37 results on '"Sharma, Shikhar"'
Search Results
2. Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer
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Sharma, Shikhar, Chung, Chi-Yeh, Uryu, Sean, Petrovic, Jelena, Cao, Joan, Rickard, Amanda, Nady, Nataliya, Greasley, Samantha, Johnson, Eric, Brodsky, Oleg, Khan, Showkhin, Wang, Hui, Wang, Zhenxiong, Zhang, Yong, Tsaparikos, Konstantinos, Chen, Lei, Mazurek, Anthony, Lapek, John, Kung, Pei-Pei, Sutton, Scott, Richardson, Paul F., Greenwald, Eric C., Yamazaki, Shinji, Jones, Rhys, Maegley, Karen A., Bingham, Patrick, Lam, Hieu, Stupple, Alexandra E., Kamal, Aileen, Chueh, Anderly, Cuzzupe, Anthony, Morrow, Benjamin J., Ren, Bin, Carrasco-Pozo, Catalina, Tan, Chin Wee, Bhuva, Dharmesh D., Allan, Elizabeth, Surgenor, Elliot, Vaillant, François, Pehlivanoglu, Havva, Falk, Hendrik, Whittle, James R., Newman, Janet, Cursons, Joseph, Doherty, Judy P., White, Karen L., MacPherson, Laura, Devlin, Mark, Dennis, Matthew L., Hattarki, Meghan K., De Silva, Melanie, Camerino, Michelle A., Butler, Miriam S., Dolezal, Olan, Pilling, Patricia, Foitzik, Richard, Stupple, Paul A., Lagiakos, H. Rachel, Walker, Scott R., Hediyeh-Zadeh, Soroor, Nuttall, Stewart, Spall, Sukhdeep K., Charman, Susan A., Connor, Theresa, Peat, Thomas S., Avery, Vicky M., Bozikis, Ylva E., Yang, Yuqing, Zhang, Ming, Monahan, Brendon J., Voss, Anne K., Thomas, Tim, Street, Ian P., Dawson, Sarah-Jane, Dawson, Mark A., Lindeman, Geoffrey J., Davis, Melissa J., Visvader, Jane E., and Paul, Thomas A.
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- 2023
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3. Epidemiological Profile and Practices of Animal Bite Victims Attending the OPD of Rural Health and Training Centre Affiliated to a Tertiary Care Centre in Rewa.
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Rai, Anamika, Marathe, Neera, Sharma, Shikhar, Nayak, Shubhangi, Sharma, Anshuman, Pradhan, Murchhana, and Namdeo, Priyanshi
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BITES & stings ,RABIES vaccines ,RURAL health ,WOUND care ,HEALTH programs ,DOG bites - Abstract
Background: In India, over 35% of global human Rabies deaths occur, primarily from dog bites which are responsible for over 95% of cases. Objective of this study was to assess the epidemiological profile and practices regarding animal bite, among animal bite victims attending the OPD of Rural Health and Training Centre affiliated to a Tertiary Care Centre in Rewa. Methods: This was a facility based cross-sectional study. Sample size was 150. New animal bite victims were interviewed using a semi-structured questionnaire after obtaining informed verbal consent. The questionnaire consisted of demographic profile and questions regarding victims’ awareness about rabies, anti-rabies vaccine and their practices following the animal bite. Conclusion: Younger age group (persons of 0-30 years age group) are more commonly affected. Awareness among participants may be raised by utilising school health programs Major biting animals were dogs. Very few people are aware of the need for observing animals post bite. Wound care practices need to be improved. Pet dog rabies vaccination rate is very low, which needs to be focused upon for achieving rabies control. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Investigating Flow around Submerged I, L and T Head Groynes in Gravel Bed.
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Priyanka, Mall, Manish Kumar, Sharma, Shikhar, Ojha, Chandra Shekhar Prasad, and Prasad, K. S. Hari
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Riverbank erosion poses a significant threat to the stability and integrity of river training structures. River training structures such as groynes are important components of sustainable development as they play a crucial role in mitigating flood risks, controlling erosion, and supporting the habitat for aquatic organisms. The habitats vary largely according to the groyne type. A comprehensive comparative analysis of the flow field around the I, L, and T head groynes in the gravel bed is drawn. This study will be of immense use for riverbank protection in hilly terrain where streams are mostly dominated by the gravel bed. Laboratory experiments were conducted in a channel with a sediment bed as gravel of size 9.36 mm. Consistent flow conditions were maintained, with a flow depth (D) of 0.136 m and Froude no (Fr) of 0.61. The performance of these groynes, quantified using L
p (length of bank protection), was investigated. LHG and THG, notably, instigate more profound scour depths, recording values of 0.295 D and 0.29 D, respectively, while IHG trails with the value of 0.21 D. The complex flow field involving velocity peaks, decelerated, and negative flow is discussed and is attributed to flow separation at the groyne tip and the horseshoe vortex. The Lp for each groyne was estimated, with the IHG providing the maximum bank protection of 1.2 L1 , L1 being the transverse length of the groyne. The cost–benefit analysis revealed IHG as the most cost-effective structure. These findings contribute to optimization of riverbank stabilization efforts, enhancing the resilience of hydraulic infrastructure and ensuring the safety and wellbeing of affected communities and ecosystems. The results also provide valuable insight into bank protection by various groynes and highlight their contribution to enhancing the resilience of river systems. [ABSTRACT FROM AUTHOR]- Published
- 2024
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5. ASL-3DCNN: American sign language recognition technique using 3-D convolutional neural networks
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Sharma, Shikhar and Kumar, Krishan
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- 2021
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6. Complement Evasion Strategies of Human Pathogenic Bacteria
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Sharma, Shikhar, Bhatnagar, Rakesh, and Gaur, Deepak
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- 2020
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7. The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review
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Rugo, Hope S., Jacobs, Ira, Sharma, Shikhar, Scappaticci, Frank, Paul, Thomas A., Jensen-Pergakes, Kristen, and Malouf, Gabriel G.
