG2 cell lines with IC50 values of 3.74 ± 0.13, 16.68 ± 2.07 and 4.12 ± 0.36 μM, respectively, which may potential to be developed as a chemotherapy agent for treatment hepatic fibrosis or carcinoma and protection against both diseases.

This study focused on the role of methionine (MET) in the autophagy of gastric cancer stem cells (GCSCs) and aims to elaborate its regulatory mechanism. In the present study, the GCSCs were isolated from human gastric cancer cell lines using an anti-CD44 antibody, and then cultured in MET(+) homocysteine (HCY)(−) or MET(−)HCY(+) medium. In MET(+)HCY(–)treated GCSCs, autophagy was suppressed, the methylation and phosphorylation of RAB37 were elevated, and miR-200b expression was down-regulated. Lentiviral vector (LV-) carrying methionine-γ lyase (an enzyme that could specifically lyse MET; Metase) promoted autophagy, reduced the methylation and phosphorylation of RAB37, and up-regulated miR-200b expression in MET(+)HCY(–)-treated GCSCs. Then, we found that miR-200b suppressed the expression of protein kinase C α (PKCα), a protein that could inactivate RAB37 through promoting its phosphorylation. LV-Metase down-regulated RAB37 phosphorylation via miR-200b/PKCα, thus promoting the RAB37-mediated autophagy and suppressing cell viability in MET(+)HCY(–)treated GCSCs. Finally, the in vivo study proved that LV-Metase treatment inhibited tumor growth through up-regulating RAB37 expression. In conclusion, MET suppressed RAB37 expression via enhancing its methylation and suppressed RAB37 activity via miR-200b/PKCα axis, thus repressing RAB37-mediated autophagy in GCSCs. The supplementation of Metase lysed MET, thus inducing the autophagy of GCSCs and inhibiting tumor growth.

In this study, we introduced 1, 2, 4-triazole groups into panaxadiol (PD) to obtain 18 panaxadiol triazole derivatives. Five cancer cells and one normal cell were evaluated for cytotoxicity by MTT assay. The results showed that most of the derivatives could inhibit cancer cell proliferation, and the anti-proliferative activity of compound A1 was the most significant. For HepG-2 cells, the IC50 value was 4.21 ± 0.54 μM, which was nearly 15 times higher than the activity of PD. Further studies showed that compound A1 could induce apoptosis in HepG-2 cells, and could enhance the expression of Cl-caspase-3, Cl-caspase-9 and Cl-PARP. Moreover, Western blot analysis showed that after treating HepG-2 cells with compound A1, the expression of p53 protein was increased and the ratio of Bax/Bcl-2 was gradually increased. The cytoplasmic Bax is then translocated to the mitochondria, causing the release of Cyt c protein. Therefore, the results indicate that compound A1 induces apoptosis through the mitochondrial pathway and can be used the potential to develop new anti-proliferative agents.

Ring finger protein 2 (RNF2), as a well-known E3 ligase, has an oncogenic role in various cancers. The role of RNF2 in colon cancer is still unknown. The aim of this work is to determine the biological role of RNF2 in colon cancer. We first examined the expression of RNF2 and interferon regulatory factor 4 (IRF4) in colon cancer patients and colon cancer cell lines (SW480 and HCT116). Compared with normal tumor-adjacent tissues, RNF2 was up-regulated whereas IRF4 was down-regulated in the colon cancer tissues. RNF2 was also up-regulated in colon cancer cells with respect to human fetal colon epithelial cells. RNF2 overexpression enhanced the ability of proliferation, migration and invasion of SW480 cells, whereas RNF2 knockdown caused an opposite result in HCT116 cells. Furthermore, a tumor xenograft model was constructed to verify the impact of RNF2 overexpressed-SW480 cells on tumor growth. RNF2 up-regulation elevated Ki-67 proliferation index, accelerated the growth of tumor tissues, and led to severe colon tissue damage in the tumor xenograft mice. In addition, RNF2 interacted with IRF4, and repressed IRF4 protein expression. IRF4 was a substrate of RNF2, and RNF2 promoted the ubiquitination and degradation of IRF4. RNF2 overexpression increased the ability of proliferation, migration and invasion in SW480 cells by promoting the ubiquitination and degradation of IRF4. In conclusion, this work demonstrated that RNF2 promoted tumor growth in colon cancer by regulating ubiquitination and degradation of IRF4. Thus, RNF2 may be served as a potential therapeutic target for colon cancer.

