aubhishek zaman

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...

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...

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. 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 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...

Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to characterize the oncogenic drivers of esophageal squamous cell carcinoma (ESCC). We found 98% of CpGs are hypomethylated across the ESCC genome and two-thirds occur in long non-coding (lnc)RNA regions. DNA methylation and epigenetic heterogeneity both coincide with chromosomal topological alterations. Gene body methylation, polycomb repressive complex occupancy, and CTCF binding sites associate with cancer-specific gene regulation. Epigenetically-mediated activation of non-canonical WNT signaling and the lncRNA ESCCAL-1 were validated as potential ESCC driver alterations. Gene-specific cancer driver roles of epigenetic alterations and heterogeneity are identified.

State-of-the-art cancer precision medicine approaches involve targeted inactivation of chemically and immunologically addressable vulnerabilities that often yield impressive initial anti-tumor responses in patients. Nonetheless, these responses are overshadowed by therapy resistance that follows. AXL, a receptor tyrosine kinase with bona fide oncogenic capacity, has been associated with the emergence of resistance in an array of cancers with varying pathophysiology and cellular origins, including in non-small-cell lung cancers (NSCLCs). Here in this review, we summarize AXL biology during normal homeostasis, oncogenic development and therapy resistance with a focus on NSCLC. In the context of NSCLC therapy resistance, we delineate AXL’s role in mediating resistance to tyrosine kinase inhibitors (TKIs) deployed against epidermal growth factor receptor (EGFR) as well as other notable oncogenes and to chemotherapeutics. We also discuss the current understanding of AXL’s role in mediati...

Initial profound responses of precision medicines against cancer are limited in duration in part due to residual disease states that are therapy refractory and serve as a prelude to acquired drug resistance and tumor relapse. A prominent clinical example is in the collection of BRAF mutant cancers, including lung cancer and melanoma, which often respond initially, but incompletely and temporarily, to targeted RAF and MEK inhibition. The Hippo pathway transcriptional coactivator, Yes-associated protein (YAP), is a chief mediator of RAF and MEK inhibitor response in BRAF mutant cancers. However, the underlying mechanism for YAP-driven resistance is not fully understood. Here, we modeled the kinetics of patient-derived and isogenic BRAF mutant (V600E) cell lines in response to BRAF inhibitor and MEK inhibitor treatment. Our analysis indicated that in response to drug treatment the cells evolve through a “persister,” residual disease state that is distinct from therapy-naive cells or cells with acquired resistance. We observed that drug treatment induced early nuclear translocalization of YAP and this response peaked at the “persister” cell state before returning towards baseline upon acquired resistance. Additionally, our functional analysis of the proteomic and transcriptional landscape of the “persister” cells demonstrated drug-dependent reversible and concomitant activation of AKT, YAP target gene expression, and an epithelial mesenchymal transition (EMT). These programs underlay acquired vulnerabilities, as pharmacologic perturbation of AKT and genetic ablation of YAP was lethal specifically in the “persister” cells. Remarkably, AKT was required and sufficient for drug-induced nuclear localization of YAP, indicating that therapy-mediated hyperactivation of AKT is required for YAP induction and YAP-mediated residual disease. Current studies are focused on characterizing the molecular events causing AKT-mediated hyperactivation of YAP in response to MAPK pathway inhibition. Overall, this work aims to deconvolute a novel molecular mechanism of YAP activation in cancer cells and establish the functional implications of YAP signaling on “persister” cell biology and the evolution of targeted cancer therapy resistance. Citation Format: Aubhishek Zaman, Trever Bivona. Therapy-induced YAP hyperactivation is a mechanism driving the evolution of residual disease and resistance to targeted cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B36.

Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to delineate the methylome landscape and characterize the oncogenic drivers of esophageal squamous cell carcinoma (ESCC). We found 98% of CpGs are hypomethylated across the ESCC genome. Hypo-methylated regions are enriched in areas with heterochromatin binding markers (H3K9me3, H3K27me3), while hyper-methylated regions are enriched in polycomb repressive complex (EZH2/SUZ12) recognizing regions. Altered methylation in promoters, enhancers, and gene bodies, as well as in polycomb repressive complex occupancy and CTCF binding sites are associated with cancer-specific gene dysregulation. Epigenetic-mediated activation of non-canonical WNT/β-catenin/MMP signaling and a YY1/lncRNA ESCCAL-1/ribosomal protein network are uncovered and validated as potential novel ESCC driver alterations. This study advances our understanding of how epigenetic landscapes shape cancer ...

