Supplemental Figure S1. Integrative Analysis of Functional Genomics and Copy Number Variation in ... more Supplemental Figure S1. Integrative Analysis of Functional Genomics and Copy Number Variation in Melanoma Cells and Tissues, Supplemental Figure S2. Elastic Net Derived Biomarker Results for Melanoma Survival Genes and Detection of These Biomarkers in TCGA SKCM, Supplemental Figure S3. The SOX10 Regulatory Network Supporting Cell Autonomous Melanoma Cell Growth and Survival, Supplemental Figure S4. SOX10 Addiction Specifies Sensitivity of BRAF Mutant Melanomas to BRAF and MEK Inhibitors In Vitro, Related to Figure 1, Supplemental Figure S5. SOX10 Addiction Specifies Sensitivity of BRAF Mutant Melanomas to BRAF and MEK Inhibitors In Patients, Related to Figure 2, Supplemental Figure S6. Bicluster of melanoma cell lines and chemical compounds in McDermott/Benes GDSC dataset, Related to Figure 3, Supplemental Figure S7. Nomination of TBK1 as a Therapeutic Target for Drug-Resistant Melanoma, Related to Figure 3, Supplemental Figure S8. TBK1/IKKε-Addiction is Conserved In Vivo, Related t...
Figure S3 shows supporting data for the identification of a TBK1-dependent molecular subtype of N... more Figure S3 shows supporting data for the identification of a TBK1-dependent molecular subtype of NSCLC cells
Figure S4 shows that modulation of mesenchymal status is sufficient to alter Ras-Mutant NSCLC sen... more Figure S4 shows that modulation of mesenchymal status is sufficient to alter Ras-Mutant NSCLC sensitivity to TBK1 inhibitors
Table S3 contains the correlation data for TBK1 inhibitor (BX795 and Compound II) toxicity vs. mR... more Table S3 contains the correlation data for TBK1 inhibitor (BX795 and Compound II) toxicity vs. mRNA expression in NSCLC lines.
Figure S1 shows that TBK1 supports AKT/mTORC1 activation during an amino acid starved-to-fed stat... more Figure S1 shows that TBK1 supports AKT/mTORC1 activation during an amino acid starved-to-fed state transition
Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorde... more Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorders, inflammatory disease, and cancer. Biochemical mechanisms accounting for direct participation of TBK1 in host defense signaling have been well described. However, the molecular underpinnings of the selective participation of TBK1 in a myriad of additional cell biological systems in normal and pathophysiologic contexts remain poorly understood. To elucidate the context-selective role of TBK1 in cancer cell survival, we employed a combination of broad-scale chemogenomic and interactome discovery strategies to generate data-driven mechanism-of-action hypotheses. This approach uncovered evidence that TBK1 supports AKT/mTORC1 pathway activation and function through direct modulation of multiple pathway components acting both upstream and downstream of the mTOR kinase itself. Furthermore, we identified distinct molecular features in which mesenchymal, Ras-mutant lung cancer is acutely depen...
Table S2 contains the data for the comparisons between TBK1 inhibitors (BX795 and Compound II) an... more Table S2 contains the data for the comparisons between TBK1 inhibitors (BX795 and Compound II) and published chemical breadth of efficacy screens in NSCLC lines
Figure S2 contains the TBK1 adaptor-focused screen assessing the relative requirement of TBK1 fir... more Figure S2 contains the TBK1 adaptor-focused screen assessing the relative requirement of TBK1 first- and second-degree interactors for amino acid activation of mTORC1
Bioscience is an interdisciplinary venture. Driven by a quantum shift in the volume of high throu... more Bioscience is an interdisciplinary venture. Driven by a quantum shift in the volume of high throughput data and in ready availability of data-intensive technologies, mathematical and quantitative approaches have become increasingly common in bioscience. For instance, a recent shift towards a quantitative description of cells and phenotypes, which is supplanting conventional qualitative descriptions, has generated immense promise and opportunities in the field of bench-to-bedside cancer OMICS, chemical biology and pharmacology. Nevertheless, like any burgeoning field, there remains a lack of shared and standardized framework for quantitative cancer research. Here, in the context of cancer, we present a basic framework and guidelines for bench-to-bedside quantitative research and therapy. We outline some of the basic concepts and their parallel use cases for chemical–protein interactions. Along with several recommendations for assay setup and conditions, we also catalog applications o...
