Generative subgoal oriented multi-agent reinforcement learning through potential field.

Multi-agent reinforcement learning (MARL) effectively improves the learning speed of agents in sparse reward tasks with the guide of subgoals. However, existing works sever the consistency of the learning objectives of the subgoal generation and subgoal reached stages, thereby significantly inhibiting the effectiveness of subgoal learning. To address this problem, we propose a novel Potential field Subgoal-based Multi-Agent reinforcement learning (PSMA) method, which introduces the potential field (PF) to unify the two-stage learning objectives. Specifically, we design a state-to-PF representation model that describes agents' states as potential fields, allowing easy measurement of the interaction effect for both allied and enemy agents. With the PF representation, a subgoal selector is designed to automatically generate multiple subgoals for each agent, drawn from the experience replay buffer that contains both individual and total PF values. Based on the determined subgoals, we define an intrinsic reward function to guide the agent to reach their respective subgoals while maximizing the joint action-value. Experimental results show that our method outperforms the state-of-the-art MARL method on both StarCraft II micro-management (SMAC) and Google Research Football (GRF) tasks with sparse reward settings.

The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization.

Mitophagy is a vital process that controls mitochondria quality, dysregulation of which can promote cancer. Oncoprotein mucin 1 (MUC1) targets mitochondria to attenuate drug-induced apoptosis. However, little is known about whether and how MUC1 contributes to mitochondrial homeostasis in cancer cells. We identified a novel role of MUC1 in promoting mitophagy. Increased mitophagy is coupled with the translocation of MUC1 to mitochondria, where MUC1 interacts with and induces degradation of ATPase family AAA domain-containing 3A (ATAD3A), resulting in protection of PTEN-induced kinase 1 (Pink1) from ATAD3A-mediated cleavage. Interestingly, MUC1-induced mitophagy is associated with increased oncogenicity of cancer cells. Similarly, inhibition of mitophagy significantly suppresses MUC1-induced cancer cell activity in vitro and in vivo. Consistently, MUC1 and ATAD3A protein levels present an inverse relationship in tumor tissues of breast cancer patients. Our data validate that MUC1/ATAD3A/Pink1 axis-mediated mitophagy constitutes a novel mechanism for maintaining the malignancy of cancer cells, providing a novel therapeutic approach for MUC1-positive cancers.

Microwave-assisted synthesis of polyethylenimine-grafted nanocellulose with ultra-high adsorption capacity for lead and phosphate scavenging from water.

Herein, polyethylenimine-grafted nanocellulose (PEIMW@NCMW) was synthetized through microwave-assisted synthesis, which was employed for Pb(II) and phosphate scavenging from water. Characterization results exhibited that the original pomegranate peel-derived cellulose could be transformed to nanometer level by microwave radiation and the amino groups were successfully grafted on the nanocellulose evenly. The adsorption performance of PEIMW@NCMW possessed outstanding improvements over that of original nanocellulose with maximum adsorption capacities reaching 916.02 mg/g for Pb(II) and 278.89 mg/g for phosphate. Furthermore, the PEIMW@NCMW had high tolerance to various co-existing ions and could maintain over 94% removal efficiency during four regeneration cycles. Additionally, the Pb(II) uptake onto PEIMW@NCMW was associated with electrostatic attraction, complexation and pore-filling, whereas high phosphate capture was achieved via H-bonding, complexation and electrostatic attraction. In summary, PEIMW@NCMW was deemed as a potential adsorbent with excellent adsorption capacity for remediation of Pb(II) and phosphate polluted water.

Erlotinib overcomes paclitaxel-resistant cancer stem cells by blocking the EGFR-CREB/GRß-IL-6 axis in MUC1-positive cervical cancer.