Acorn has been used as a functional food with numerous nutritional and active ingredients. In this study, 3 new triterpenoids, together with 22 known compounds were isolated from acorns (Quercus liaotungensis) and further confirmed by NMR. In order to disclose the hypoglycaemic ingredients, the extracts and all the discovered compounds were researched for enzyme inhibition using in-vitro assays on α-amylase, α-glucosidase, and protein-tyrosine phosphatase 1B (PTP1B). The results suggested that 75% EtOH, PE, EtOAc, and n-BuOH extracts of acorns all exhibited potent inhibitory activities against PTP1B and α-glucosidase. Most of the compounds showed strong inhibitory effects on PTP1B and α-glucosidase, especially new compounds and compound 12, their IC50 values were about 6-fold to 20-fold lower than positive control, all showed competitive inhibitory pattern. The result suggested that triterpenoids from acorns are potential functional food ingredients that can be used as new anti-diabetic agent.

Background: Stem cells isolated from peripheral blood of gastric adenocarcinoma patients have noninvasive advantages. However, at present, there is no simple and effective separation technique. Purpose: In this study, CD133+ cells were isolated from peripheral blood of patients with gastric adenocarcinoma by using specific immunomagnetic particles, and the immunology of subcultured cells was identified to evaluate whether the immune magnetic particle separation had any effect on the cells themselves. Methods: Immune magnetic particles, made by a specific technique, are used to sort out the cells whose membrane could express CD133 from peripheral blood of gastric adenocarcinoma patients. By observing the sorted cells within serum-free culturing, we compare the differences in morphology and proliferation ability between the collected cells and cells from a standard tumor cell line. At the same time, an immunofluorescence method is used to detect the expression of the CD133 antibody. Moreover, this study explores the inhibition effect on gastric adenocarcinoma stem cell growth when combining 5-fluorouracil and methionine enzymes. Results and Conclusions: The specific immunomagnetic particles have a small diameter and strong sorting characteristics. In the experiment, there were 20 patients with gastric adenocarcinoma. CD133+ cells were separated successfully from peripheral blood of 13 patients (65%), among which subcultured cells of 9 cases (69.2%) were found to express CD44+ antigens. The sorted cells grew vigorously with a variety of morphologies in non-inducing culture, while the cells induced by β transforming growth factor presented slow growth and uniform morphology. There was a significant difference (P < 0.05) in cell proliferation between these two groups and the standard tumor cell line. In addition, 5-fluorouracil combined with methionine enzyme inhibited the growth of gastric adenocarcinoma stem cells significantly (P < 0.05). Accordingly, the CD133+/CD44+ cells from peripheral blood of gastric adenocarcinoma patients, sorted by specific immune magnetic particles, had clear stem cell properties as determined by cell function and structure. This lays a foundation for gastric adenocarcinoma stem cell extraction, culture and further research on stem cell characteristics.

Momordica charantia L. has been widely used in different countries as a functional food source, particularly as a remedy for type 2 diabetes. In the present study, 21 cucurbitane-type triterpenoids, including two new compounds named charantoside IX and X ( 1 − 2 ), were isolated from the extract of M . Charantia L. Their chemical structures were identified by 1D, 2D-NMR and FT-ICR-MS techniques. Three anti-diabetes target assays of all triterpenoids were carried out, with all compounds exhibiting α -glucosidase inhibitory activity. Particularly, compounds 6 , 9 and 11 exhibited excellent α -glucosidase inhibitory activity with IC 50 values of 10.19, 28.55, and 20.20 μM, respectively. Some of the tested isolates showed inhibitory activity against the protein tyrosine phosphatase 1B (PTP1B) and α -amylase, with compound 6 exhibiting the strongest activity against PTP1B. These chemical and biological results indicated that cucurbitane triterpenoids in functional foods may represent attractive candidates for regulation of blood glucose levels.

