Publications by authors named "Sonal Gupta"

87 Publications

Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma.

Cancers (Basel) 2021 Nov 15;13(22). Epub 2021 Nov 15.

Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of and loss-of-function mutations of () have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing -Cre mice bearing conditional alleles of mutant and/or floxed Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant alone (KA), bi-allelic loss of hepatic (BA), and heterozygous loss of in conjunction with mutant expression (BKA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of in conjunction with mutant expression (BKA) developed discrete foci of HCC and ICC. Further, the median survival of BKA mice was significantly shorter at 24 weeks when compared to the median survival of ≥40 weeks in BKA mice and approximately 50 weeks in BA and KA mice ( < 0.001). Microarray analysis performed on liver tissue from KA and BKA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm.
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http://dx.doi.org/10.3390/cancers13225709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616431PMC
November 2021

The Omic Insights on Unfolding Saga of COVID-19.

Front Immunol 2021;12:724914. Epub 2021 Oct 20.

Bioclues.org, Hyderabad, India.

The year 2019 has seen an emergence of the novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease of 2019 (COVID-19). Since the onset of the pandemic, biological and interdisciplinary research is being carried out across the world at a rapid pace to beat the pandemic. There is an increased need to comprehensively understand various aspects of the virus from detection to treatment options including drugs and vaccines for effective global management of the disease. In this review, we summarize the salient findings pertaining to SARS-CoV-2 biology, including symptoms, hosts, epidemiology, SARS-CoV-2 genome, and its emerging variants, viral diagnostics, host-pathogen interactions, alternative antiviral strategies and application of machine learning heuristics and artificial intelligence for effective management of COVID-19 and future pandemics.
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http://dx.doi.org/10.3389/fimmu.2021.724914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564481PMC
November 2021

The incidence and prevalence of cardiovascular diseases in gout: a systematic review and meta-analysis.

Rheumatol Int 2021 Jul 13;41(7):1209-1219. Epub 2021 May 13.

Department of Health Data Science, University of Liverpool, Liverpool, UK.

The aims of this systematic review and meta-analysis were to describe prevalence of cardiovascular disease in gout, compare these results with non-gout controls and consider whether there were differences according to geography. PubMed, Scopus and Web of Science were systematically searched for studies reporting prevalence of any cardiovascular disease in a gout population. Studies with non-representative sampling, where a cohort had been used in another study, small sample size (< 100) and where gout could not be distinguished from other rheumatic conditions were excluded, as were reviews, editorials and comments. Where possible meta-analysis was performed using random-effect models. Twenty-six studies comprising 949,773 gout patients were included in the review. Pooled prevalence estimates were calculated for five cardiovascular diseases: myocardial infarction (2.8%; 95% confidence interval (CI)s 1.6, 5.0), heart failure (8.7%; 95% CI 2.9, 23.8), venous thromboembolism (2.1%; 95% CI 1.2, 3.4), cerebrovascular accident (4.3%; 95% CI 1.8, 9.7) and hypertension (63.9%; 95% CI 24.5, 90.6). Sixteen studies reported comparisons with non-gout controls, illustrating an increased risk in the gout group across all cardiovascular diseases. There were no identifiable reliable patterns when analysing the results by country. Cardiovascular diseases are more prevalent in patients with gout and should prompt vigilance from clinicians to the need to assess and stratify cardiovascular risk. Future research is needed to investigate the link between gout, hyperuricaemia and increased cardiovascular risk and also to establish a more thorough picture of prevalence for less common cardiovascular diseases.
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http://dx.doi.org/10.1007/s00296-021-04876-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164620PMC
July 2021

Genome-editing approaches and applications: a brief review on CRISPR technology and its role in cancer.

3 Biotech 2021 Mar 26;11(3):146. Epub 2021 Feb 26.

Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Statue Circle, Jaipur, India.

