In current social networking world, organizations are demanding high-speed security for client da... more In current social networking world, organizations are demanding high-speed security for client data such as images, audio video files even huge databases. Also no flexibility to connect and share remote devices and servers reduces the performance of service given by organization. To overcome this issues Storage Area Network (SAN) was introduced which is a dedicated storage network that carries I/O traffic only between servers and storage devices. The paper describes requirement of SAN in real world by implementing a SAN using Openfiler, Based on seven cases SAN’s performance analysis done with help of Iometer tool and SAN’s importance in clustered Database.
The epigenetic mechanisms regulating developmental gene expression are examples of a strategy to ... more The epigenetic mechanisms regulating developmental gene expression are examples of a strategy to generate unique expression profiles with global regulators controlling several genes. In a simplified view, a common set of tools, that include DNA motif recognizing proteins (recruiters), binding/interacting surfaces (ARPs- actin related proteins), epigenetic writers (histone methyltransferases, acetylases), readers (chromatin remodeling proteins, PRC1 members) and erasers (demethylases, deacetylases) form complexes which not only regulate transcription, but also retain the transcriptional memory through mitosis. There are two arms of epigenetic regulation: covalent modification of DNA and the post-translational modification of histones. In this review, we discuss both of these aspects briefly to illustrate functional diversity. We discuss our efforts at utilization of the genome sequence data for de novo identification of new players and their functional validation in this remarkable p...
Heat shock proteins (HSPs) are evolutionary conserved 'stress-response' proteins that fac... more Heat shock proteins (HSPs) are evolutionary conserved 'stress-response' proteins that facilitate cell survival against various adverse conditions. HSP-mediated cytoprotection was hitherto reported to occur principally in two ways. Firstly, HSPs interact directly or indirectly with apoptosis signaling components and suppress apoptosis. Secondly, through chaperon activity, HSPs suppress proteotoxicity and maintain protein-homeostasis. Recent studies highlight the interaction of HSPs with cytoplasmic stress granules (SGs). SGs are conserved cytoplasmic mRNPs granules that aid in cell survival under stressful conditions. We primarily aim to describe the distinct cell survival strategy mediated by HSPs as the crucial regulators of SGs assembly and disassembly. Based on the growing evidence, HSPs and associated co-chaperones act as important determinants of SG assembly, composition and dissolution. Under cellular stress, as a 'stress-coping mechanism', the formation of SGs reprograms protein translation machinery and modulates signaling pathways indispensable for cell survival. Besides their role in suppressing apoptosis, HSPs also regulate protein-homeostasis by their chaperone activity as well as by their tight regulation of SG dynamics. The intricate molecular signaling in and around the nexus of HSPs-SGs and its importance in diseases has to be unearthed. These studies have significant implications in the management of chronic diseases such as cancer and neurodegenerative diseases where SGs possess pathological functions.
Triple negative breast cancer (TNBC) still remains a challenge to treat in the clinic due to a la... more Triple negative breast cancer (TNBC) still remains a challenge to treat in the clinic due to a lack of good targets for treatment. Although TNBC lacks expression of ERα, the expression of ERβ and its variants are detected quite frequently in this cancer type and can represent an avenue for treatment. We show that the variants of ERβ, namely ERβ1, ERβ2, ERβ4, and ERβ5, regulate aggressiveness of TNBC by regulating hypoxic signaling. RNA-seq of patient derived xenografts (PDX) from TNBC show expression of ERβ4 and ERβ5 variants in more than half of the samples. Furthermore, expression of ERβ4 in the immortalized, normal mammary epithelial cell line MCF-10A that is resistant to mammosphere formation caused transformation and development of mammospheres. By contrast, ERβ1, ERβ2 or ERβ5 were unable to support mammosphere formation. We have previously shown that all variants except ERβ1 stabilizes HIF-1α but only ERβ4 appear to have the ability to transform normal mammary epithelial cells...