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- 2020
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8. Parallel multi-objective multi-robot coalition formation
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Agarwal, Manoj, Agrawal, Nitin, Sharma, Shikhar, Vig, Lovekesh, and Kumar, Naveen
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- 2015
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9. An efficient method for link prediction in weighted multiplex networks
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Sharma, Shikhar and Singh, Anurag
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- 2016
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10. FIRE: A Failure-Adaptive Reinforcement Learning Framework for Edge Computing Migrations
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Siew, Marie, Sharma, Shikhar, Guo, Kun, Xu, Chao, Quek, Tony Q. S., and Joe-Wong, Carlee
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Networking and Internet Architecture (cs.NI) ,FOS: Computer and information sciences ,Computer Science - Networking and Internet Architecture ,Computer Science - Machine Learning ,FOS: Electrical engineering, electronic engineering, information engineering ,Systems and Control (eess.SY) ,Electrical Engineering and Systems Science - Systems and Control ,Machine Learning (cs.LG) - Abstract
In edge computing, users' service profiles must be migrated in response to user mobility. Reinforcement learning (RL) frameworks have been proposed to do so. Nevertheless, these frameworks do not consider occasional server failures, which although rare, can prevent the smooth and safe functioning of edge computing users' latency sensitive applications such as autonomous driving and real-time obstacle detection, because users' computing jobs can no longer be completed. As these failures occur at a low probability, it is difficult for RL algorithms, which are inherently data-driven, to learn an optimal service migration solution for both the typical and rare event scenarios. Therefore, we introduce a rare events adaptive resilience framework FIRE, which integrates importance sampling into reinforcement learning to place backup services. We sample rare events at a rate proportional to their contribution to the value function, to learn an optimal policy. Our framework balances service migration trade-offs between delay and migration costs, with the costs of failure and the costs of backup placement and migration. We propose an importance sampling based Q-learning algorithm, and prove its boundedness and convergence to optimality. Following which we propose novel eligibility traces, linear function approximation and deep Q-learning versions of our algorithm to ensure it scales to real-world scenarios. We extend our framework to cater to users with different risk tolerances towards failure. Finally, we use trace driven experiments to show that our algorithm gives cost reductions in the event of failures.
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- 2022
11. Legislative Framework against Organ Trafficking In India.
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Sharma, Shikhar
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TRANSPLANTATION of organs, tissues, etc. , *LEGAL documents , *CRIME , *LEGISLATORS - Abstract
The legislative framework against organ trafficking in India has become an imperative issue in recent years due to the increasing incidence of illegal organ trade within the country. This abstract explores the legislative measures adopted by India to combat organ trafficking, focusing on the key laws, regulations, and initiatives introduced to address this grave concern. It examines the legal provisions pertaining to organ transplantation, the prohibition of organ trade, and the protection of vulnerable individuals from exploitation. The analysis also includes an assessment of the effectiveness of the legislative framework, highlighting the challenges and potential areas for improvement. By understanding the existing laws and their implementation, this abstract aims to contribute to the ongoing discourse on organ trafficking and inform policymakers, lawmakers, and stakeholders about the crucial legislative steps required to combat this heinous crime in India. [ABSTRACT FROM AUTHOR]
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- 2023
12. DNA Methylation Screening Identifies Driver Epigenetic Events of Cancer Cell Survival
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De Carvalho, Daniel D., Sharma, Shikhar, You, Jueng Soo, Su, Sheng-Fang, Taberlay, Phillippa C., Kelly, Theresa K., Yang, Xiaojing, Liang, Gangning, and Jones, Peter A.
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- 2012
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13. Recombinant full-length Bacillus Anthracis protective antigen and its 63 kDa form elicits protective response in formulation with addavax.