Cancer stem cells (CSCs) are often enriched after chemotherapy and contribute to tumor relapse. While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of diverse types of cancer, whether EGFR-TKIs are effective against chemoresistant CSCs in cervical cancer is largely unknown. Here, we reveal that EGFR correlates with reduced disease-free survival in cervical cancer patients with chemotherapy. Erlotinib, an EGFR-TKI, effectively impedes CSCs enrichment in paclitaxel-resistant cells through inhibiting IL-6. In this context, MUC1 induces CSCs enrichment in paclitaxel-resistant cells via activation of EGFR, which directly enhances IL-6 transcription through cAMP response element-binding protein (CREB) and glucocorticoid receptor ß (GRß). Treatment with erlotinib sensitizes CSCs to paclitaxel therapy both in vitro and in vivo. More importantly, positive correlations between the expressions of MUC1, EGFR, and IL-6 were found in 20 cervical cancer patients after chemotherapy. Mining TCGA data sets also uncovered the expressions of MUC1-EGFR-IL-6 correlates with poor disease-free survival in chemo-treated cervical cancer patients. Collectively, our work has demonstrated that the MUC1-EGFR-CREB/GRß axis stimulates IL-6 expression to induce CSCs enrichment and importantly, this effect can be abrogated by erlotinib, uncovering a novel strategy to treat paclitaxel-resistant cervical cancer.

Correlations of MicroRNA-21 Gene Polymorphisms With Chemosensitivity and Prognosis of Cervical Cancer.

BACKGROUND: We investigated correlations of miR-21 gene polymorphisms including rs1292037 (A > G) and rs13137 (A > T) with the chemosensitivity to cisplatin plus paclitaxel, and prognosis before cervical cancer (CC) surgery, which may provide a novel target for prevention and treatment of CC. MATERIALS AND METHODS: A total of 165 patients with CC were divided into 2 groups, a sensitive group and resistance group. Gene polymorphisms of rs1292037 (A > G) and rs13137 (A > T) were detected respectively. Logistic and Cox multivariate regression analyses were used to explore factors that influence resistance to cisplatin plus paclitaxel. RESULTS: rs1292037 (A > G) locus AG, GG, AG + GG and G allele in miR-21 gene may increase chemoresistance to cisplatin plus paclitaxel in CC. The risk factors of prognosis included rs1292037 (A > G) locus, tumor stage, maximum lesion diameter and lymph node metastasis (hazard ratio [HR] = 1.819, 95% CI = 1.127-2.935; HR = 1.504, 95% CI = 1.070-2.114; HR = 1.671, 95% CI = 1.038-2.689; HR = 3.043, 95% CI = 1.783-5.193). The influencing factors of resistance to cisplatin plus paclitaxel included maximum lesion diameter, tumor stage, lymph node metastasis and rs1292037 (odds ratio [OR] = 14.047, 95% CI = 5.694-34.653; OR = 5.873, 95% CI = 3.104-11.110; OR = 3.574, 95% CI = 1.554-8.216; OR = 2.449, 95% CI = 1.052-5.705). CONCLUSIONS: rs1292037 (A > G) locus are associated with the chemoresistance to cisplatin plus paclitaxel and prognosis of patients with CC. In addition to that, the G allele at rs1292037 (A > G) locus increases the risk of preoperative chemoresistance to cisplatin plus paclitaxel and is a poor prognostic factor for patients with CC.

miRNA-218 regulates the proliferation and apoptosis of cervical cancer cells via targeting Gli3.

Cervical cancer (CC) is one of the most malignant tumors that affect women. Recent studies have reported that microRNAs (miRs) serve important roles in CC. The aim of the present study was to investigate the role of miR-218 in CC and to verify its underlying mechanism. The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) revealed that miR-218 was dramatically downregulated in CC tissues and cell lines. Furthermore, the expression of Gli3 and Ki67 was measured using RT-qPCR and the results revealed that levels of these proteins were negatively correlated with miR-218 in CC tissues. The protein expression levels were determined by western blotting. Then SiHa cell line was used to investigate the mechanism of CC. Following cell transfection, cell apoptosis and cycle analyses were performed using the flow cytometry. The results revealed that miR-218 overexpression significantly inhibited cell proliferation, apoptosis and cell cycle. Additionally, luciferase reporter assay revealed that Gli3 may be a novel and direct target of miR-218 in CC. Taken together, the results of the present study suggest that miR-218 overexpression or Gli3 knockdown may have potential as therapeutic strategies for the treatment of CC.

Serum expression level of squamous cell carcinoma antigen, highly sensitive C-reactive protein, and CA-125 as potential biomarkers for recurrence of cervical cancer.