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.

Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAF-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRAS). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and n...

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 pathophysiological 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 dep...

Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathological activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathological ERK1/2 signaling. By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKE inhibitors. Importantly, subtype membership can be predicted using a robust quantitative 5-feature genetic biomarker. This biomarker, and the mechanistic relationships linked to it, can identify a cohort of best r...

ABSTRACT Drug discovery today has become immensely dependent on computational methods. Ayurvedic medicines are no exception to this. Here in this manuscript we review a book that outlines two studies to offer an in silico solution for predicting drugs from herbal sources. The computational methods mentioned in the book ranges from simple datamining techniques to more complex techniques such as interaction analysis and molecular docking techniques. This review tries to report the readers of the inside contents of the book and also analyzes its impact of the work in general. Although, like other computational predictions, the study results elucidated in the book are not entirely beyond doubts, the book is set apart from some other ones in ayurvedic drugs due to its unique subject matter and its effort to link up ancient treatment practices with the modern ones.

ABSTRACT Coilin proteins are an integral part of Cajal bodies, subnuclear structures responsible for biogenesis of telomerase and ribonucleoprotein. In silico nucleotide binding region of Coilin has been described here. The region showed a long trench-like groove suggesting presence of a long nucleotide sequence as ligand. Sequence variation in the region may account for variation in embryogenesis across a diverse array of species. Variation may have occurred over the course of evolution as the sequence might be responsible for binding the nucleotide sequence non-specifically. The stretch of positive charges found in the region may be significant.

ABSTRACT Postpartum negative energy balance (NEB) in the dairy cattle is associated with delayed return to ovarian cyclicity and reduced fertility. Lactation significantly delayed postpartum follicular growth and ovulation. Low energy intake also had a delaying effect, especially when only the lactating animals were considered. The aim of the present study was to determine the effect of fatty acid supplementation on postpartum dairy cows on the basis of daily milk yield, and glucose level, blood urea nitrogen level, progesterone level, and resumption of first estrus cycle after calving. For this experiment 10 post-partum dairy Pabna cows (locally popular) were taken. Among the cows 5 kept as controlled and rest of the 5 treated with essential fatty acid with conjugated linoleic acid (CLA). There was no significant difference found in blood glucose level and blood urea nitrogen level, although in the treated group blood glucose level was higher (4.14mmol/L) than the controlled group (2.85mmol/L). However, those cows, that received fat supplemented feed, significantly produce (p<0.01) more milk (10.61L) than controlled group (8.61L). Moreover, the milk fat percentage was also higher in the treated group (4.07%) than that of the controlled group (3.82%) and the difference was significant (p<0.05). Moreover, maintaining a desirable BCS (Body Condition scoring) is crucial for optimum production and early resumption. In treated group it was found to be as approximately as 20% whereas, it was 40% in the controlled group. In short, the treated group of cows produces more milk and regains their BCS quickly after calving than controlled group.

Sissotrin is a major small molecule found abundant in the herbal plant Dalbergia sisso (Sisso/Black Wood/Rose Wood). The plant is widely found and used in Bangladesh for medical purposes. However, how this small molecule mediates its action in the body is poorly understood. One of the applications of the plant is to cure bleeding disorders such as thrombocytopenic purpura. However what macromolecules inside the cell interact with the small molecule and finally mediate this action is yet to be confirmed. Here, in this study, it was predicted that sissotrin binds Platelet Derived Growth Factor Receptor- a molecular target hypothesized by docking technique- and thus initiates the subsequent drug action. This study confirmed the basis of the traditional herbal practice and can be useful further for developing an even more effective synthetic drug mimicking sissotrin structure in the future.