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Sharma, Shikhar, Bahl, Vanndita, Srivastava, Gaurav, Shamim, Risha, Bhatnagar, Rakesh, and Gaur, Deepak
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BACILLUS anthracis ,ANTIGENS ,ESCHERICHIA coli ,VACCINE effectiveness ,RECOMBINANT proteins - Abstract
Introduction: Bacillus anthracis is the causative agent for the lethal disease anthrax, primarily affecting animals and humans in close contact with an infected host. The pathogenicity of B. anthracis is attributed to the secreted exotoxins and their outer capsule. The host cell-binding exotoxin component "protective antigen" (PA) is reported to be a potent vaccine candidate. The aim of our study is to produce several PA constructs and analyze their vaccine potential. Methods: We have designed the various subunit, PA-based recombinant proteins, i.e., full-length Protective antigen (PA-FL), C-terminal 63 kDa fragment (PA63), Protective antigen domain 1-domain 4 chimeras (PA-D1-4) and protective antigen domain 4 (PA-D4) and analyzed their vaccine potential with different human-compatible adjuvants in the mouse model. We have optimized the process and successfully expressed our recombinant antigens as soluble proteins, except full-length PA. All the recombinant antigen formulations with three different adjuvants i.e., Addavax, Alhydrogel, and Montanide ISA 720, were immunized in different mouse groups. The vaccine efficacy of the formulations was analyzed by mouse serum antigen-specific antibody titer, toxin neutralization assay, and survival analysis of mouse groups challenged with a lethal dose of B. anthracis virulent spores. Results: We have demonstrated that the PA-FL addavax and PA63 addavax formulations were most effective in protecting spore-challenged mice and serum from the mice immunized with PAFL addavax, PA-FL alhydrogel, PA63 addavax, and PA63 alhydrogel formulations were equivalently efficient in neutralizing the anthrax lethal toxin. The higher levels of serum Th1, Th2, and Th17 cytokines in PA-FL addavax immunized mice correspond to the enhanced protection provided by the formulation in challenged mice. Discussion: We have demonstrated that the PA-FL addavax and PA63 addavax formulations exhibit equivalent efficiency as vaccine formulation both in a mouse model of anthrax and mammalian cell lines. However, PA63 is a smaller antigen than PA-FL and more importantly, PA63 is expressed as a soluble protein in E. coli, which imparts a translational advantage to PA63-based formulation. Thus, the outcome of our study has significant implications for the development of protective antigen-based vaccine formulations for human use against the lethal disease anthrax. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Deep Eigen Space Based ASL Recognition System.
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Sharma, Shikhar, Kumar, Krishan, and Singh, Navjot
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SIGN language , *LANGUAGE arts , *NUCLEOTIDE sequence , *DEEP learning , *GESTURE - Abstract
Sign language is the art of communicating using hand gestures. The communication between an impaired person and the one who doesn't understand sign language could be easy using the computer as a tool. Inconsistent previous works in the field posed a need for more stable and effective model. We take an efficient step in order to tackle the problem of automatic fingerspelling recognition system using the concept that in order to efficiently perceive things, human brain alters some of the information. Moreover, the comparison between previous works and our model is mentioned systematically in this paper. Also, the model is capable to classify the real-time sign without dependency on environment. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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15. Intrinsic and acquired drug resistance to LSD1 inhibitors in small cell lung cancer occurs through a TEAD4-driven transcriptional state.
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Wen Yan, Chi-Yeh Chung, Tao Xie, Ozeck, Mark, Nichols, Timothy C., Frey, Jessica, Udyavar, Akshata R., Sharma, Shikhar, and Paul, Thomas A.
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Small-cell lung cancer (SCLC) is a heterogeneous disease, consisting of intratumoral and intertumoral neuroendocrine (ASCL1 and/or NEUROD1), mesenchymal-like, and YAP-driven transcriptional states. Lysinespecific demethylase 1 (LSD1; also known as KDM1A) inhibitors have recently been progressed to clinical trials in SCLC based on a promising preclinical antitumor activity. A potential clinical limitation of LSD1 inhibitors is the heterogeneous drug responses that have been observed in SCLC cell lines and patient-derived models. Based on these observations, we studied molecular and transcriptional signatures that predict patient response to this class of drug. Employing SCLC patient-derived transcriptional signatures, we define that SCLC cell lines sensitive to LSD1 inhibitors are enriched in neuroendocrine transcriptional markers, whereas cell lines enriched in a mesenchymal-like transcriptional program demonstrate intrinsic resistance to LSD1 inhibitors. We have identified a reversible, adaptive resistance mechanism to LSD1 inhibitors through epigenetic reprogramming to a TEAD4-driven mesenchymal-like state. Our data suggest that only a segment of SCLC patients, with a defined neuroendocrine differentiation state, will likely benefit from LSD1 inhibitors. It provides novel evidence for the selection of a TEAD4-driven mesenchymal-like subpopulation resistant to LSD1 inhibitors in SCLC patients that may require effective drug combinations to sustain effective clinical responses. [ABSTRACT FROM AUTHOR]
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- 2022
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16. Epigenetics in cancer
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Sharma, Shikhar, Kelly, Theresa K., and Jones, Peter A.
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- 2010
17. DNA methylation analysis by digital bisulfite genomic sequencing and digital MethyLight
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Weisenberger, Daniel J., Trinh, Binh N., Campan, Mihaela, Sharma, Shikhar, Long, Tiffany I., Ananthnarayan, Suchitra, Liang, Gangning, Esteva, Francisco J., Hortobagyi, Gabriel N., McCormick, Frank, Jones, Peter A., and Laird, Peter W.