SUMMARYDeregulated gene expression through epigenetic, transcriptional, and copy number alteratio... more SUMMARYDeregulated gene expression through epigenetic, transcriptional, and copy number alterations is a major driver of melanoma progression and metastasis. In addition to serving as blueprints for translation, some mRNAs post-transcriptionally regulate gene expression by competitively sequestering miRNAs they share with other targets. Here we report that such mRNAs, termed competitive endogenous RNAs (ceRNAs), contribute to melanoma progression and metastasis. ceRNA predictions identified multiple candidate genes on chromosome 1q, which is recurrently amplified in melanoma. Genetic studies reveal that three of these mRNAs, CEP170, NUCKS1, and ZC3H11A, promote melanoma migration, invasion, and metastasis in a protein coding-independent and miRNA binding site-dependent manner. Interestingly, CEP170, NUCKS1, and ZC3H11A cooperate to elicit oncogenic effects by collectively impairing the tumor suppressor activity of 8 miRNAs on several pro-metastatic target genes. Finally, this comple...
Background. Identification of a shared gene expression pattern between T cell–mediated rejection ... more Background. Identification of a shared gene expression pattern between T cell–mediated rejection (TCMR) and antibody-mediated rejection (AMR) in human kidney allografts may help prioritize targets for the treatment of both types of acute rejection. Methods. We performed RNA sequencing and bioinformatics of genome-wide transcriptome profiles of urinary cells to identify novel mRNAs shared between TCMR and AMR and of mechanistic relevance. Customized RT-QPCR assays were then used to validate their abundance in urinary cells. Urinary cell transcriptome profiles and mRNA abundance were assessed in 22 urine samples matched to 22 TCMR biopsies, 7 samples matched to 7 AMR biopsies, and 24 samples matched to 24 No Rejection (NR) biopsies and correlated with biopsy diagnosis. Results. RNA sequencing data and bioinformatics identified 127 genes in urine to be shared between TCMR and AMR. We selected 3 novel mRNAs—ITM2A, SLAMF6, and IKZF3—for absolute quantification and validation by customized RT-QPCR assays. The abundance of all 3 mRNAs was significantly higher in urine matched to TCMR or AMR than in urine matched to NR biopsies. Receiver-operating-characteristic curve analysis showed that all 3 mRNAs distinguished TCMR or AMR from NR. Their abundance was similar in patients with TCMR and those with AMR. Conclusions. State-of-the-art antirejection therapies are mostly effective to treat TCMR but not AMR. Our identification of mRNAs shared between TCMR and AMR and contributing to T cell–B cell interactions may help prioritize therapeutic targets for the simultaneous treatment of TCMR and AMR.
These findings provide insights into the metabolic requirements of colorectal cancer and reveal a... more These findings provide insights into the metabolic requirements of colorectal cancer and reveal a novel approach for its treatment. Serine is a nonessential amino acid generated by the sequential actions of phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1), and phosphoserine phosphatase (PSPH). Increased serine biosynthesis occurs in several cancers and supports tumor growth. In addition, cancer cells can harness exogenous serine to enhance their metabolism and proliferation. Here we tested the relative contributions of exogenous and endogenous sources of serine on the biology of colorectal cancer. In murine tumors, Apc status was identified as a determinant of the expression of genes controlling serine synthesis. In patient samples, PSAT1 was overexpressed in both colorectal adenomas and adenocarcinomas. Combining genetic deletion of PSAT1 with exogenous serine deprivation maximally suppressed the proliferation of colorectal cancer cells and induced profound metabolic defects including diminished nucleotide production. Inhibition of serine synthesis enhanced the transcriptional changes following exogenous serine removal as well as alterations associated with DNA damage. Both loss of PSAT1 and removal of serine from the diet were necessary to suppress colorectal cancer xenograft growth and enhance the antitumor activity of 5-fluorouracil (5-FU). Restricting endogenous and exogenous serine in vitro augmented 5-FU–induced cell death, DNA damage, and metabolic perturbations, likely accounting for the observed antitumor effect. Collectively, our results suggest that both endogenous and exogenous sources of serine contribute to colorectal cancer growth and resistance to 5-FU. Significance: These findings provide insights into the metabolic requirements of colorectal cancer and reveal a novel approach for its treatment. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/81/9/2275/F1.large.jpg. Graphical Abstract
Summary Chromosomal instability (CIN) is a hallmark of human cancer yet not readily testable for ... more Summary Chromosomal instability (CIN) is a hallmark of human cancer yet not readily testable for patients with cancer in routine clinical setting. In this study, we sought to explore whether CIN status can be predicted using ubiquitously available hematoxylin and eosin histology through a deep learning-based model. When applied to a cohort of 1,010 patients with breast cancer (Training set: n = 858, Test set: n = 152) from The Cancer Genome Atlas where 485 patients have high CIN status, our model accurately classified CIN status, achieving an area under the curve of 0.822 with 81.2% sensitivity and 68.7% specificity in the test set. Patch-level predictions of CIN status suggested intra-tumor heterogeneity within slides. Moreover, presence of patches with high predicted CIN score within an entire slide was more predictive of clinical outcome than the average CIN score of the slide, thus underscoring the clinical importance of intra-tumor heterogeneity.
