Publications by authors named "Anshita Goel"

12 Publications

  • Page 1 of 1

An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer.

Nat Commun 2021 04 16;12(1):2301. Epub 2021 Apr 16.

Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
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http://dx.doi.org/10.1038/s41467-021-22465-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052448PMC
April 2021

PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium.

Front Oncol 2021 25;11:626748. Epub 2021 Feb 25.

Bladder Cancer Research Centre, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.

The use of immune checkpoint blockade, in particular PD-1 and PD-L1 inhibitors, is now commonplace in many clinical settings including the treatment of muscle-invasive bladder cancer (MIBC). Notwithstanding, little information exists regarding the expression of the alternative PD-1 ligand, PD-L2 in urothelial bladder cancer (UBC). We therefore set out to characterise the expression of PD-L2 in comparison to PD-L1. Firstly, we assessed PD-L2 expression by immunohistochemistry and found widespread expression of PD-L2 in UBC, albeit with reduced expression in MIBC. We further investigated these findings using RNA-seq data from a cohort of 575 patients demonstrating that PDCD1LG2 (PD-L2) is widely expressed in UBC and correlated with CD274 (PD-L1). However, in contrast to our immunohistochemistry findings, expression was significantly increased in advanced disease. We have also provided detailed evidence of constitutive PD-L2 expression in normal urothelium and propose a mechanism by which PD-L2 is cleaved from the cell surface in MIBC. These data provide a comprehensive assessment of PD-L2 in UBC, showing PD-L2 is abundant in UBC and, importantly, constitutively present in normal urothelium. These data have implications for future development of immune checkpoint blockade, and also the understanding of the function of the immune system in the normal urinary bladder.
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http://dx.doi.org/10.3389/fonc.2021.626748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951139PMC
February 2021

COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study.

Lancet Oncol 2020 10 24;21(10):1309-1316. Epub 2020 Aug 24.

Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.

Background: Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK.

Methods: We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case-fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models.

Findings: 319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case-fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40-49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio [OR] 1·57, 95% CI 1·15-2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case-fatality rate (2·25, 1·13-4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09-4·08; p=0·028).

Interpretation: Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk-benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies.

Funding: University of Birmingham and University of Oxford.
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http://dx.doi.org/10.1016/S1470-2045(20)30442-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444972PMC
October 2020

Back-Splicing Transcript Isoforms (Circular RNAs) Affect Biologically Relevant Pathways and Offer an Additional Layer of Information to Stratify NMIBC Patients.

Front Oncol 2020 22;10:812. Epub 2020 May 22.

Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Circularized transcript isoforms due to back-splicing are increasingly being reported in different tissues types and pathological states including cancer. Since these circular RNAs (circRNAs) are more stable than linear messenger RNA their identification and profiling in tumor tissue could aid in stratifying patients and may serve as biomarkers. In this study, we have investigated the relationship between circRNA expression and tumor grade in a cohort of 58, mostly non-muscle-invasive bladder cancer patients. From 4571 circRNAs detected, we identified 157 that were significantly differentially expressed between tumor grades relative to the linear transcript. We demonstrated that such grade-related differences can be identified in an independent cohort, and that a large fraction of circRNAs can be, in principle, detected in urine. The differentially expressed circRNAs cluster into subgroups according to their co-expression, subgroups which are enriched for DNA repair, cell cycle and intracellular signaling genes. Since one proposed function of circRNAs is to interfere with gene-regulation by acting as microRNA "sponges," candidates which were differentially expressed between tumor grades were investigated for potential miRNA target sites. By investigating the circRNAs from bladder cancer related pathways we demonstrated that the expression of these pathways, the circRNAs, and their parental genes are often decoupled and do not correlate, yet that some circRNAs do not follow this tendency. The present study provides the next step for the comprehensive evaluation of this novel class of RNAs in the context of non-muscle-invasive bladder cancer. Intriguingly, despite their possible function as microRNA sponges, they potentially affect host mRNA levels at the transcriptional stage, as compared to post-transcriptional control by miRNAs. Our analysis indicates differences of their activity between bladder cancer tumor stages, and their relative expression levels may provide an additional layer of information for patient stratification.
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http://dx.doi.org/10.3389/fonc.2020.00812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326039PMC
May 2020

COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study.

Lancet 2020 06 28;395(10241):1919-1926. Epub 2020 May 28.

Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.

