LncRNA AWPPH and miRNA-21 regulates cancer cell proliferation and chemosensitivity in triple-negative breast cancer by interacting with each other.

Long-non-coding RNAs (lncRNA) AWPPH promotes the progression of liver and bladder cancer, indicating its oncogenic role. The current study aimed to explore the involvement of AWPPH in triple-negative breast cancer (TNBC). In the current study, we found that plasma levels of lncRNA AWPPH and microRNA-21 (miRNA-21) were upregulated in patients with TNBC than in healthy controls, and the upregulation of plasma lncRNA AWPPH and miRNA-21 distinguished early-stage patients with TNBC from healthy controls. Plasma levels of lncRNA AWPPH and miRNA-21 were significantly and positively correlated in both patients with TNBC and healthy controls. LncRNA AWPPH and miRNA-21 overexpression led to promoted cancer cells proliferation and improved cancer cell viability under carboplatin treatment, while lncRNA AWPPH small interfering RNA (siRNA) silencing played an opposite role. In addition, miRNA-21 overexpression attenuated the effects of lncRNA AWPPH siRNA silencing on of cancer cell behaviors. LncRNA AWPPH overexpression led to upregulated miRNA-21 in TNBC cells, while miRNA-21 overexpression also led to significantly upregulated lncRNA AWPPH expression. Therefore, lncRNA AWPPH and miRNA-21 may regulate cancer cell proliferation and chemosensitivity in TNBC by interacting with each other.

Calculating binding free energies of host-guest systems using the AMOEBA polarizable force field.

Molecular recognition is of paramount interest in many applications. Here we investigate a series of host-guest systems previously used in the SAMPL4 blind challenge by using molecular simulations and the AMOEBA polarizable force field. The free energy results computed by Bennett's acceptance ratio (BAR) method using the AMOEBA polarizable force field ranked favorably among the entries submitted to the SAMPL4 host-guest competition [Muddana, et al., J. Comput.-Aided Mol. Des., 2014, 28, 305-317]. In this work we conduct an in-depth analysis of the AMOEBA force field host-guest binding thermodynamics by using both BAR and the orthogonal space random walk (OSRW) methods. The binding entropy-enthalpy contributions are analyzed for each host-guest system. For systems of inordinate binding entropy-enthalpy values, we further examine the hydrogen bonding patterns and configurational entropy contribution. The binding mechanism of this series of host-guest systems varies from ligand to ligand, driven by enthalpy and/or entropy changes. Convergence of BAR and OSRW binding free energy methods is discussed. Ultimately, this work illustrates the value of molecular modelling and advanced force fields for the exploration and interpretation of binding thermodynamics.

A valence bond model for aqueous Cu(II) and Zn(II) ions in the AMOEBA polarizable force field.

A general molecular mechanics (MM) model for treating aqueous Cu(2+) and Zn(2+) ions was developed based on valence bond (VB) theory and incorporated into the atomic multipole optimized energetics for biomolecular applications (AMOEBA) polarizable force field. Parameters were obtained by fitting MM energies to that computed by ab initio methods for gas-phase tetra- and hexa-aqua metal complexes. Molecular dynamics (MD) simulations using the proposed AMOEBA-VB model were performed for each transition metal ion in aqueous solution, and solvent coordination was evaluated. Results show that the AMOEBA-VB model generates the correct square-planar geometry for gas-phase tetra-aqua Cu(2+) complex and improves the accuracy of MM model energetics for a number of ligation geometries when compared to quantum mechanical (QM) computations. On the other hand, both AMOEBA and AMOEBA-VB generate results for Zn(2+)-water complexes in good agreement with QM calculations. Analyses of the MD trajectories revealed a six-coordination first solvation shell for both Cu(2+) and Zn(2+) ions in aqueous solution, with ligation geometries falling in the range reported by previous studies.

CRM1, a novel independent prognostic factor overexpressed in invasive breast carcinoma of poor prognosis.

Breast cancer (BC) is the most commonly diagnosed cancer in females globally and is more aggressive at later stages. Chromosome region maintenance 1 (CRM1) is involved in the nuclear export of proteins and RNAs and has been associated with a number of malignancies. However, the clinicopathological significance of its expression in BC remains to be elucidated therefore this was investigated in the present study. CRM1 expression in 280 breast cancer tissues and 60 normal tissues was retrospectively analyzed using immunohistochemistry (IHC) and western blotting. IHC investigation demonstrated that CRM1 expression was significantly increased in BC compared with the normal breast epithelium (P<0.0001). Overexpression of CRM1 was markedly associated with poor prognostic characteristics, including larger tumor size (P=0.024), positive lymph node metastasis (P=0.032), invasive histological type (P=0.004) and distant metastasis (P=0.026). Significant associations were also observed between increased CRM1 expression and the progesterone receptor (P=0.028) and Ki67 (P=0.019). Kaplan-Meier survival analysis demonstrated that patients with high CRM1 expression exhibited a reduced disease-free survival and overall survival compared with those with low CRM1 expression (P=0.013). In the multivariate analysis, CRM1 expression (P=0.011), tumor size (P=0.001) and lymph node metastasis (P<0.001) were independent prognostic markers of BC. In conclusion, CRM1 serves an important role in BC and may serve as a predictive and prognostic factor for a poor outcome in patients with BC.