lncRNA-TUG1 (Taurine upregulated 1) is up-regulated and highly correlated with poor prognosis and disease status in osteosarcoma. TUG1 knockdown inhibits osteosarcoma cell proliferation, migration and invasion, and promotes apoptosis. However, its mechanism of action has not been well addressed. Growing evidence documented that lncRNA works as competing endogenous (ce)RNAs to modulate the expression and biological functions of miRNA. As a putative combining target of TUG1, miR-144-3p has been associated with the progress of osteosarcoma. To verify whether TUG1 functions through regulating miR-144-3p, the expression levels of TUG1 and miR-144-3p in osteosarcoma tissues and cell lines were determined. TUG1 was upregulated in osteosarcoma tissues and cell lines, and negatively correlated with miR-144-3p. TUG1 knockdown induced miR-144-3p expression in MG63 and U2OS cell lines. Results from dual luciferase reporter assay, RNA-binding protein immuno-precipitation (RIP) and applied biotin-avidin pull-down system confirmed TUG1 regulated miR-144-3p expression through direct binding. EZH2, a verified target of miR-144-3p was upregulated in osteosarcoma tissues and negatively correlated with miR-144-3p. EZH2 was negatively regulated by miR-144-3p and positively regulated by TUG1. Gain-and loss-of-function experiments were performed to analyze the role of TUG1, miR-144-3p and EZH2 in the migration and EMT of osteosarcoma cells. EZH2 over-expression partly abolished TUG1 knockdown or miR-144-3p overexpression induced inhibition of migration and EMT in osteosarcoma cells. In addition, TUG1 knockdown represses the activation of Wnt/β-catenin pathway, which was reversed by EZH2 over-expression. The activator of Wnt/β-catenin pathway LiCl could partially block the TUG1-knockdown induced osteosarcoma cell migration and EMT inhibition. In conclusion, our results showed that TUG1 plays an important role in osteosarcoma development through miRNA-144-3p/EZH2/Wnt/β-catenin pathway.

The intraoperatively rotational control of femoral shaft fractures treated with a closed intramedullary interlocking nailing is a challenging problem. A novel surgical technique that includes respective insertions of guidewires into the proximal and distal femur under the guidance of a 2-dimensional fluoroscopy-based navigation system and the measurements of the intersection angle subtended by the proximal and distal guidewires with the smartphone positional software has been designed to provide intraoperatively quantitative parameters of femoral rotation deformation. The comparison of these parameters with preoperative measurement values of the contralateral intact femur on computed tomography images was used to align the proximal and distal femur fragments based on periaxial rotation. The purpose of this study was to evaluate its clinical suitability. Ten adult patients with femoral shaft fractures were attempted to correct intraoperatively femoral rotational deformity using this novel technique. The additional operation time was 20.04 ± 3.27 minutes. The angle of femoral anteversion was 20.85° ± 4.22°, 38.14° ± 19.07°, and 22.77° ± 3.38° in the contralateral intact and preoperatively and postoperatively injured femur, respectively. The mean absolute difference between both limbs was preoperatively 21.55° ± 10.14° with a statistically significant difference ( P = .005) and postoperatively 3.24° ± 1.69° with no statistically significant difference ( P = .092). Our results showed this novel technique could become an effective tool to correct intraoperatively rotational malalignment of femoral fractures.

Impatiens balsamina L. is an edible plant and it has also been used as traditional medicine in Asia. Phytochemical investigations of the Impatiens balsamina L. flowers afforded four new triterpene saponins (Balsaminside A-D, 1 – 4 ) and six known compounds ( 5 – 10 ) which were first isolated from this plant. The structures were elucidated by extensive spectroscopic methods including NMR (1D and 2D), and HR-ESI-MS. Analysis of the bioassay result showed that all the new compound had significant cytotoxic activity against t-HSC/Cl-6 cells. The result suggested that triterpene saponins from Impatiens balsamina L. are potential functional food ingredients that can be used as new anti-hepatic fibrosis agent.