OBJECTIVE: The aim of this study was to evaluate the serum expression levels of squamous cell carcinoma antigen (SCC-Ag), highly sensitive C-reactive protein (hs-CRP), and CA-125 as potential serum biomarkers for recurrence of cervical cancer. METHODS: Eighty-six cervical cancer patients who received radical treatment were retrospectively included in this study from February 2011 to January 2014. Of the included 86 cases, 23 were recurred within the 36 months (recurrence group [RG]) and other 63 patients did not (non-RG [NRG]). The serum levels of SCC-Ag, hs-CRP, and CA-125 were examined and compared between the two groups. The prediction recurrence sensitivity, specificity area under the receiver operating characteristic curve were calculated by STATA11.0 software (http://www.stata.com). The correlation among SCC-Ag, hs-CRP, and CA-125 were analyzed by Pearson correlation test. RESULTS: The serum levels of SCC-Ag, hs-CRP, and CA-125 were 1.29 (0.21-33.20) mg/mL, 4.78 (0.22-175.20) mg/mL, and 11.56 (2.028-123.66) IU/mL for NRG and 5.64 (0.50-136.80) mg/mL, 22.41 (0.56-588.90) mg/mL, and 25.41 (3.658-3687.00) IU/mL for RG, respectively. The serum levels of SCC-Ag, hs-CRP, and CA-125 in NG group were significant higher than those of NRG group (P < 0.05). The recurrence prediction sensitivity was 0.74, 0.65, and 0.74; specificity was 0.65, 0.63, and 0.58; area under the curve was 0.75, 0.66, and 0.67, respectively, for serum SCC-Ag, hs-CRP, and CA-125. Significant positive correlation between SCC-Ag and hs-CRP (rpearson = 0.20, P = 0.04), SCC-Ag and CA-125 (rpearson = 0.64, P < 0.001), hs-CRP and CA-125 (rpearson= -0.13, P = 0.56) was found in the RG patients. CONCLUSION: Serum SCC-Ag, hs-CRP, and CA-125 were higher in recurrence cervical patients which could be potential biomarkers for predicting cervical cancer recurrence risk.

[Th1/Th2 and Treg/Th17 cell balance in peripheral blood of patients with ovarian cancer].

OBJECTIVE: To investigate the changes in the percentages and balance of CD4+T cell subsets including T helper cells (Thl, Th2, and Thl7) and T regulatory cells (Treg) in patients with ovarian cancer. METHODS: Peripheral blood samples were collected from 30 patients with ovarian cancer and 20 healthy subjects for analysis of the percentages of Thl, Th2, Thl7 and Treg using flow cytometry. RESULTS: Compared with the control subjects, the patients with ovarian cancer showed significantly increased percentages of Th2, Thl7 and Treg (P<0.05) but significantly decreased percentage of Th1 in the peripheral blood of patients with ovarian cancer (P<0.05). The changes in CD4+ T cell subsets were significantly correlated with the clinical stage of the tumor (P<0.05) but not with the histological type or cell differentiation (P>0.05). The Th1/Th2 ratio was significantly decreased in ovarian cancer patients (P<0.05) with obvious Th2 polarization compared with control group. The Treg/Th17 ratio was significantly increased in ovarian cancer patients (P<0.05). CONCLUSION: Patients with in ovarian cancer have abnormal expressions of CD4+T cell subsets in the peripheral blood with Th1/Th2 and Treg/Th17 imbalance, and these findings provide evidence for clinical immunotherapy of ovarian cancer.

HSP70 inhibitor combined with cisplatin suppresses the cervical cancer proliferation in vitro and transplanted tumor growth: An experimental study.