Coronavirus disease 19 (COVID-19) infection pandemic has affected remarkable morbidity and mortal... more Coronavirus disease 19 (COVID-19) infection pandemic has affected remarkable morbidity and mortality in a very short span of time. The overall disease profile and epidemiology is yet evolving but it seems to be highly infectious. Perinatal coronavirus infection is altogether a different perspective which has to be taken care of in a different way.
Despite infiltrating immune cells having an essential function in human disease and patients’ res... more Despite infiltrating immune cells having an essential function in human disease and patients’ responses to treatments, mechanisms influencing variability in infiltration patterns remain unclear. Here, using bulk RNA-seq data from 46 tissues in the Genotype-Tissue Expression project, we apply cell-type deconvolution algorithms to evaluate the immune landscape across the healthy human body. We discover that 49 of 189 infiltration-related phenotypes are associated with either age or sex (FDR
Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their ... more Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their aggressiveness with African ancestry is not established. We investigated primary TNBCs for gene expression among self-reported race (SRR) groups of African American (AA, n=42) and European American (EA, n=33) women. Using The Cancer Genome Atlas (TCGA) approaches, we analyzed RNA sequencing data to measure changes in genome-wide expression and used logistic regressions to identify ancestry-associated gene expression signatures. To determine global ancestry, GATK best practices were followed for variant calling, and used the 1000 Genomes Project as reference data. We identified >150 African ancestry-associated genes and found that, compared to SRR, quantitative genetic analysis was a more robust method to identify racial/ethnic-specific genes that were differentially expressed. A subset of African ancestry-specific genes that were upregulated in TNBCs of our AA patients were validated ...
7546Background: EZH2 is the catalytic subunit of PRC2, and induces methylation of H3K27. Activati... more 7546Background: EZH2 is the catalytic subunit of PRC2, and induces methylation of H3K27. Activating mutations and overexpression of EZH2 are found in NHL. Inactivating mutations in histone acetyltr...
International Journal of Applied and Computational Mathematics
In this paper, we discuss the multi-layer perceptron artificial neural network technique for the ... more In this paper, we discuss the multi-layer perceptron artificial neural network technique for the solution of homogeneous and non-homogeneous Lane–Emden type differential equations. Our aim is to produce an optimal solution of Lane–Emden equations with less computation using multi-layer perceptron artificial neural network technique, comparatively other numerical techniques. Several test examples have been considered to determine the robustness of the given method. The results obtained prove that the given technique has the capability to develop into an effective approach for solving Lane–Emden type problems with less computation time and memory space.
Obesity is associated with adipose inflammation, defined by macrophages encircling dead adipocyte... more Obesity is associated with adipose inflammation, defined by macrophages encircling dead adipocytes, as well as extracellular matrix (ECM) remodeling and increased risk of breast cancer. Whether ECM affects macrophage phenotype in obesity is uncertain. A better understanding of this relationship could be strategically important to reduce cancer risk or improve outcomes in the obese. Utilizing clinical samples, computational approaches, and in vitro decellularized ECM models, this study quantified the relative abundance of pro (M1)- and anti (M2)-inflammatory macrophages in human breast adipose tissue, determined molecular similarities between obesity and tumor-associated macrophages, and assessed the regulatory effect of obese versus lean ECM on macrophage phenotype. Our results suggest that breast adipose tissue contains more M2-biased than M1-biased macrophages across all body mass index (BMI) categories. Obesity further increased M2-biased macrophages but did not affect M1-biased macrophage density. Gene Set Enrichment Analysis (GSEA) suggested that breast tissue macrophages from obese versus lean women are more similar to tumor-associated macrophages (TAMs). These changes positively correlated with adipose tissue interstitial fibrosis, and in vitro experiments indicated that obese ECM directly stimulates M2-biased macrophage functions. However, mammographic density cannot be used as a clinical indicator of these changes. Collectively, these data suggest that obesity-associated interstitial fibrosis promotes a macrophage phenotype similar to TAMs, which may contribute to the link between obesity and breast cancer.