- Published
- 2008
18. Lysine methyltransferase G9a is not required for DNMT3A/3B anchoring to methylated nucleosomes and maintenance of DNA methylation in somatic cells
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Sharma Shikhar, Gerke Daniel S, Han Han F, Jeong Shinwu, Stallcup Michael R, Jones Peter A, and Liang Gangning
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G9a ,DNMT3A ,DNMT3B ,DNA methylation ,Nucleosome ,Maintenance ,Epigenetics ,Genetics ,QH426-470 - Abstract
Abstract Background DNA methylation, histone modifications and nucleosome occupancy act in concert for regulation of gene expression patterns in mammalian cells. Recently, G9a, a H3K9 methyltransferase, has been shown to play a role in establishment of DNA methylation at embryonic gene targets in ES cells through recruitment of de novo DNMT3A/3B enzymes. However, whether G9a plays a similar role in maintenance of DNA methylation in somatic cells is still unclear. Results Here we show that G9a is not essential for maintenance of DNA methylation in somatic cells. Knockdown of G9a has no measurable effect on DNA methylation levels at G9a-target loci. DNMT3A/3B remain stably anchored to nucleosomes containing methylated DNA even in the absence of G9a, ensuring faithful propagation of methylated states in cooperation with DNMT1 through somatic divisions. Moreover, G9a also associates with nucleosomes in a DNMT3A/3B and DNA methylation-independent manner. However, G9a knockdown synergizes with pharmacologic inhibition of DNMTs resulting in increased hypomethylation and inhibition of cell proliferation. Conclusions Taken together, these data suggest that G9a is not involved in maintenance of DNA methylation in somatic cells but might play a role in re-initiation of de novo methylation after treatment with hypomethylating drugs, thus serving as a potential target for combinatorial treatments strategies involving DNMTs inhibitors.
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- 2012
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19. The complex role of EZH2 in the tumor microenvironment: opportunities and challenges for immunotherapy combinations.
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Qiu, Jing, Sharma, Shikhar, Rollins, Robert A, and Paul, Thomas A
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- 2020
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20. Bacillus anthracis Poly-γ-D-Glutamate Capsule Inhibits Opsonic Phagocytosis by Impeding Complement Activation.
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Sharma, Shikhar, Bhatnagar, Rakesh, and Gaur, Deepak
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BACILLUS anthracis ,COMPLEMENT activation ,PHAGOCYTOSIS ,ECULIZUMAB ,CARRIER proteins ,SERUM-free culture media - Abstract
Bacillus anthracis poly-γ-D-glutamic acid (PGA) capsule is an essential virulent factor that helps the bacterial pathogen to escape host immunity. Like other encapsulated bacterial species, the B. anthracis capsule may also inhibit complement-mediated clearance and ensure bacterial survival in the host. Previous reports suggest that B. anthracis spore proteins inhibit complement activation. However, the mechanism through which the B. anthracis capsule imparts a survival advantage to the active bacteria has not been demonstrated till date. Thus, to evaluate the role of the PGA capsule in evading host immunity, we have undertaken the present head-to-head comparative study of the phagocytosis and complement activation of non-encapsulated and encapsulated B. anthracis strains. The encapsulated virulent strain exhibited resistance toward complement-dependent and complement-independent bacterial phagocytosis by human macrophages. The non-encapsulated Sterne strain was highly susceptible to phagocytosis by THP-1 macrophages, after incubation with normal human serum (NHS), heat-inactivated serum, and serum-free media, thus indicating that the capsule inhibited both complement-dependent and complement-independent opsonic phagocytosis. An increased binding of C3b and its subsequent activation to C3c and C3dg, which functionally act as potent opsonins, were observed with the non-encapsulated Sterne strain compared with the encapsulated strain. Other known mediators of complement fixation, IgG, C-reactive protein (CRP), and serum amyloid P component (SAP), also bound more prominently with the non-encapsulated Sterne strain. Studies with complement pathway-specific, component-deficient serum demonstrated that the classical pathway was primarily involved in mediating C3b binding on the non-encapsulated bacteria. Both strains equally bound the complement regulatory proteins C4BP and factor H. Importantly, we demonstrated that the negative charge of the PGA capsule was responsible for the differential binding of the complement proteins between the non-encapsulated and encapsulated strains. At lower pH closer to the isoelectric point of PGA, the neutralization of the negative charge was associated with an increased binding of C3b and IgG with the encapsulated B. anthracis strain. Overall, our data have demonstrated that the B. anthracis capsule inhibits complement fixation and opsonization resulting in reduced phagocytosis by macrophages, thus allowing the bacterial pathogen to evade host immunity. [ABSTRACT FROM AUTHOR]
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- 2020
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21. Iris recognition based on sparse representation and k-nearest subspace with genetic algorithm
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Bhateja, Ashok K, Sharma, Shikhar, Chaudhury, Santanu, and Agrawal, Nitin
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- 2016
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22. Natural Language Generation in Dialogue using Lexicalized and Delexicalized Data
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Sharma, Shikhar, He, Jing, Suleman, Kaheer, Schulz, Hannes, and Bachman, Philip
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FOS: Computer and information sciences ,Computer Science - Computation and Language ,Computation and Language (cs.CL) - Abstract
Natural language generation plays a critical role in spoken dialogue systems. We present a new approach to natural language generation for task-oriented dialogue using recurrent neural networks in an encoder-decoder framework. In contrast to previous work, our model uses both lexicalized and delexicalized components i.e. slot-value pairs for dialogue acts, with slots and corresponding values aligned together. This allows our model to learn from all available data including the slot-value pairing, rather than being restricted to delexicalized slots. We show that this helps our model generate more natural sentences with better grammar. We further improve our model's performance by transferring weights learnt from a pretrained sentence auto-encoder. Human evaluation of our best-performing model indicates that it generates sentences which users find more appealing.