In the search for new anti-tumor agents with higher potency than our previously identified compound 1 (25-OH-PPD, 25-hydroxyprotopanaxadiol), 12 novel sulfamic and succinic acid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 1, compounds 2, 3, and 7 exhibited higher cytotoxic activity on A-549 and BGC-823 cell lines, together with lower toxicity in the normal cell. In particular, compound 2 exhibited the best anti-tumor activity in the in vitro assays, which may provide valuable data for the research and development of new anti-tumor agents.

The anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase, is responsible for the transition from metaphase to anaphase and the exit from mitosis. The anaphase promoting complex subunit 10 (APC10), a subunit of the APC/C, executes a vital function in substrate recognition. However, no research has reported the connection between APC10 and cancer until now. In this study, we uncovered a novel, unprecedented role of APC10 in tumor progression, which is independent of APC/C. First, aberrant increase of APC10 expression was validated in non-small cell lung cancer (NSCLC) cells and tissues, and the absence of APC10 repressed cell proliferation and migration. Of great interest, we found that APC10 inhibition induced cell cycle arrest at the G0/G1 phase and reduced the expression of the APC/C substrate, Cyclin B1; this finding is different from the conventional concept of the accumulation of Cyclin B1 and cell cycle arrest in metaphase. Further, APC10 was found to interact with glutaminase C (GAC), and the inhibition of APC10 weakened glutamine metabolism and induced excessive autophagy. Taken together, these findings identify a novel function of APC10 in the regulation of NSCLC tumorigenesis and point to the possibility of APC10 as a new target for cancer therapy.

Breast cancer is the most common malignant tumor among women in China, which seriously threatens women's physical and mental health. Tumorigenesis is closely related to the dysregulation of cell cycle. The cell cycle progression includes interphase and mitotic phase (M phase). Cyclin B1 is a key protein in regulating M phase, which is essential for the whole cell cycle progression. CyclinB1 can be degraded through ubiquitination mediated by the anaphase promoting complex/cyclosome (APC/C). However, the mechanism of how CyclinB1 is deubiquitinated in breast cancer still remains unclear. In this study, we discovered that CyclinB1 interacted with ubiquitin-specific peptidase 14 (USP14). Based on the deubiquitinating function of USP14, we detected the effect of USP14 on the ubiquitination of CyclinB1. Inhibiting the activity of USP14 or USP14 knockdown significantly increased the ubiquitination of CyclinB1. In accordance with this, knocking down USP14 arrested cell cycle at G2/M phase. Knocking down USP14 with siRNAs significantly inhibited the proliferation and migration of breast cancer cells. In conclusion, our study demonstrated that USP14 regulated the cell cycle of breast cancer cells by regulating the ubiquitination of CyclinB1, which will provide a solid theoretical basis for the development of anti-cancer drugs targeting USP14.

Background: Short-term outcomes after laparoscopic pancreaticoduodenectomy (LPD) seem promising, but long-term outcomes of LPD for pancreatic cancer (PC) warrant further investigation. Met...

The homopolymer of 2,8-bis(octyloxy)-dibenzothiophene-S,S-dioxide (HPSO) was synthesized by Suzuki polycondensation reaction and utilized as the light-emitting material in fluorescence-based PLED and the host material in phosphorescence-based PLED, respectively. The homopolymer HPSO possesses the LUMO/HOMO levels at −3.10 eV/−6.20 eV and the triplet energy level at 3.02 eV. Utilizing the homopolymer HPSO as the light-emitting material, the fluorescence-based device with the configuration of ITO/PEDOT:PSS/HPSO/CsF/Al displayed maximal luminous efficiency of 1.3 cd/A. Utilizing the homopolymer HPSO as the host material, the phosphorescence-based device with the configuration of ITO/PEDOT:PSS/PVK/HPSO:FIrpic/Ba/Al displayed maximal luminous efficiency of 6.6 cd/A. The results indicate that the homopolymer HPSO is a promising candidate as a new type of blue-light-emitting material for fluorescence-based PLED and a new type of host material for phosphorescence-based PLED.