The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We ... more The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that humanRHAMMBpromoted liver metastasis. It was unknown whetherRHAMMBis upregulated in pancreatic cancer or contributes to its progression. In this study, we found that RHAMM protein was frequently upregulated in human PNETs. We investigated alternative splicing isoforms,RHAMMAandRHAMMB, by RNA-Seq analysis of primary PNETs and liver metastases.RHAMMB, but notRHAMMA, was significantly upregulated in liver metastases. RHAMMBwas crucial forin vivometastatic capacity of mouse and human PNETs. RHAMMA, carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover,RHAMMBwas substantially higher thanRHAMMAin pancreatic ductal adenocarcinoma (PDAC)....
Hürthle cell carcinoma (HCC) is an unusual and relatively rare type of differentiated thyroid can... more Hürthle cell carcinoma (HCC) is an unusual and relatively rare type of differentiated thyroid cancer. Currently, cytologic analysis of fine-needle aspiration biopsy is limited in distinguishing benign Hürthle cell neoplasms from malignant ones. The aim of this study was to determine whether differences in the expression of specific genes could differentiate HCC from benign Hürthle cell nodules by evaluating differential gene expression in Hürthle cell disease. Eighteen benign Hürthle cell nodules and seven HCC samples were analyzed by whole-transcriptome sequencing. Bioinformatics analysis was carried out to identify candidate differentially expressed genes. Expression of these candidate genes was re-examined by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was quantified by immunohistochemistry. Close homolog of L1 (CHL1) was identified as overexpressed in HCC. CHL1 was found to have greater than 15-fold higher expression in fragments per kilobase m...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 16, 2018
Based on the identified stress-independent cellular functions of activating transcription factor ... more Based on the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in triple negative breast cancer (TNBC) patients, but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine effects on breast cancer patient survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature. Patient survival data was determined by Kaplan-Meier analysis. Relationship between TGFβ and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and using patient-derived xenografts (PDXs). overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFβ was identified. expression inhib...
In current social networking world, organizations are demanding high-speed security for client da... more In current social networking world, organizations are demanding high-speed security for client data such as images, audio video files even huge databases. Also no flexibility to connect and share remote devices and servers reduces the performance of service given by organization. To overcome this issues Storage Area Network (SAN) was introduced which is a dedicated storage network that carries I/O traffic only between servers and storage devices. The paper describes requirement of SAN in real world by implementing a SAN using Openfiler, Based on seven cases SAN’s performance analysis done with help of Iometer tool and SAN’s importance in clustered Database.
The epigenetic mechanisms regulating developmental gene expression are examples of a strategy to ... more The epigenetic mechanisms regulating developmental gene expression are examples of a strategy to generate unique expression profiles with global regulators controlling several genes. In a simplified view, a common set of tools, that include DNA motif recognizing proteins (recruiters), binding/interacting surfaces (ARPs- actin related proteins), epigenetic writers (histone methyltransferases, acetylases), readers (chromatin remodeling proteins, PRC1 members) and erasers (demethylases, deacetylases) form complexes which not only regulate transcription, but also retain the transcriptional memory through mitosis. There are two arms of epigenetic regulation: covalent modification of DNA and the post-translational modification of histones. In this review, we discuss both of these aspects briefly to illustrate functional diversity. We discuss our efforts at utilization of the genome sequence data for de novo identification of new players and their functional validation in this remarkable p...
Heat shock proteins (HSPs) are evolutionary conserved 'stress-response' proteins that fac... more Heat shock proteins (HSPs) are evolutionary conserved 'stress-response' proteins that facilitate cell survival against various adverse conditions. HSP-mediated cytoprotection was hitherto reported to occur principally in two ways. Firstly, HSPs interact directly or indirectly with apoptosis signaling components and suppress apoptosis. Secondly, through chaperon activity, HSPs suppress proteotoxicity and maintain protein-homeostasis. Recent studies highlight the interaction of HSPs with cytoplasmic stress granules (SGs). SGs are conserved cytoplasmic mRNPs granules that aid in cell survival under stressful conditions. We primarily aim to describe the distinct cell survival strategy mediated by HSPs as the crucial regulators of SGs assembly and disassembly. Based on the growing evidence, HSPs and associated co-chaperones act as important determinants of SG assembly, composition and dissolution. Under cellular stress, as a 'stress-coping mechanism', the formation of SGs reprograms protein translation machinery and modulates signaling pathways indispensable for cell survival. Besides their role in suppressing apoptosis, HSPs also regulate protein-homeostasis by their chaperone activity as well as by their tight regulation of SG dynamics. The intricate molecular signaling in and around the nexus of HSPs-SGs and its importance in diseases has to be unearthed. These studies have significant implications in the management of chronic diseases such as cancer and neurodegenerative diseases where SGs possess pathological functions.