Relationship Between HSP70 and ERBB2 Expression in Breast Cancer Cell Lines Regarding Drug Resistance.

BACKGROUND: Heat shock protein 70 (HSP70) is known to be downstream of human epidermal growth factor receptor-2 (ERBB2), but little is known regarding the relationship between HSP70 and drug resistance mediated by ERBB2 in breast cancer. MATERIALS AND METHODS: After infecting breast cancer cells with lentivirus-mediated Lenti-ShHSP70 and Lenti-ShERBB2, we examined the expression of HSP70 and ERBB2 by real-time polymerase chain reaction and western blotting. RESULTS: Compared to the control groups, mRNA expression of HSP70 was decreased in lentivirus-infected, and western blotting indicated a concordant reduction of HSP70 protein. On the other hand, ERBB2 was significantly down-regulated by HSP70 silencing in SK-BR-3 cells at both the mRNA and protein levels. Expression of HSP70 in transfected cells was also reduced by Lenti-ShERBB2. CCK8 viability assay indicated that inhibition of HSP70 increased the sensitivity of SK-BR-3 cells to fluorouracil treatment. CONCLUSION: HSP70 affects ERBB2 and ERBB2-mediated drug-resistance in breast cancer cells.

OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins.

The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS_2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small molecule and protein force field lead to a high level of accuracy in predicting protein-ligand binding measured over a wide range of targets and ligands (less than 1 kcal/mol RMS error) representing a 30% improvement over earlier variants of the OPLS force field.

An Angular Overlap Model for Cu(II) Ion in the AMOEBA Polarizable Force Field.

An extensible polarizable force field for transition metal ion was developed based on AMOEBA and the angular overlap model (AOM) with consistent treatment of electrostatics for all atoms. Parameters were obtained by fitting molecular mechanics (MM) energies to various ab initio gas-phase calculations. The results of parameterization were presented for copper (II) ion ligated to water and model fragments of amino acid residues involved in the copper binding sites of type 1 copper proteins. Molecular dynamics (MD) simulations were performed on aqueous copper (II) ion at various temperatures, as well as plastocyanin (1AG6) and azurin (1DYZ). Results demonstrated that the AMOEBA-AOM significantly improves the accuracy of classical MM in a number of test cases when compared to ab initio calculations. The Jahn-Teller distortion for hexa-aqua copper (II) complex was handled automatically without specifically designating axial and in-plane ligands. Analyses of MD trajectories resulted in a 6-coordination first solvation shell for aqueous copper (II) ion and a 1.8ns average residence time of water molecules. The ensemble average geometries of 1AG6 and 1DYZ copper binding sites were in general agreement with X-ray and previous computational studies.

[Effect of early oral enteral nutrition on clinical outcomes after colorectal cancer surgery].

OBJECTIVE: To investigate the effect of early oral feeding with enteral nutrition after surgery on clinical outcomes in patients with colorectal cancer. METHODS: Forty-eight patients with colorectal cancer undergoing elective operation between January 2012 and May 2012 were randomly divided into study group (n=24) and control group (n=24). Patients in the group were given small amount of water several times and enteral nutrition early after surgery. Patients in the control group received conventional postoperative care protocol. Nutritional status, immune function, time of flatus, postoperative hospital stay, medical cost and incidence of complications between the two groups were compared. RESULTS: As compared to the control group, nutritional status and immune function in the study group were significantly better (P<0.05). In the study group, time to flatus [(54.3±11.9) h vs. (65.7±10.0) h, P<0.05] and postoperative hospital stay [(5.4±1.1) d vs. (7.1±1.4) d, P<0.05] were significantly shorter, and medical cost [(36.3±6.4) thousand RMB vs. (42.8±4.3) thousand RMB, P<0.05] was significantly less as compared with the control group. No difference of the complication incidence was found [12.5% (3/24) vs. 16.7% (4/24), P>0.05]. CONCLUSION: Early oral feeding with enteral nutrition after surgery can improve the nutritional status and immune function, and accelerate the recovery of patients with colorectal cancer.