OBJECTIVE: To study the regulating effect of HSP70 inhibitor (PES) combined with cisplatin on cervical cancer proliferation in vitro and transplanted tumor growth. METHODS: Cervical cancer Hela cell lines were cultured and divided into control group, cisplatin group, PES group and cisplatin + PES group that were treated with serum-free DMEM, cisplatin with final concentration of 10 µmol/L, PES 20 µmol/L and cisplatin 10 µmol/L combined with PES with 20 µmol/L, respectively; animal models with cervical cancer xenografts were established and divided into control group, cisplatin group, PES group and cisplatin + PES group who received intra-tumor injection of normal saline, 10 µmol/L cisplatin, 20 µmol/L PES as well as 10 µmol/L cisplatin + 20 µmol/L PES, respectively. Cell proliferation activity, transplanted tumor volume and mitochondria apoptosis molecule expression were detected. RESULTS: Cell viability value and Bcl-2 mRNA expression in cells of cisplatin group, PES group and cisplatin + PES group were significantly lower than those of control group while Bax, Caspase-3 and Caspase-9 mRNA expression in cells were significantly higher than those of control group; transplanted tumor volume and the Bcl-2 mRNA expression in transplanted tumor tissue of cisplatin group, PES group and cisplatin + PES group were significantly lower than those of control group while Bax, Caspase-3 and Caspase-9 mRNA expression in transplanted tumor tissue were significantly higher than those of control group. CONCLUSIONS: HSP70 inhibitor combined with cisplatin can inhibit cervical cancer cell proliferation in vitro and transplanted tumor growth through mitochondrial apoptosis pathway.

Expression and mechanism of action of miR-196a in epithelial ovarian cancer.

OBJECTIVE: To explore the expression, biological function and possible mechanism of action of microRNA molecular-196a (miR-196a) in epithelial ovarian cancer. METHODS: RT-PCR was used to detect the expression quantities of epithelial ovarian tissue, benign ovarian tissue, normal ovary epithelial tissue, ovarian cancer cell lines and miR-196a in normal ovarian epithelial cells to analyze the relationship between the expression of miR-196a and the clinical pathologic parameters of ovarian cancer. Among those cell lines, the cell line of which miR-196a expressed the most or least was selected and transfected the ovarian cancer cell line by using negative control plasma and miR-196a inhibitor. After transfection, RT-PCR was used to test the expression quantity of miR-196a, Transwell chamber method was applied to determine the migration and invasion abilities of ovarian carcinoma cells and Western blot was employed to detect the expression of HOXA10 protein. RESULTS: The relative expression quantities of miR-196a in ovarian cancer tissue and benign ovarian tissue were significantly higher than that in normal ovarian epithelial tissue, and the expression quantity of miR-196a in ovarian cancer tissue was distinctively higher than that in benign ovarian tissue (P < 0.05). Among 78 cases of epithelial ovarian cancer, the expression quantities of miR-196a in patients with low differentiation were all significantly higher than those in patients with high differentiation (P < 0.05). The expression of miR-196a showed no significant relation with age, clinical stage and whether CA125 was positive or not in patients (P > 0.05). Compared with normal ovarian epithelial cell line IOSE80, the expression quantities of miR-196a of all ovarian cancer cell lines increased obviously and differences were statistically significant (P < 0.05). Among them, the expression of miR-196a of ovarian cancer cell line SKOV3 was the highest, while it decreased significantly (4.678 ± 0.785 vs. 2.131 ± 0.345, t = 2.938, P < 0.05) after the ovarian cancer cell line SKOV3 was transfected by miR-196a inhibitor. The results of Transwell chamber method showed that the migration and invasion abilities of ovarian cancer cells SKOV3 were declined significantly after the expression of miR-196a was down-regulated and the difference showed statistical significance (P < 0.05). The results of Western blot revealed that the relative expression of HOXA10 decreased distinctly after the expression of miR-196a was down-regulated and also the difference showed statistical significance (P < 0.05). CONCLUSIONS: The miR-196a might serve as a cancer-promoting gene to promote the migration and invasion of epithelial ovarian cancer by downstream target gene HOXA10.

Enhanced identification and functional protective role of carbon nanoparticles on parathyroid in thyroid cancer surgery: A retrospective Chinese population study.