Triple negative breast cancer (TNBC) still remains a challenge to treat in the clinic due to a la... more Triple negative breast cancer (TNBC) still remains a challenge to treat in the clinic due to a lack of good targets for treatment. Although TNBC lacks expression of ERα, the expression of ERβ and its variants are detected quite frequently in this cancer type and can represent an avenue for treatment. We show that the variants of ERβ, namely ERβ1, ERβ2, ERβ4, and ERβ5, regulate aggressiveness of TNBC by regulating hypoxic signaling. RNA-seq of patient derived xenografts (PDX) from TNBC show expression of ERβ4 and ERβ5 variants in more than half of the samples. Furthermore, expression of ERβ4 in the immortalized, normal mammary epithelial cell line MCF-10A that is resistant to mammosphere formation caused transformation and development of mammospheres. By contrast, ERβ1, ERβ2 or ERβ5 were unable to support mammosphere formation. We have previously shown that all variants except ERβ1 stabilizes HIF-1α but only ERβ4 appear to have the ability to transform normal mammary epithelial cells...
SUMMARYDeregulated gene expression through epigenetic, transcriptional, and copy number alteratio... more SUMMARYDeregulated gene expression through epigenetic, transcriptional, and copy number alterations is a major driver of melanoma progression and metastasis. In addition to serving as blueprints for translation, some mRNAs post-transcriptionally regulate gene expression by competitively sequestering miRNAs they share with other targets. Here we report that such mRNAs, termed competitive endogenous RNAs (ceRNAs), contribute to melanoma progression and metastasis. ceRNA predictions identified multiple candidate genes on chromosome 1q, which is recurrently amplified in melanoma. Genetic studies reveal that three of these mRNAs, CEP170, NUCKS1, and ZC3H11A, promote melanoma migration, invasion, and metastasis in a protein coding-independent and miRNA binding site-dependent manner. Interestingly, CEP170, NUCKS1, and ZC3H11A cooperate to elicit oncogenic effects by collectively impairing the tumor suppressor activity of 8 miRNAs on several pro-metastatic target genes. Finally, this comple...
Background. Identification of a shared gene expression pattern between T cell–mediated rejection ... more Background. Identification of a shared gene expression pattern between T cell–mediated rejection (TCMR) and antibody-mediated rejection (AMR) in human kidney allografts may help prioritize targets for the treatment of both types of acute rejection. Methods. We performed RNA sequencing and bioinformatics of genome-wide transcriptome profiles of urinary cells to identify novel mRNAs shared between TCMR and AMR and of mechanistic relevance. Customized RT-QPCR assays were then used to validate their abundance in urinary cells. Urinary cell transcriptome profiles and mRNA abundance were assessed in 22 urine samples matched to 22 TCMR biopsies, 7 samples matched to 7 AMR biopsies, and 24 samples matched to 24 No Rejection (NR) biopsies and correlated with biopsy diagnosis. Results. RNA sequencing data and bioinformatics identified 127 genes in urine to be shared between TCMR and AMR. We selected 3 novel mRNAs—ITM2A, SLAMF6, and IKZF3—for absolute quantification and validation by customized RT-QPCR assays. The abundance of all 3 mRNAs was significantly higher in urine matched to TCMR or AMR than in urine matched to NR biopsies. Receiver-operating-characteristic curve analysis showed that all 3 mRNAs distinguished TCMR or AMR from NR. Their abundance was similar in patients with TCMR and those with AMR. Conclusions. State-of-the-art antirejection therapies are mostly effective to treat TCMR but not AMR. Our identification of mRNAs shared between TCMR and AMR and contributing to T cell–B cell interactions may help prioritize therapeutic targets for the simultaneous treatment of TCMR and AMR.