ABSTRACT Human adenovirus-65 is associated with infantile gastroenteritis in Bangladesh. Promiscu... more ABSTRACT Human adenovirus-65 is associated with infantile gastroenteritis in Bangladesh. Promiscuous T cell epitopes for capsid proteins Hexon, Fiber, Penton, pIVa2, pVI, pVIII and pIX were predicted. Core components pX, pVII, pV and protease conservancy in adenovirus genotypes 1, 2 and 3 belonging to different geographical regions from the NCBI database were analyzed and 191,056 promiscuous epitopes for MHC-I molecules based on their binding affinity to different MHC-I alleles were predicted. Epitopes with an IC50 score ≤ 50 nM were selected based on TAP, proteasomal and IC50 scores. Their number of interactions with ≥ 3 MHC-I alleles were selected for a final catalogue of epitopes. Hexon protein showed the maximum 26.14% T cell promiscuous epitopes of all viral antigenic proteins. 219 T cell epitopes as promiscuous binders against subjected 51 MHC-II alleles were predicted. 23 epitopes were predicted to bind with all of the subjected MHC-II alleles. A considerable number of predicted epitopes having higher affinity for both MHC-I and MHC-II alleles were found to be conserved in other adenovirus genotypes and thus were potential candidates to design epitope vaccines. To our knowledge, this study is the first in silico approach to predict the promiscuous epitopes for antigenic proteins in HAdV-65 and we believe that the study will shed light into the epitope based vaccine designing which would be effective for most population of the world, especially the Bangladeshi Population. Although the computational predictions made here are based on concrete confidence, it should be mentioned that in vitro experimentation does not fall into the scopes of this study and thus the results found here has to be further validated in-vitro.
Aim: Chikungunya virus, an arthropod-borne alphavirus, belongs to the Togavirus family. Despite s... more Aim: Chikungunya virus, an arthropod-borne alphavirus, belongs to the Togavirus family. Despite severe epidemic outbreaks on several occasions, not much progress has been made with regard to epitope-based drug design for chikungunya virus. In this study we performed a proteome-wide search to look for a conserved region among the available viral proteins, one which has the capacity to trigger a significant immune response. Materials & methods: The conserved region was analyzed by performing an alignment of sequences collected from sources from varied geographic locations and time periods. Subsequently, the immune parameters for the peptide sequences were determined using several in silico tools and immune databases. Results: Both T-cell immunity and B-cell immunity were checked for the peptides to ensure that they had the capacity to induce both humoral and cell-based immunity. Our study reveals a stretch of conserved region in glycoprotein E2; yet this peptide sequence could interac...
Supplemental Figure S1. Integrative Analysis of Functional Genomics and Copy Number Variation in ... more Supplemental Figure S1. Integrative Analysis of Functional Genomics and Copy Number Variation in Melanoma Cells and Tissues, Supplemental Figure S2. Elastic Net Derived Biomarker Results for Melanoma Survival Genes and Detection of These Biomarkers in TCGA SKCM, Supplemental Figure S3. The SOX10 Regulatory Network Supporting Cell Autonomous Melanoma Cell Growth and Survival, Supplemental Figure S4. SOX10 Addiction Specifies Sensitivity of BRAF Mutant Melanomas to BRAF and MEK Inhibitors In Vitro, Related to Figure 1, Supplemental Figure S5. SOX10 Addiction Specifies Sensitivity of BRAF Mutant Melanomas to BRAF and MEK Inhibitors In Patients, Related to Figure 2, Supplemental Figure S6. Bicluster of melanoma cell lines and chemical compounds in McDermott/Benes GDSC dataset, Related to Figure 3, Supplemental Figure S7. Nomination of TBK1 as a Therapeutic Target for Drug-Resistant Melanoma, Related to Figure 3, Supplemental Figure S8. TBK1/IKKε-Addiction is Conserved In Vivo, Related t...
Figure S3 shows supporting data for the identification of a TBK1-dependent molecular subtype of N... more Figure S3 shows supporting data for the identification of a TBK1-dependent molecular subtype of NSCLC cells
Figure S4 shows that modulation of mesenchymal status is sufficient to alter Ras-Mutant NSCLC sen... more Figure S4 shows that modulation of mesenchymal status is sufficient to alter Ras-Mutant NSCLC sensitivity to TBK1 inhibitors
Table S3 contains the correlation data for TBK1 inhibitor (BX795 and Compound II) toxicity vs. mR... more Table S3 contains the correlation data for TBK1 inhibitor (BX795 and Compound II) toxicity vs. mRNA expression in NSCLC lines.