Colorectal cancer is considered as the fourth leading reason of cancer-linked deaths worldwide. However, our knowledge about its pathogenic mechanism remains inadequate. MicroRNA 32 (miR-32), a member of small noncoding RNAs, has been found vital roles in tumorigenesis. This study studied its functions and underlying mechanism in colorectal cancer. The experiment revealed the obvious upregulation of miR-32 in colorectal cancer tissues and six cancer cell lines, compared with normal tissues and cells. Moreover, miR-32 upregulation reduced cell apoptosis and promoted cell proliferation and migration, while its downregulation displayed opposite effects. Dual luciferase reporter assays proved that miR-32 bound to the 3'-untranslated region (3'-UTR) of OTU domain containing 3 (OTUD3), suggesting that miR-32 directly targeted OTUD3. Further experiments demonstrated that overexpression of miR-32 could reduce the expression level of OTUD3. Furthermore, OTUD3 silence promoted proliferation and motility and decreased apoptosis for HCT116 cells and restored partly miR-32-mediated cell proliferation, migration, and antiapoptosis for colon cancer. Therefore, our study indicated that miR-32 enhanced cell proliferation and motility abilities, and inhibited apoptosis by directly targeting OTUD3 in colon cancer cells, which implied that miR-32 was hopeful to be a biomarker or target used for diagnosis and therapy of colon cancer.

Reduced autophagy has been implied in chondrocyte death and osteoarthritis. Curcumin (Cur) owns therapeutic effect against osteoarthritis (OA) and enhances autophagy in various tumor cells. Whether the cartilage protection of curcumin is associated with autophagy promotion and the potential signaling pathway involved remains unclear. The present study aimed to investigate the role of autophagy in the anti-OA activity of curcumin using spontaneous and surgically induced OA mice model. Spontaneous and surgically induced OA mice model was established and treated with Cur. Articular cartilage destruction and proteoglycan loss were scored through Safranin O/Fast green staining. Apoptotic cell death was detected with TUNEL (terminal deoxynucleotidyl transferase-mediated dTUP-biotin nick end labeling assay) staining and Western blot for caspase-3, Bcl-2 associated X protein (Bax), and Bcl-2 (B-cell lymphoma-2). Light chain 3 (LC3) immunohistochemistry was used to evaluate autophagy. In vitro, primary chondrocytes were treated with interleukin 1 beta (IL-1β) and Cur. Autophagy was inhibited using 3-methyladenine. Apoptosis and autophagy were detected using flow cytometry and Western blotting assay. Curcumin treatment enhanced autophagy, reduced apoptosis, and cartilage loss in both OA models. In vitro, curcumin treatment improved IL-1β induced autophagy inhibition, cell viability decrease, and apoptosis. Mechanistically, in vivo studies suggested curcumin promoted autophagy through regulating Akt/mTOR pathway. In conclusion, our results demonstrate that curcumin-induced autophagy via Akt/mTOR signaling pathway contributes to the anti-OA effect of curcumin.

Dual-path side-to-side jejunoileal bypass (SSJIB) can markedly ameliorate diabetes and obesity. However, whether SSJIB requires the ligation of the bypassed loop (single-path) and what is the most appropriate length of the bypassed small bowel remain unknown. The aim of this study was to evaluate the role of ligation and the length of the bypassed small bowel in mediating changes in glucose homeostasis after SSJIB in streptozotocin (STZ)-induced diabetic rats. Fourteen STZ-induced diabetic rats were randomized into two groups: one group was subjected to 50% SSJIB (SSJIB-50 group) and one group was subjected to sham surgery (sham group). Three weeks later, the SSJIB-50 group was re-operated, and the bypassed segment was ligated (SSJIBL-50 group). Three weeks later, the SSJIBL-50 group was operated again, and 60% of the length of the proximal small intestine was bypassed (SSJIBL-60 group). The measured primary outcomes were body weight, food intake, fasting blood glucose (FBG), and oral glucose tolerance test (OGTT). Body weight in the SSJIBL-60 group was lower than that in the sham group. Food intakes in the SSJIBL-50 and SSJIBL-60 groups were lower than that in the sham group. FBG and OGTT were not improved in the SSJIB-50 group compared with the sham group. However, FBG and OGTT were improved in the SSJIBL-50 group and were further improved in the SSJIBL-60 group. Ligation of the first portion of the bypassed loop is essential to SSJIB, and bypassing approximately 60% of the small intestine length may be appropriate in SSJIBL.