These findings provide insights into the metabolic requirements of colorectal cancer and reveal a... more These findings provide insights into the metabolic requirements of colorectal cancer and reveal a novel approach for its treatment. Serine is a nonessential amino acid generated by the sequential actions of phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1), and phosphoserine phosphatase (PSPH). Increased serine biosynthesis occurs in several cancers and supports tumor growth. In addition, cancer cells can harness exogenous serine to enhance their metabolism and proliferation. Here we tested the relative contributions of exogenous and endogenous sources of serine on the biology of colorectal cancer. In murine tumors, Apc status was identified as a determinant of the expression of genes controlling serine synthesis. In patient samples, PSAT1 was overexpressed in both colorectal adenomas and adenocarcinomas. Combining genetic deletion of PSAT1 with exogenous serine deprivation maximally suppressed the proliferation of colorectal cancer cells and induced profound metabolic defects including diminished nucleotide production. Inhibition of serine synthesis enhanced the transcriptional changes following exogenous serine removal as well as alterations associated with DNA damage. Both loss of PSAT1 and removal of serine from the diet were necessary to suppress colorectal cancer xenograft growth and enhance the antitumor activity of 5-fluorouracil (5-FU). Restricting endogenous and exogenous serine in vitro augmented 5-FU–induced cell death, DNA damage, and metabolic perturbations, likely accounting for the observed antitumor effect. Collectively, our results suggest that both endogenous and exogenous sources of serine contribute to colorectal cancer growth and resistance to 5-FU. Significance: These findings provide insights into the metabolic requirements of colorectal cancer and reveal a novel approach for its treatment. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/81/9/2275/F1.large.jpg. Graphical Abstract
Summary Chromosomal instability (CIN) is a hallmark of human cancer yet not readily testable for ... more Summary Chromosomal instability (CIN) is a hallmark of human cancer yet not readily testable for patients with cancer in routine clinical setting. In this study, we sought to explore whether CIN status can be predicted using ubiquitously available hematoxylin and eosin histology through a deep learning-based model. When applied to a cohort of 1,010 patients with breast cancer (Training set: n = 858, Test set: n = 152) from The Cancer Genome Atlas where 485 patients have high CIN status, our model accurately classified CIN status, achieving an area under the curve of 0.822 with 81.2% sensitivity and 68.7% specificity in the test set. Patch-level predictions of CIN status suggested intra-tumor heterogeneity within slides. Moreover, presence of patches with high predicted CIN score within an entire slide was more predictive of clinical outcome than the average CIN score of the slide, thus underscoring the clinical importance of intra-tumor heterogeneity.
Coronavirus disease 19 (COVID-19) infection pandemic has affected remarkable morbidity and mortal... more Coronavirus disease 19 (COVID-19) infection pandemic has affected remarkable morbidity and mortality in a very short span of time. The overall disease profile and epidemiology is yet evolving but it seems to be highly infectious. Perinatal coronavirus infection is altogether a different perspective which has to be taken care of in a different way.
Despite infiltrating immune cells having an essential function in human disease and patients’ res... more Despite infiltrating immune cells having an essential function in human disease and patients’ responses to treatments, mechanisms influencing variability in infiltration patterns remain unclear. Here, using bulk RNA-seq data from 46 tissues in the Genotype-Tissue Expression project, we apply cell-type deconvolution algorithms to evaluate the immune landscape across the healthy human body. We discover that 49 of 189 infiltration-related phenotypes are associated with either age or sex (FDR
Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their ... more Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their aggressiveness with African ancestry is not established. We investigated primary TNBCs for gene expression among self-reported race (SRR) groups of African American (AA, n=42) and European American (EA, n=33) women. Using The Cancer Genome Atlas (TCGA) approaches, we analyzed RNA sequencing data to measure changes in genome-wide expression and used logistic regressions to identify ancestry-associated gene expression signatures. To determine global ancestry, GATK best practices were followed for variant calling, and used the 1000 Genomes Project as reference data. We identified >150 African ancestry-associated genes and found that, compared to SRR, quantitative genetic analysis was a more robust method to identify racial/ethnic-specific genes that were differentially expressed. A subset of African ancestry-specific genes that were upregulated in TNBCs of our AA patients were validated ...