Background: Individuals with cancer, particularly those who are receiving systemic anticancer treatments, have been postulated to be at increased risk of mortality from COVID-19. This conjecture has considerable effect on the treatment of patients with cancer and data from large, multicentre studies to support this assumption are scarce because of the contingencies of the pandemic. We aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in patients with cancer.

Methods: In this prospective observational study, all patients with active cancer and presenting to our network of cancer centres were eligible for enrolment into the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effects of COVID-19 on patients with cancer. Eligible patients tested positive for severe acute respiratory syndrome coronavirus 2 on RT-PCR assay from a nose or throat swab. We excluded patients with a radiological or clinical diagnosis of COVID-19, without a positive RT-PCR test. The primary endpoint was all-cause mortality, or discharge from hospital, as assessed by the reporting sites during the patient hospital admission.

Findings: From March 18, to April 26, 2020, we analysed 800 patients with a diagnosis of cancer and symptomatic COVID-19. 412 (52%) patients had a mild COVID-19 disease course. 226 (28%) patients died and risk of death was significantly associated with advancing patient age (odds ratio 9·42 [95% CI 6·56-10·02]; p<0·0001), being male (1·67 [1·19-2·34]; p=0·003), and the presence of other comorbidities such as hypertension (1·95 [1·36-2·80]; p<0·001) and cardiovascular disease (2·32 [1·47-3·64]). 281 (35%) patients had received cytotoxic chemotherapy within 4 weeks before testing positive for COVID-19. After adjusting for age, gender, and comorbidities, chemotherapy in the past 4 weeks had no significant effect on mortality from COVID-19 disease, when compared with patients with cancer who had not received recent chemotherapy (1·18 [0·81-1·72]; p=0·380). We found no significant effect on mortality for patients with immunotherapy, hormonal therapy, targeted therapy, radiotherapy use within the past 4 weeks.

Interpretation: Mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from COVID-19 disease compared with those not on active treatment.

Funding: University of Birmingham, University of Oxford.
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http://dx.doi.org/10.1016/S0140-6736(20)31173-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255715PMC
June 2020

Integrative analysis of spontaneous CLL regression highlights genetic and microenvironmental interdependency in CLL.

Blood 2020 02;135(6):411-428

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.

Spontaneous regression is a recognized phenomenon in chronic lymphocytic leukemia (CLL) but its biological basis remains unknown. We undertook a detailed investigation of the biological and clinical features of 20 spontaneous CLL regression cases incorporating phenotypic, functional, transcriptomic, and genomic studies at sequential time points. All spontaneously regressed tumors were IGHV-mutated with no restricted IGHV usage or B-cell receptor (BCR) stereotypy. They exhibited shortened telomeres similar to nonregressing CLL, indicating prior proliferation. They also displayed low Ki-67, CD49d, cell-surface immunoglobulin M (IgM) expression and IgM-signaling response but high CXCR4 expression, indicating low proliferative activity associated with poor migration to proliferation centers, with these features becoming increasingly marked during regression. Spontaneously regressed CLL displayed a transcriptome profile characterized by downregulation of metabolic processes as well as MYC and its downstream targets compared with nonregressing CLL. Moreover, spontaneous regression was associated with reversal of T-cell exhaustion features including reduced programmed cell death 1 expression and increased T-cell proliferation. Interestingly, archetypal CLL genomic aberrations including HIST1H1B and TP53 mutations and del(13q14) were found in some spontaneously regressing tumors, but genetic composition remained stable during regression. Conversely, a single case of CLL relapse following spontaneous regression was associated with increased BCR signaling, CLL proliferation, and clonal evolution. These observations indicate that spontaneously regressing CLL appear to undergo a period of proliferation before entering a more quiescent state, and that a complex interaction between genomic alterations and the microenvironment determines disease course. Together, the findings provide novel insight into the biological processes underpinning spontaneous CLL regression, with implications for CLL treatment.
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http://dx.doi.org/10.1182/blood.2019001262DOI Listing
February 2020

Tropomyosins: Potential Biomarkers for Urothelial Bladder Cancer.

Int J Mol Sci 2019 Mar 4;20(5). Epub 2019 Mar 4.