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- 2016
23. Action Recognition using Visual Attention
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Sharma, Shikhar, Kiros, Ryan, and Salakhutdinov, Ruslan
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FOS: Computer and information sciences ,Computer Science - Learning ,Computer Vision and Pattern Recognition (cs.CV) ,Computer Science - Computer Vision and Pattern Recognition ,Machine Learning (cs.LG) - Abstract
We propose a soft attention based model for the task of action recognition in videos. We use multi-layered Recurrent Neural Networks (RNNs) with Long Short-Term Memory (LSTM) units which are deep both spatially and temporally. Our model learns to focus selectively on parts of the video frames and classifies videos after taking a few glimpses. The model essentially learns which parts in the frames are relevant for the task at hand and attaches higher importance to them. We evaluate the model on UCF-11 (YouTube Action), HMDB-51 and Hollywood2 datasets and analyze how the model focuses its attention depending on the scene and the action being performed.
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- 2015
24. A-PNR.
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Sharma, Shikhar, Kumar, Piyush, and Kumar, Krishan
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- 2017
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25. Emerging therapeutic targets for patients with advanced prostate cancer.
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Saad, Fred, Shore, Neal, Zhang, Tian, Sharma, Shikhar, Cho, Helen K., and Jacobs, Ira A.
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Although recent advances in the treatment of castration-resistant prostate cancer (CRPC) have significantly improved patient outcomes, advanced prostate cancer is still associated with substantial morbidity and mortality, particularly in patients who develop resistance after multiple lines of therapy. Various cell signaling, DNA repair, and epigenetic enzymatic pathways are being targeted with small-molecule inhibitors in order to identify treatment strategies for patients with CRPC. In this review, we discuss novel targets and agents, studied preclinically and now being validated in clinical trials, including poly ADP-ribose polymerase (PARP), enhancer of zeste homologue 2 (EZH2), hedgehog pathway, MDM2/p53, and tyrosine kinase inhibitors. Further, we outline current approaches for novel prostate cancer vaccines such as DCVAC/PCa, PROSTVAC-V/F, MVI-816, CV9104, and PF-06753512. This wide spectrum of potential treatment strategies holds promise for additional improvements in the treatment of patients with CRPC, as these novel agents are aimed at targets known to be associated with growth and malignant progression of prostate cancer. If primary study endpoints are met, findings from ongoing phase III trials of well-tolerated and active combinations may provide new effective treatment options for advanced prostate cancer and thereby contribute to enhanced disease control in CRPC patients. [ABSTRACT FROM AUTHOR]
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- 2019
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26. Beyond Geometric Path Planning: Learning Context-Driven Trajectory Preferences via Sub-optimal Feedback.
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Jain, Ashesh, Sharma, Shikhar, and Saxena, Ashutosh
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- 2016
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27. An Efficient Method for Link Prediction in Complex Multiplex Networks.
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Sharma, Shikhar and Singh, Anurag
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- 2015
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28. Learning preferences for manipulation tasks from online coactive feedback.
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Jain, Ashesh, Sharma, Shikhar, Joachims, Thorsten, and Saxena, Ashutosh
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ROBOTIC path planning , *PERSONAL robotics , *HUMAN-robot interaction , *ASSEMBLY line methods , *TRAJECTORIES (Mechanics) , *DEGREES of freedom , *DISTANCE education - Abstract
We consider the problem of learning preferences over trajectories for mobile manipulators such as personal robots and assembly line robots. The preferences we learn are more intricate than simple geometric constraints on trajectories; they are rather governed by the surrounding context of various objects and human interactions in the environment. We propose a coactive online learning framework for teaching preferences in contextually rich environments. The key novelty of our approach lies in the type of feedback expected from the user: the human user does not need to demonstrate optimal trajectories as training data, but merely needs to iteratively provide trajectories that slightly improve over the trajectory currently proposed by the system. We argue that this coactive preference feedback can be more easily elicited than demonstrations of optimal trajectories. Nevertheless, theoretical regret bounds of our algorithm match the asymptotic rates of optimal trajectory algorithms. We implement our algorithm on two high-degree-of-freedom robots, PR2 and Baxter, and present three intuitive mechanisms for providing such incremental feedback. In our experimental evaluation we consider two context rich settings, household chores and grocery store checkout, and show that users are able to train the robot with just a few feedbacks (taking only a few minutes). [ABSTRACT FROM AUTHOR]
- Published
- 2015
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29. Nucleosomes Containing Methylated DNA Stabilize DNA Methyltransferases 3A/3B and Ensure Faithful Epigenetic Inheritance.
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Sharma, Shikhar, De Carvalho, Daniel D., Shinwu Jeong, Jones, Peter A., and Gangning Liang
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DNA , *METHYLATION , *METHYLTRANSFERASES , *SOMATIC cells , *CELL division , *GENE expression , *PROTEINS , *ENZYMES - Published
- 2011
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30. Hypomethylation of a LINE-1 Promoter Activates an Alternate Transcript of the MET Oncogene in Bladders with Cancer.
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Wolff, Erika M., Hyang-Min Byun, Han, Han F., Sharma, Shikhar, Nichols, Peter W., Siegmund, Kimberly D., Yang, Allen S., Jones, Peter A., and Gangning Liang
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ONCOGENES ,GENETIC regulation ,BLADDER cancer ,DISEASE susceptibility ,CHROMOSOMES - Abstract
It was recently shown that a large portion of the human transcriptome can originate from within repetitive elements, leading to ectopic expression of protein-coding genes. However the mechanism of transcriptional activation of repetitive elements has not been definitively elucidated. For the first time, we directly demonstrate that hypomethylation of retrotransposons can cause altered gene expression in humans. We also reveal that active LINE-1s switch from a tetranucleosome to dinucleosome structure, acquiring H2A.Z- and nucleosome-free regions upstream of TSSs, previously shown only at active single-copy genes. Hypomethylation of a specific LINE-1 promoter was also found to induce an alternate transcript of the MET oncogene in bladder tumors and across the entire urothelium of tumor-bearing bladders. These data show that, in addition to contributing to chromosomal instability, hypomethylation of LINE-1s can alter the functional transcriptome and plays a role not only in human disease but also in disease predisposition. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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31. Selective Anchoring of DNA Methyltransferases 3A and 3B to Nucleosomes Containing Methylated DNA.