7546Background: EZH2 is the catalytic subunit of PRC2, and induces methylation of H3K27. Activati... more 7546Background: EZH2 is the catalytic subunit of PRC2, and induces methylation of H3K27. Activating mutations and overexpression of EZH2 are found in NHL. Inactivating mutations in histone acetyltr...
International Journal of Applied and Computational Mathematics
In this paper, we discuss the multi-layer perceptron artificial neural network technique for the ... more In this paper, we discuss the multi-layer perceptron artificial neural network technique for the solution of homogeneous and non-homogeneous Lane–Emden type differential equations. Our aim is to produce an optimal solution of Lane–Emden equations with less computation using multi-layer perceptron artificial neural network technique, comparatively other numerical techniques. Several test examples have been considered to determine the robustness of the given method. The results obtained prove that the given technique has the capability to develop into an effective approach for solving Lane–Emden type problems with less computation time and memory space.
Obesity is associated with adipose inflammation, defined by macrophages encircling dead adipocyte... more Obesity is associated with adipose inflammation, defined by macrophages encircling dead adipocytes, as well as extracellular matrix (ECM) remodeling and increased risk of breast cancer. Whether ECM affects macrophage phenotype in obesity is uncertain. A better understanding of this relationship could be strategically important to reduce cancer risk or improve outcomes in the obese. Utilizing clinical samples, computational approaches, and in vitro decellularized ECM models, this study quantified the relative abundance of pro (M1)- and anti (M2)-inflammatory macrophages in human breast adipose tissue, determined molecular similarities between obesity and tumor-associated macrophages, and assessed the regulatory effect of obese versus lean ECM on macrophage phenotype. Our results suggest that breast adipose tissue contains more M2-biased than M1-biased macrophages across all body mass index (BMI) categories. Obesity further increased M2-biased macrophages but did not affect M1-biased macrophage density. Gene Set Enrichment Analysis (GSEA) suggested that breast tissue macrophages from obese versus lean women are more similar to tumor-associated macrophages (TAMs). These changes positively correlated with adipose tissue interstitial fibrosis, and in vitro experiments indicated that obese ECM directly stimulates M2-biased macrophage functions. However, mammographic density cannot be used as a clinical indicator of these changes. Collectively, these data suggest that obesity-associated interstitial fibrosis promotes a macrophage phenotype similar to TAMs, which may contribute to the link between obesity and breast cancer.
The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We ... more The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that humanRHAMMBpromoted liver metastasis. It was unknown whetherRHAMMBis upregulated in pancreatic cancer or contributes to its progression. In this study, we found that RHAMM protein was frequently upregulated in human PNETs. We investigated alternative splicing isoforms,RHAMMAandRHAMMB, by RNA-Seq analysis of primary PNETs and liver metastases.RHAMMB, but notRHAMMA, was significantly upregulated in liver metastases. RHAMMBwas crucial forin vivometastatic capacity of mouse and human PNETs. RHAMMA, carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover,RHAMMBwas substantially higher thanRHAMMAin pancreatic ductal adenocarcinoma (PDAC)....
Hürthle cell carcinoma (HCC) is an unusual and relatively rare type of differentiated thyroid can... more Hürthle cell carcinoma (HCC) is an unusual and relatively rare type of differentiated thyroid cancer. Currently, cytologic analysis of fine-needle aspiration biopsy is limited in distinguishing benign Hürthle cell neoplasms from malignant ones. The aim of this study was to determine whether differences in the expression of specific genes could differentiate HCC from benign Hürthle cell nodules by evaluating differential gene expression in Hürthle cell disease. Eighteen benign Hürthle cell nodules and seven HCC samples were analyzed by whole-transcriptome sequencing. Bioinformatics analysis was carried out to identify candidate differentially expressed genes. Expression of these candidate genes was re-examined by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was quantified by immunohistochemistry. Close homolog of L1 (CHL1) was identified as overexpressed in HCC. CHL1 was found to have greater than 15-fold higher expression in fragments per kilobase m...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 16, 2018
Based on the identified stress-independent cellular functions of activating transcription factor ... more Based on the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in triple negative breast cancer (TNBC) patients, but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine effects on breast cancer patient survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature. Patient survival data was determined by Kaplan-Meier analysis. Relationship between TGFβ and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and using patient-derived xenografts (PDXs). overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFβ was identified. expression inhib...
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Papers by AKANKSHA VERMA