Institute of Cancer and Genomic Sciences, College of Medicine and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

Despite the incidence and prevalence of urothelial bladder cancer (UBC), few advances in treatment and diagnosis have been made in recent years. In this review, we discuss potential biomarker candidates: the tropomyosin family of genes, encoded by four loci in the human genome. The expression of these genes is tissue-specific. Tropomyosins are responsible for diverse cellular roles, most notably based upon their interplay with actin to maintain cellular processes, integrity and structure. Tropomyosins exhibit a large variety of splice forms, and altered isoform expression levels have been associated with cancer, including UBC. Notably, tropomyosin isoforms are detectable in urine, offering the potential for non-invasive diagnosis and risk-stratification. This review collates the basic knowledge on tropomyosin and its isoforms, and discusses their relationships with cancer-related phenomena, most specifically in UBC.
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http://dx.doi.org/10.3390/ijms20051102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429115PMC
March 2019

Seed Pro-Nutra Care: A tool for characterization of seed storage proteins and database of bioactive peptides having potential health benefits.

Bioinformation 2014 30;10(9):592-4. Epub 2014 Sep 30.

Department of Molecular Biology & Genetic Engineering College of Basic Sciences & Humanities, G.B. Pant University of Agriculture & Technology, Pantnagar-263 145 (India).

Unlabelled: Seed storage proteins, the major food proteins, possess unique physicochemical characteristics which determine their nutritional importance and influence their utilization by humans. Here, we describe a database driven tool named Seed Pro-Nutra Care which comprises a systematic compendium of seed storage proteins and their bioactive peptides influencing several vital organ systems for maintenance of health. Seed Pro-Nutra Careis an integrated resource on seed storage protein. This resource help in the (I) Characterization of proteins whether they belong to seed storage protein group or not. (II) Identification the bioactive peptides with their sequences using peptide name (III) Determination of physico chemical properties of seed storage proteins. (IV) Epitope identification and mapping (V) Allergenicity prediction and characterization. Seed Pro-Nutra Care is a compilation of data on bioactive peptides present in seed storage proteins from our own collections and other published and unpublished sources. The database provides an information resource of a variety of seed related biological information and its use for nutritional and biomedical application.

Availability: http://www.gbpuat-cbsh.ac.in/departments/bi/database/seed_pro_nutra_care/
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http://dx.doi.org/10.6026/97320630010592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209369PMC
October 2014

TRIPATH: A Biological Genetic and Genomic Database of Three Economically Important Fungal Pathogen of Wheat - Rust: Smut: Bunt.

Bioinformation 2014 22;10(7):466-8. Epub 2014 Jul 22.

Department of Molecular Biology & Genetic Engineering, College of Basic Sciences & Humanities, G.B. Pant University of Agriculture & Technology, Pantnagar-263 145 (India).

Unlabelled: Wheat, the major source of vegetable protein in human diet, provides staple food globally for a large proportion of the human population. With higher protein content than other major cereals, wheat has great socio- economic importance. Nonetheless for wheat, three important fungal pathogens i.e. rust, smut and bunt are major cause of significant yield losses throughout the world. Researchers are putting up a strong fight against devastating wheat pathogens, and have made progress in tracking and controlling disease outbreaks from East Africa to South Asia. The aim of the present work hence was to develop a fungal pathogens database dedicated to wheat, gathering information about different pathogen species and linking them to their biological classification, distribution and control. Towards this end, we developed an open access database Tripath: A biological, genetic and genomic database of economically important wheat fungal pathogens - rust: smut: bunt. Data collected from peer-reviewed publications and fungal pathogens were added to the customizable database through an extended relational design. The strength of this resource is in providing rapid retrieval of information from large volumes of text at a high degree of accuracy. Database TRIPATH is freely accessible.

Availability: http://www.gbpuat-cbsh.ac.in/departments/bi/database/tripath/
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http://dx.doi.org/10.6026/97320630010466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135297PMC
September 2014

Phyto diab care: Phytoremedial database for antidiabetics.

Bioinformation 2013 13;9(7):375-7. Epub 2013 Apr 13.

Department of Molecular Biology & Genetic Engineering College of Basic Sciences & Humanities G.B. Pant University of Agriculture & Technology, Pantnagar-263 145 India.