The aim of this study was to determine the effects of nanocarbon particles in combination with meticulous capsular dissection on enhancing the identification and protecting the function of parathyroid glands in thyroid cancer surgery.The data of 97 patients with papillary thyroid tumors diagnosed and treated at the Second Affiliated Hospital, Harbin Medical University between January 2014 and February 2015 were reviewed. Data regarding the sex, age, calcium and parathyroid hormone (PTH) levels, tumor size, multifocality, T stage, and extrathyroid invasion were collected. The incidence of surgeries in which the parathyroid glands were cut mistakenly, the concentration of serum calcium and parathyroid hormone before surgery (baseline) and after surgery on days 1, 3, and 7, and 1 and 6 months in the patients of the two groups (the nanocarbon and control groups) were analyzed.Fifty-two patients underwent meticulous capsular dissection combined with nanocarbon treatment (nanocarbon group), and 45 underwent meticulous capsular dissection alone (control group). The nanocarbon group showed a significantly higher total and average number of revealed parathyroid glands (average number is the mean for different individuals have different number) and a lower incidence of the parathyroid glands being mistakenly cut, in addition to a lower level of hypoparathyroidism than control group following surgery (P < 0.05). Serum calcium and PTH levels were significantly lower in patients from both groups after surgery on days 1, 3, and 7 and after 1 month, compared with the preoperative levels (P < 0.05). Compared with the control group, the serum calcium and PTH levels were significantly higher in the nanocarbon group after surgery on days 1, 3, 7, than in the control group.Treatment with nanocarbon in combination with meticulous capsular dissection can significantly facilitate the identification of the parathyroid in thyroid cancer surgery, reduce the risk of mistakenly cutting the parathyroid, and reduce the incidence of postoperative hypoparathyroidism.

[Inhibiting HSP70 expression enhances cisplatin sensitivity of cervical cancer cells].

OBJECTIVE: To investigate the relationship between sensitivity to cisplatin (DDP) and the expression of HSP70 in cervical cancer cells in vitro. METHODS: Cervical cancer Hela229 cells treated with different concentrations of DDP and the HSP70 inhibitor (PFT-µ) were examined for cell viability using MTT assay and colony forming ability. The cell apoptosis was analyzed by flow cytometry with propidium iodide staining and DAPI staining, and JC-1 staining was used to determine mitochondrial membrane potential. The expressions of HSP70, Bcl-2, Bax and caspase-3 were measured with Western blotting. A nude mouse model bearing Hela229 cell xenograft was used to evaluate the effect of DDP and PFT-µ on tumor growth. RESULTS: Hela229 cells expressed a higher level of HSP70 than normal cervical cells. The combined use of PFT-µ significantly enhanced the inhibitory effect of DDP (P<0.01) and increased the cell apoptosis in Hela229 cells. JC-1 staining demonstrated that DDP combined with PFT-µ more obviously reduced mitochondrial membrane potential. DDP combined with PFT-µ more strongly lowered Bcl-2 expression and increased the expressions of casepase-3 and Bax than DDP alone. In the nude mouse model, PFT-µ significantly enhanced DDP sensitivity of Hela229 cell xenografts (P<0.01). CONCLUSIONS: Inhibition of HSP70 expression can enhance the sensitivity of cervical cancer cell to DDP both in vivo and in vitro possibly by promoting cell apoptosis, suggesting the potential of HSP70 as a new target for gene therapy of cervical cancer.

[Expression and clinical significance of phosphatidylinositol 3-kinase and protein kinase B in cervical carcinoma].

BACKGROUND & OBJECTIVE: Phosphatidylinositol 3-kinase /protein kinase B (PI3K/Akt) signaling pathway is involved in a variety of important cellular functions, including genesis and progression of neoplasms. However, its role in cervical cancer is unclear. This study was to detect the expression of PI3K and Akt proteins in different cervical lesions, and to investigate the correlation of PI3K/Akt signal transduction pathway to biological behaviors of cervical carcinoma. METHODS: The expression of PI3K and Akt in 76 specimens of cervical carcinoma,21 specimens of cervical intraepithelial neoplasia and 10 specimens of normal cervical epithelium were detected by SP immunohistochemistry. Their correlations to clinicopathologic features of cervical carcinoma were analyzed. RESULTS: The positive rates of PI3K and Akt were significantly lower in normal cervical epithelium and cervical intraepithelial neoplasia than in cervical carcinoma (0.0% and 42.9% vs. 69.7%, P<0.01;10.0% and 52.4% vs. 75.0%,P<0.01). The expression of PI3K and Akt proteins were correlated to clinical stage, pathologic grade and lymph node metastasis(P<0.01), but not to age, the size of primary focus, and histological type(P>0.05).The expression of PI3K protein was positively correlated to the expression of Akt protein(r=0.425,P<0.01). CONCLUSION: High expression of PI3K and Akt are involved in proliferation, malignant transformation, invasion and metastasis of cervical carcinoma, both of which may play important roles in the occurrence and development of human cervical carcinoma.