Melanoma is a highly aggressive malignant tumor of melanocyte for which treatment options have been scarce to date. Here, using high throughput cell-based screening of a large chemical compound file, we are isolating synthetic small molecules that are toxic against metastatic melanoma cells. We identified a methoxyphenyl-oxadiazole (SW174769) to be a promising candidate. SW174769 induced cell death in 15 of 19 melanoma cell lines with IC50s between 2.5 to 8 uM, but showed no detectable toxicity to normal melanocytes, human bronchial epithelial cells or majority of the non-small cell lung cancer cells with doses as high as 50uM. These results suggest that the toxicity of SW174769 may be limited to cancer cells with melanocytic origin and hence indicate the potential for a large therapeutic window. Small modifications in the structure of the compound caused a huge drop in the overall efficacy indicating the requirement of an alkyne functional group for toxic effects. Mode-of-action st...

ABSTRACT Endophytes are plant-associated microbes that live within plants as an integral part of the host metabolism and function. This study aimed to identify the molecular and physiological characteristics of both culturable and non-culturable endophytic bacteria and fungi present in different parts of the jute (Corchorus olitorius) plant. Using universal primers used to amplify hypervariable bacterial 16S rDNA and fungal internal transcribed spacer (ITS) regions of 18S rDNA, we identified five different culturable and 20 non-culturable endophytic bacteria as well as 14 different fungal endophytes from various parts of jute. Biochemical and physiological tests suggest that these microbes may bring a wide range of benefits to their hosts. For example, all five culturable endophytic bacteria were positive for auxin and catalase activity, which may lead to improved root elongation and stress resistance, respectively. These bacteria also have metal uptake, haemolytic and hydrolytic activities that could be useful in medical, environmental and industrial applications. The fungal endophytes were positive for lignin peroxidase, cellulase and xylanase activities, all of which may influence jute physiology. Another important finding was the antifungal activity of one of the fungi against a devastating pernicious fungus that affects hundreds of plant species.

Endophytes are plant-associated microbes that live within plants as an integral part of the host metabolism and function. This study aimed to identify the molecular and physiological characteristics of both culturable and non-culturable endophytic bacteria and fungi present in different parts of the jute (Corchorus olitorius) plant. Using universal primers used to amplify hypervariable bacterial 16S rDNA and fungal internal transcribed spacer (ITS) regions of 18S rDNA, we identified five different culturable and 20 non-culturable endophytic bacteria as well as 14 different fungal endophytes from various parts of jute. Biochemical and physiological tests suggest that these microbes may bring a wide range of benefits to their hosts. For example, all five culturable endophytic bacteria were positive for auxin and catalase activity, which may lead to improved root elongation and stress resistance, respectively. These bacteria also have metal uptake, haemolytic and hydrolytic activities ...

ABSTRACT Postpartum negative energy balance (NEB) in the dairy cattle is associated with delayed return to ovarian cyclicity and reduced fertility. Lactation significantly delayed postpartum follicular growth and ovulation. Low energy intake also had a delaying effect, especially when only the lactating animals were considered. The aim of the present study was to determine the effect of fatty acid supplementation on postpartum dairy cows on the basis of daily milk yield, and glucose level, blood urea nitrogen level, progesterone level, and resumption of first estrus cycle after calving. For this experiment 10 post-partum dairy Pabna cows (locally popular) were taken. Among the cows 5 kept as controlled and rest of the 5 treated with essential fatty acid with conjugated linoleic acid (CLA). There was no significant difference found in blood glucose level and blood urea nitrogen level, although in the treated group blood glucose level was higher (4.14mmol/L) than the controlled group (2.85mmol/L). However, those cows, that received fat supplemented feed, significantly produce (p<0.01) more milk (10.61L) than controlled group (8.61L). Moreover, the milk fat percentage was also higher in the treated group (4.07%) than that of the controlled group (3.82%) and the difference was significant (p<0.05). Moreover, maintaining a desirable BCS (Body Condition scoring) is crucial for optimum production and early resumption. In treated group it was found to be as approximately as 20% whereas, it was 40% in the controlled group. In short, the treated group of cows produces more milk and regains their BCS quickly after calving than controlled group.

ABSTRACT Coilin proteins are an integral part of Cajal bodies, subnuclear structures responsible for biogenesis of telomerase and ribonucleoprotein. In silico nucleotide binding region of Coilin has been described here. The region showed a long trench-like groove suggesting presence of a long nucleotide sequence as ligand. Sequence variation in the region may account for variation in embryogenesis across a diverse array of species. Variation may have occurred over the course of evolution as the sequence might be responsible for binding the nucleotide sequence non-specifically. The stretch of positive charges found in the region may be significant.