Figure S1 shows that TBK1 supports AKT/mTORC1 activation during an amino acid starved-to-fed stat... more Figure S1 shows that TBK1 supports AKT/mTORC1 activation during an amino acid starved-to-fed state transition
Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorde... more Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorders, inflammatory disease, and cancer. Biochemical mechanisms accounting for direct participation of TBK1 in host defense signaling have been well described. However, the molecular underpinnings of the selective participation of TBK1 in a myriad of additional cell biological systems in normal and pathophysiologic contexts remain poorly understood. To elucidate the context-selective role of TBK1 in cancer cell survival, we employed a combination of broad-scale chemogenomic and interactome discovery strategies to generate data-driven mechanism-of-action hypotheses. This approach uncovered evidence that TBK1 supports AKT/mTORC1 pathway activation and function through direct modulation of multiple pathway components acting both upstream and downstream of the mTOR kinase itself. Furthermore, we identified distinct molecular features in which mesenchymal, Ras-mutant lung cancer is acutely depen...
Table S2 contains the data for the comparisons between TBK1 inhibitors (BX795 and Compound II) an... more Table S2 contains the data for the comparisons between TBK1 inhibitors (BX795 and Compound II) and published chemical breadth of efficacy screens in NSCLC lines
Figure S2 contains the TBK1 adaptor-focused screen assessing the relative requirement of TBK1 fir... more Figure S2 contains the TBK1 adaptor-focused screen assessing the relative requirement of TBK1 first- and second-degree interactors for amino acid activation of mTORC1
Bioscience is an interdisciplinary venture. Driven by a quantum shift in the volume of high throu... more Bioscience is an interdisciplinary venture. Driven by a quantum shift in the volume of high throughput data and in ready availability of data-intensive technologies, mathematical and quantitative approaches have become increasingly common in bioscience. For instance, a recent shift towards a quantitative description of cells and phenotypes, which is supplanting conventional qualitative descriptions, has generated immense promise and opportunities in the field of bench-to-bedside cancer OMICS, chemical biology and pharmacology. Nevertheless, like any burgeoning field, there remains a lack of shared and standardized framework for quantitative cancer research. Here, in the context of cancer, we present a basic framework and guidelines for bench-to-bedside quantitative research and therapy. We outline some of the basic concepts and their parallel use cases for chemical–protein interactions. Along with several recommendations for assay setup and conditions, we also catalog applications o...
ABSTRACT Human adenovirus-65 is associated with infantile gastroenteritis in Bangladesh. Promiscu... more ABSTRACT Human adenovirus-65 is associated with infantile gastroenteritis in Bangladesh. Promiscuous T cell epitopes for capsid proteins Hexon, Fiber, Penton, pIVa2, pVI, pVIII and pIX were predicted. Core components pX, pVII, pV and protease conservancy in adenovirus genotypes 1, 2 and 3 belonging to different geographical regions from the NCBI database were analyzed and 191,056 promiscuous epitopes for MHC-I molecules based on their binding affinity to different MHC-I alleles were predicted. Epitopes with an IC50 score ≤ 50 nM were selected based on TAP, proteasomal and IC50 scores. Their number of interactions with ≥ 3 MHC-I alleles were selected for a final catalogue of epitopes. Hexon protein showed the maximum 26.14% T cell promiscuous epitopes of all viral antigenic proteins. 219 T cell epitopes as promiscuous binders against subjected 51 MHC-II alleles were predicted. 23 epitopes were predicted to bind with all of the subjected MHC-II alleles. A considerable number of predicted epitopes having higher affinity for both MHC-I and MHC-II alleles were found to be conserved in other adenovirus genotypes and thus were potential candidates to design epitope vaccines. To our knowledge, this study is the first in silico approach to predict the promiscuous epitopes for antigenic proteins in HAdV-65 and we believe that the study will shed light into the epitope based vaccine designing which would be effective for most population of the world, especially the Bangladeshi Population. Although the computational predictions made here are based on concrete confidence, it should be mentioned that in vitro experimentation does not fall into the scopes of this study and thus the results found here has to be further validated in-vitro.
Aim: Chikungunya virus, an arthropod-borne alphavirus, belongs to the Togavirus family. Despite s... more Aim: Chikungunya virus, an arthropod-borne alphavirus, belongs to the Togavirus family. Despite severe epidemic outbreaks on several occasions, not much progress has been made with regard to epitope-based drug design for chikungunya virus. In this study we performed a proteome-wide search to look for a conserved region among the available viral proteins, one which has the capacity to trigger a significant immune response. Materials & methods: The conserved region was analyzed by performing an alignment of sequences collected from sources from varied geographic locations and time periods. Subsequently, the immune parameters for the peptide sequences were determined using several in silico tools and immune databases. Results: Both T-cell immunity and B-cell immunity were checked for the peptides to ensure that they had the capacity to induce both humoral and cell-based immunity. Our study reveals a stretch of conserved region in glycoprotein E2; yet this peptide sequence could interac...
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