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Shinwu Jeong, Gangning Liang, Sharma, Shikhar, Joy C. Lin, Si Ho Choi, Han Han, Yoo, Christine B., Egger, Gerda, Yang, Allen S., and Jones, Peter A.
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DNA ,METHYLATION ,METHYLTRANSFERASES ,WESTERN immunoblotting ,CHROMATIN ,ENZYMES - Abstract
Proper DNA methylation patterns are essential for mammalian development and differentiation. DNA methyltransferases (DNMTs) primarily establish and maintain global DNA methylation patterns; however, the molecular mechanisms for the generation and inheritance of methylation patterns are still poorly understood. We used sucrose density gradients of nucleosomes prepared by partial and maximum micrococcal nuclease digestion, coupled with Western blot analysis to probe for the interactions between DNMTs and native nucleosomes. This method allows for analysis of the in vivo interactions between the chromatin modification enzymes and their actual nucleosomal substrates in the native state. We show that little free DNA methyltransferase 3A and 3B (DNMT3A/3B) exist in the nucleus and that almost all of the cellular contents of DNMT3A/3B, but not DNMT1, are strongly anchored to a subset of nucleosomes. This binding of DNMT3A/3B does not require the presence of other well-known chromatin-modifying enzymes or proteins, such as proliferating cell nuclear antigen, heterochromatin protein 1, methyl-CpG binding protein 2, Enhancer of Zeste homolog 2, histone deacetylase 1, and UHRF1, but it does require an intact nucleosomal structure. We also show that nucleosomes containing methylated SINE and LINE elements and CpG islands are the main sites of DNMT3A/3B binding. These data suggest that inheritance of DNA methylation requires cues from the chromatin component in addition to hemimethylation. [ABSTRACT FROM AUTHOR]
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- 2009
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32. ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer.
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Mullen, Nicholas J., Thakur, Ravi, Shukla, Surendra K., Chaika, Nina V., Kollala, Sai Sundeep, Wang, Dezhen, He, Chunbo, Fujii, Yuki, Sharma, Shikhar, Mulder, Scott E., Sykes, David B., and Singh, Pankaj K.
- Subjects
- *
PANCREATIC cancer , *NUCLEOSIDE transport proteins - Abstract
Inhibitors of dihydroorotate dehydrogenase (DHODH), a key enzyme for de novo synthesis of pyrimidine nucleotides, have failed in clinical trials for various cancers despite robust efficacy in preclinical animal models. To probe for druggable mediators of DHODH inhibitor resistance, we performed a combination screen with a small molecule library against pancreatic cancer cell lines that are highly resistant to the DHODH inhibitor brequinar (BQ). The screen revealed that CNX-774, a preclinical Bruton tyrosine kinase (BTK) inhibitor, sensitizes resistant cell lines to BQ. Mechanistic studies showed that this effect is independent of BTK and instead results from inhibition of equilibrative nucleoside transporter 1 (ENT1) by CNX-774. We show that ENT1 mediates BQ resistance by taking up extracellular uridine, which is salvaged to generate pyrimidine nucleotides in a DHODH-independent manner. In BQ-resistant cell lines, BQ monotherapy slowed proliferation and caused modest pyrimidine nucleotide depletion, whereas combination treatment with BQ and CNX-774 led to profound cell viability loss and pyrimidine starvation. We also identify N-acetylneuraminic acid accumulation as a potential marker of the therapeutic efficacy of DHODH inhibitors. In an aggressive, immunocompetent pancreatic cancer mouse model, combined targeting of DHODH and ENT1 dramatically suppressed tumor growth and prolonged mouse survival. Overall, our study defines CNX-774 as a previously uncharacterized ENT1 inhibitor and provides strong proof of concept support for dual targeting of DHODH and ENT1 in pancreatic cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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33. Intrinsic and acquired drug resistance to LSD1 inhibitors in small cell lung cancer occurs through a TEAD4-driven transcriptional state.