Unlabelled: Diabetes, a chronic disease debilitating to normal healthy lifestyle, onsets due to insufficient amount of insulin production or ineffective utilization of the amount produced. Although, pharmaceutical research has brought up remedial drugs and numerous candidates in various phases of clinical trials, off-target effects and unwanted physiological actions are a constant source of concern and contra indicatory in case of diabetic patients. Here we present a phytoremedial database, Phyto Diab Care, broadly applicable to any known anti-diabetic medicinal plant and phytochemicals sourced from them. Utilization of the traditional medicine knowledge for combating diabetes without creating unwanted physiological actions is our major emphasis. Data collected from peer-reviewed publications and phytochemicals were added to the customizable database by means of an extended relational design. The strength of this resource is in providing rapid retrieval of data from large volumes of text at a high degree of accuracy. Enhanced web interface allows multi-criteria based information filtering. Furthermore, the availability of 2D and 3D structures from molecular docking studies with any efficacy on the insulin signaling pathway makes the resource searchable and comparable in an intuitive manner. Phyto Diab Care compendium is publicly available and can be found in online.

Availability: http://www.gbpuat-cbsh.ac.in/departments/bi/database/phytodiabcare/HOME%20PAGE/Home%20page.html.
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http://dx.doi.org/10.6026/97320630009375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669791PMC
June 2013

In silico analysis of expression data for identification of genes involved in spatial accumulation of calcium in developing seeds of rice.

OMICS 2012 Jul-Aug;16(7-8):402-13. Epub 2012 Jun 26.

Department of Molecular Biology and Genetic Engineering, College of Basic Sciences and Humanities, G.B. Pant University of Agriculture and Technology, Pantnagar, India.

The calcium (Ca(2+)) transporters, like Ca(2+) channels, Ca(2+) ATPases, and Ca(2+) exchangers, are instrumental for signaling and transport. However, the mechanism by which they orchestrate the accumulation of Ca(2+) in grain filling has not yet been investigated. Hence the present study was designed to identify the potential calcium transporter genes that may be responsible for the spatial accumulation of calcium during grain filling. In silico expression analyses were performed to identify Ca(2+) transporters that predominantly express during the different developmental stages of Oryza sativa. A total of 13 unique calcium transporters (7 from massively parallel signature sequencing [MPSS] data analysis, and 9 from microarray analysis) were identified. Analysis of variance (ANOVA) revealed differential expression of the transporters across tissues, and principal component analysis (PCA) exhibited their seed-specific distinctive expression profile. Interestingly, Ca(2+) exchanger genes are highly expressed in the initial stages, whereas some Ca(2+) ATPase genes are highly expressed throughout seed development. Furthermore, analysis of the cis-elements located in the promoter region of the subset of 13 genes suggested that D of proteins play essential roles in regulating the expression of Ca(2+) transporter genes during rice seed development. Based on these results, we developed a hypothetical model explaining the transport and tissue specific distribution of calcium in developing cereal seeds. The model may be extrapolated to understand the mechanism behind the exceptionally high level of calcium accumulation seen in grains like finger millet.
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http://dx.doi.org/10.1089/omi.2012.0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394857PMC
November 2012

Genome-wide comparative in silico analysis of calcium transporters of rice and sorghum.

Genomics Proteomics Bioinformatics 2011 Oct;9(4-5):138-50

Department of Molecular Biology and Genetic Engineering, College of Basic Sciences and Humanities, G.B. Pant University of Agriculture and Technology, Pantnagar 263145, India.

The mechanism of calcium uptake, translocation and accumulation in Poaceae has not yet been fully understood. To address this issue, we conducted genome-wide comparative in silico analysis of the calcium (Ca(2+)) transporter gene family of two crop species, rice and sorghum. Gene annotation, identification of upstream cis-acting elements, phylogenetic tree construction and syntenic mapping of the gene family were performed using several bioinformatics tools. A total of 31 Ca(2+) transporters, distributed on 9 out of 12 chromosomes, were predicted from rice genome, while 28 Ca(2+) transporters predicted from sorghum are distributed on all the chromosomes except chromosome 10 (Chr 10). Interestingly, most of the genes on Chr 1 and Chr 3 show an inverse syntenic relationship between rice and sorghum. Multiple sequence alignment and motif analysis of these transporter proteins revealed high conservation between the two species. Phylogenetic tree could very well identify the subclasses of channels, ATPases and exchangers among the gene family. The in silico cis-regulatory element analysis suggested diverse functions associated with light, stress and hormone responsiveness as well as endosperm- and meristem-specific gene expression. Further experiments are warranted to validate the in silico analysis of the predicted transporter gene family and elucidate the functions of Ca(2+) transporters in various biological processes.
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http://dx.doi.org/10.1016/S1672-0229(11)60017-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054455PMC
October 2011