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| 1 | New insights into estrogenic regulation of O^6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: Co-degradation of ER-α and MGMT proteins by fulvestrant or O^6-benzylguanine indicates fresh avenues for therapy显示文摘Endocrine therapy using estrogen receptor-α(ER-α) antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers.To exploit any DNA repair deficiencies associated with endocrine therapy,we investigated the functional and physical interactions of ER-α with O^6-methylguanine DNA methyltransferase(MGMT),a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents.The ER-α-positive breast cancer cell lines(MCF-7,T47D) and ER- negative cell lines(MDAMB-468,MDAMB-231),and established inhibitors of ER-α and MGMT,namely,ICI-182,780(Faslodex) and O^6-benzylguanine,respectively,were used to study MGMT- ER interactions.The MGMT gene promoter was found to harbor one full and two half estrogen-responsive elements(EREs) and two antioxidant-responsive elements(AREs).MGMT expression was upregulated by estrogen,downregulated by tamoxifen in Western blot and promoter-linked reporter assays.Similarly,both transient and stable transfections of Nrf-2(nuclear factor-erythroid 2-related factor-2)increased the levels of MGMT protein and activity 3 to 4-fold reflecting novel regulatory nodes for this drugresistance determinant.Of the different ER-α antagonists tested,the pure anti-estrogen fulvestrant was most potent in inhibiting the MGMT activity in a dose,time and ER-α dependent manner,similar to O^6-benzylguanine.Interestingly,fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O^6-benzylguanine also induced a specific loss of ER-α and MGMT proteins in MCF-7 and T47 D breast cancer cells with similar kinetics.Immunoprecipitation revealed a specific association of ER-α and MGMT proteins in breast cancer cells.Furthermore,silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-α proteins.The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated.Fulvestrant enhanced the cytotoxicity of MGMT-targeted alkylating agents,namely,temozolomide and BCNU by 3 to 4-fold in ER-α positive cells,but not in ER-negative cells.We conclude that MGMT and ER-α proteins exist as a complex and are co-targeted for ubiquitin-conjugation and subsequent proteasomal degradation.The findings offer a clear rationale for combining alkylating agents with endocrine therapy. | Ameya Paranjpe Nathan I. Bailes Santhi Konduri George C. Bobustuc Francis Ali-Osman Mohd. A. Yusuf Surendra R. Punganuru Hanumantha Rao Madal Debasish Basak AGM Mostofa Kalkunte S. Srivenugopa | 2016 | The Journal of Biomedical Research2016，30，5： | 5 |
| 2 | Support Veetor Regression 显示文摘 | Debasish Basak Sfimanta Pal Dipak Chandra Patranabis | 2007 | Neural Information Processing-Letters and Reviews2007，11，10： | 1 |
| 3 | Support vector regression显示文摘 | Debasish Basak Srimanta Pal Dipak Chandra Patranabis | 2003 | Neural Information Processing-Letters and Reviews2003，11，10： | 1 |
| 4 | Electric discharge phenomenon in dielectric and electrolyte medium显示文摘Electric discharge is a common tool nowadays for machining of materials. It may be through a liquid medium or through air. Any metals, hard alloys, and nonmetals can be machined using the energy of electric discharge. In electric discharge machining (EDM), the discharge occurs between two electrodes through a liquid medium and it is applicable only for electrically con ducting materials and alloys. In electrochemical discharge machining (ECDM), the medium is an aqueous electrolyte and it is of two types. In the first type, the discharge occurs between two electrodes. One of the electrodes is the workpiece, and the other is the tool. In the second type, the discharge occurs between one electrode and an electrolyte. It is used for electrically nonconducting materials and the discharge energy is utilized maintaining the nonconducting workpiece in proximity of the discharge. All these electrical discharges are transient phenomena and do not result in a stable discharge in the form of arc. The output parameters depend on the discharge energy that requires precise control to maintain the accuracy of the machining. For micromachining, the control of the discharge is paramount both in terms of energy and pattern. Using various shaped tools, machining media with additives, different types of applied potentials, and supporting mechanical motions are some of the attempts made to improve the machining output. Optimization of these parameters for machining particular materials (or alloys) is a popular field of research. The present work is directed toward the investigation of discharge initiation and development by analyzing the cell current and discharge voltage relationship for both EDM and ECDM. The rectangular direct current (DC) pulse with different frequencies and the duty factor (on-off time ratio) are used for investigation. Observations on the voltage-current relationship are made for the external potential prior to discharge at discharge and above the discharge potential. Though the external poten tial above the discharge voltage is useful for machining, these observations elucidate the mechanism regarding the initiation of the electric discharge under different condi tions. The manner of discharge development in dielectrics and electrolytes is observed to be different. This understanding will aid in deciding the design of the discharge circuit including the external potential and its pattern for certain desired outputs in machining. | Mukesh Kumar Sindhu Debasish Nandi Indrajit Basak | 2018 | Advances in Manufacturing2018，6，4： | 0 |
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