- Author
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Yan W, Chung CY, Xie T, Ozeck M, Nichols TC, Frey J, Udyavar AR, Sharma S, and Paul TA
- Subjects
- DNA-Binding Proteins genetics, Drug Resistance, Histone Demethylases, Humans, Muscle Proteins, TEA Domain Transcription Factors, Transcription Factors genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms metabolism, Small Cell Lung Carcinoma drug therapy, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma metabolism
- Abstract
Small-cell lung cancer (SCLC) is a heterogeneous disease, consisting of intratumoral and intertumoral neuroendocrine (ASCL1 and/or NEUROD1), mesenchymal-like, and YAP-driven transcriptional states. Lysine-specific demethylase 1 (LSD1; also known as KDM1A) inhibitors have recently been progressed to clinical trials in SCLC based on a promising preclinical antitumor activity. A potential clinical limitation of LSD1 inhibitors is the heterogeneous drug responses that have been observed in SCLC cell lines and patient-derived models. Based on these observations, we studied molecular and transcriptional signatures that predict patient response to this class of drug. Employing SCLC patient-derived transcriptional signatures, we define that SCLC cell lines sensitive to LSD1 inhibitors are enriched in neuroendocrine transcriptional markers, whereas cell lines enriched in a mesenchymal-like transcriptional program demonstrate intrinsic resistance to LSD1 inhibitors. We have identified a reversible, adaptive resistance mechanism to LSD1 inhibitors through epigenetic reprogramming to a TEAD4-driven mesenchymal-like state. Our data suggest that only a segment of SCLC patients, with a defined neuroendocrine differentiation state, will likely benefit from LSD1 inhibitors. It provides novel evidence for the selection of a TEAD4-driven mesenchymal-like subpopulation resistant to LSD1 inhibitors in SCLC patients that may require effective drug combinations to sustain effective clinical responses., (© 2021 Pfizer, Inc. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Published
- 2022
- Full Text
- View/download PDF
34. Translational Pharmacokinetic-Pharmacodynamic Modeling for an Orally Available Novel Inhibitor of Epigenetic Regulator Enhancer of Zeste Homolog 2.
- Author
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Yamazaki S, Gukasyan HJ, Wang H, Uryu S, and Sharma S
- Subjects
- Administration, Oral, Animals, Dose-Response Relationship, Drug, Female, Mice, Models, Biological, Xenograft Model Antitumor Assays, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Epigenesis, Genetic drug effects, Histones antagonists & inhibitors, Isoquinolines administration & dosage, Isoquinolines pharmacokinetics, Isoquinolines pharmacology, Lymphoma, Large B-Cell, Diffuse drug therapy, Pyridines administration & dosage, Pyridines pharmacokinetics, Pyridines pharmacology
- Abstract
PF06821497 has been identified as an orally available small-molecule enhancer of zeste homolog 2 inhibitor. The objectives of the present study were to characterize pharmacokinetic-pharmacodynamic-disease relationships of PF06821497 in xenograft mouse models with diffuse large B-cell lymphoma (Karpas422). An indirect-response model reasonably fit dose-dependent pharmacodynamic responses [histone H3 on lysine 27 (H3K27) me3 inhibition] with an unbound EC
50 of 76 nM, whereas a signal-transduction model sufficiently fit dose-dependent disease responses (tumor growth inhibition) with an unbound tumor stasis concentration ( Tsc ) of 168 nM. Thus, effective concentration for 70% of maximal effect (EC70 ) for H3K27me3 inhibition was roughly comparable to Tsc , suggesting that 70% H3K27me3 inhibition could be required for tumor stasis. Consistently, an integrated pharmacokinetic-pharmacodynamic-disease model adequately describing tumor growth inhibition also suggested that ∼70% H3K27me3 inhibition was associated with tumor stasis. Based on these results, we would propose that an EC70 estimate for H3K27me3 inhibition corresponding to tumor stasis could be considered a minimum target efficacious concentration of PF06821497 in cancer patients. SIGNIFICANCE STATEMENT: Using a mathematical modeling approach, the quantitative relationships of an orally available anticancer small-molecule enhancer of zeste homolog 2 inhibitor, PF06821497, were characterized among pharmacokinetics, pharmacodynamic biomarker inhibition, and disease responses in nonclinical xenograft models with diffuse large B-cell lymphoma. The modeling results suggest that >70% histone H3 on lysine 27 (H3K27) me3 inhibition would be required for tumor stasis (i.e., 100% tumor growth inhibition). Accordingly, we would propose that an effective concentration for 70% of maximal effect estimate for H3K27me3 inhibition could be considered a minimum target efficacious concentration of PF06821497 in cancer patients., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2020
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35. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).
- Author
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Kung PP, Bingham P, Brooun A, Collins M, Deng YL, Dinh D, Fan C, Gajiwala KS, Grantner R, Gukasyan HJ, Hu W, Huang B, Kania R, Kephart SE, Krivacic C, Kumpf RA, Khamphavong P, Kraus M, Liu W, Maegley KA, Nguyen L, Ren S, Richter D, Rollins RA, Sach N, Sharma S, Sherrill J, Spangler J, Stewart AE, Sutton S, Uryu S, Verhelle D, Wang H, Wang S, Wythes M, Xin S, Yamazaki S, Zhu H, Zhu J, Zehnder L, and Edwards M
- Subjects
- Administration, Oral, Biological Availability, Cell Line, Tumor, Humans, Isoquinolines administration & dosage, Isoquinolines chemistry, Models, Molecular, Molecular Conformation, Drug Design, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Isoquinolines pharmacokinetics, Isoquinolines pharmacology
- Abstract
A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp
3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.- Published
- 2018
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- View/download PDF
36. The SMARCA2/4 ATPase Domain Surpasses the Bromodomain as a Drug Target in SWI/SNF-Mutant Cancers: Insights from cDNA Rescue and PFI-3 Inhibitor Studies.
- Author
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Vangamudi B, Paul TA, Shah PK, Kost-Alimova M, Nottebaum L, Shi X, Zhan Y, Leo E, Mahadeshwar HS, Protopopov A, Futreal A, Tieu TN, Peoples M, Heffernan TP, Marszalek JR, Toniatti C, Petrocchi A, Verhelle D, Owen DR, Draetta G, Jones P, Palmer WS, Sharma S, and Andersen JN
- Subjects
- Binding, Competitive, Catalysis, Cell Line, Tumor, Chromatin metabolism, Chromosomal Proteins, Non-Histone genetics, DNA Helicases chemistry, DNA Helicases deficiency, DNA, Complementary genetics, Gene Knockout Techniques, Genetic Complementation Test, Humans, Lung Neoplasms pathology, Microarray Analysis, Neoplasms genetics, Nuclear Proteins chemistry, Nuclear Proteins deficiency, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering pharmacology, Rhabdoid Tumor genetics, Rhabdoid Tumor pathology, Sarcoma, Synovial genetics, Sarcoma, Synovial pathology, Transcription Factors chemistry, Transcription Factors genetics, Azabicyclo Compounds pharmacology, Chromatin Assembly and Disassembly drug effects, Chromosomal Proteins, Non-Histone deficiency, DNA Helicases antagonists & inhibitors, Molecular Targeted Therapy, Neoplasm Proteins antagonists & inhibitors, Neoplasms drug therapy, Nuclear Proteins antagonists & inhibitors, Pyridines pharmacology, Transcription Factors antagonists & inhibitors, Transcription Factors deficiency
- Abstract
The SWI/SNF multisubunit complex modulates chromatin structure through the activity of two mutually exclusive catalytic subunits, SMARCA2 and SMARCA4, which both contain a bromodomain and an ATPase domain. Using RNAi, cancer-specific vulnerabilities have been identified in SWI/SNF-mutant tumors, including SMARCA4-deficient lung cancer; however, the contribution of conserved, druggable protein domains to this anticancer phenotype is unknown. Here, we functionally deconstruct the SMARCA2/4 paralog dependence of cancer cells using bioinformatics, genetic, and pharmacologic tools. We evaluate a selective SMARCA2/4 bromodomain inhibitor (PFI-3) and characterize its activity in chromatin-binding and cell-functional assays focusing on cells with altered SWI/SNF complex (e.g., lung, synovial sarcoma, leukemia, and rhabdoid tumors). We demonstrate that PFI-3 is a potent, cell-permeable probe capable of displacing ectopically expressed, GFP-tagged SMARCA2-bromodomain from chromatin, yet contrary to target knockdown, the inhibitor fails to display an antiproliferative phenotype. Mechanistically, the lack of pharmacologic efficacy is reconciled by the failure of bromodomain inhibition to displace endogenous, full-length SMARCA2 from chromatin as determined by in situ cell extraction, chromatin immunoprecipitation, and target gene expression studies. Furthermore, using inducible RNAi and cDNA complementation (bromodomain- and ATPase-dead constructs), we unequivocally identify the ATPase domain, and not the bromodomain of SMARCA2, as the relevant therapeutic target with the catalytic activity suppressing defined transcriptional programs. Taken together, our complementary genetic and pharmacologic studies exemplify a general strategy for multidomain protein drug-target validation and in case of SMARCA2/4 highlight the potential for drugging the more challenging helicase/ATPase domain to deliver on the promise of synthetic-lethality therapy., (©2015 American Association for Cancer Research.)
- Published
- 2015
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- View/download PDF
37. Selective anchoring of DNA methyltransferases 3A and 3B to nucleosomes containing methylated DNA.
- Author
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Jeong S, Liang G, Sharma S, Lin JC, Choi SH, Han H, Yoo CB, Egger G, Yang AS, and Jones PA
- Subjects
- Cell Line, Chromatin, DNA (Cytosine-5-)-Methyltransferases genetics, DNA Methyltransferase 3A, Humans, Isoenzymes genetics, Isoenzymes metabolism, Protein Binding, Repetitive Sequences, Nucleic Acid, DNA Methyltransferase 3B, CpG Islands, DNA (Cytosine-5-)-Methyltransferases metabolism, DNA Methylation, Nucleosomes enzymology
- Abstract
Proper DNA methylation patterns are essential for mammalian development and differentiation. DNA methyltransferases (DNMTs) primarily establish and maintain global DNA methylation patterns; however, the molecular mechanisms for the generation and inheritance of methylation patterns are still poorly understood. We used sucrose density gradients of nucleosomes prepared by partial and maximum micrococcal nuclease digestion, coupled with Western blot analysis to probe for the interactions between DNMTs and native nucleosomes. This method allows for analysis of the in vivo interactions between the chromatin modification enzymes and their actual nucleosomal substrates in the native state. We show that little free DNA methyltransferase 3A and 3B (DNMT3A/3B) exist in the nucleus and that almost all of the cellular contents of DNMT3A/3B, but not DNMT1, are strongly anchored to a subset of nucleosomes. This binding of DNMT3A/3B does not require the presence of other well-known chromatin-modifying enzymes or proteins, such as proliferating cell nuclear antigen, heterochromatin protein 1, methyl-CpG binding protein 2, Enhancer of Zeste homolog 2, histone deacetylase 1, and UHRF1, but it does require an intact nucleosomal structure. We also show that nucleosomes containing methylated SINE and LINE elements and CpG islands are the main sites of DNMT3A/3B binding. These data suggest that inheritance of DNA methylation requires cues from the chromatin component in addition to hemimethylation.
- Published
- 2009
- Full Text
- View/download PDF
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