The development of genome-editing technologies in 1970s has discerned a new beginning in the field of science. Out of different genome-editing approaches such as Zing-finger nucleases, TALENs, and meganucleases, clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 (CRISPR/Cas9) is a recent and versatile technology that has the ability of making changes to the genome of different organisms with high specificity. Cancer is a complex process that is characterized by multiple genetic and epigenetic changes resulting in abnormal cell growth and proliferation. As cancer is one of the leading causes of deaths worldwide, a large number of studies are done to understand the molecular mechanisms underlying the development of cancer. Because of its high efficiency and specificity, CRISPR/Cas9 has emerged as a novel and powerful tool in the field of cancer research. CRISPR/Cas9 has the potential to accelerate cancer research by dissecting tumorigenesis process, generating animal and cellular models, and identify drug targets for chemotherapeutic approaches. However, despite having tremendous potential, there are certain challenges associated with CRISPR/Cas9 such as safe delivery to the target, potential off-target effects and its efficacy which needs to be addressed prior to its clinical application. In this review, we give a gist of different genome-editing technologies with a special focus on CRISPR/Cas9 development, its mechanism of action and its applications, especially in different type of cancers. We also highlight the importance of CRISPR/Cas9 in generating animal models of different cancers. Finally, we present an overview of the clinical trials and discuss the challenges associated with translating CRISPR/Cas9 in clinical use.
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http://dx.doi.org/10.1007/s13205-021-02680-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910401PMC
March 2021

Interaction of Plasmodium falciparum apicortin with α- and β-tubulin is critical for parasite growth and survival.

Sci Rep 2021 02 25;11(1):4688. Epub 2021 Feb 25.

Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.

Cytoskeletal structures of Apicomplexan parasites are important for parasite replication, motility, invasion to the host cell and survival. Apicortin, an Apicomplexan specific protein appears to be a crucial factor in maintaining stability of the parasite cytoskeletal assemblies. However, the function of apicortin, in terms of interaction with microtubules still remains elusive. Herein, we have attempted to elucidate the function of Plasmodium falciparum apicortin by monitoring its interaction with two main components of parasite microtubular structure, α-tubulin-I and β-tubulin through in silico and in vitro studies. Further, a p25 domain binding generic drug Tamoxifen (TMX), was used to disrupt PfApicortin-tubulin interactions which led to the inhibition in growth and progression of blood stage life cycle of P. falciparum.
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http://dx.doi.org/10.1038/s41598-021-83513-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907060PMC
February 2021

Pathogen induced subversion of NAD metabolism mediating host cell death: a target for development of chemotherapeutics.

Cell Death Discov 2021 Jan 13;7(1):10. Epub 2021 Jan 13.

Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.

Hijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.
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http://dx.doi.org/10.1038/s41420-020-00366-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806871PMC
January 2021

Comorbidities in psoriatic arthritis: a systematic review and meta-analysis.

Rheumatol Int 2021 Feb 9;41(2):275-284. Epub 2021 Jan 9.

Musculoskeletal Biology, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L69 3GA, UK.

The aims of this systematic review and meta-analysis were to: (1) describe the prevalence of commonly reported comorbidities in psoriatic arthritis (PsA), (2) compare the incidence and/or prevalence of comorbidities between PsA and control populations; and (3) examine the impact of comorbidities on PsA outcomes. We systematically searched Medline, PubMed, Scopus, and Web of Science using a predefined protocol in accordance with PRISMA guidelines. Studies reporting only one comorbidity, or a few closely related diseases within one organ system, were excluded. Where possible, meta-analysis was performed using random-effects models. We included 39 studies amounting to over 152 thousand PsA patients. We performed meta-analysis for the prevalence of 21 commonly reported comorbidities. The most prevalent comorbidities were hypertension (pooled prevalence 34%), metabolic syndrome (29%), obesity (27%), hyperlipidaemia (24%) and any cardiovascular diseases (19%). Eleven studies consistently showed higher prevalence of comorbidities in PsA than controls. Five studies showed that comorbid patients had more severe disease, poorer quality of life, and increased discontinuation of treatment. Comorbidities, particularly cardiometabolic disorders, were highly prevalent in PsA and more common than in healthy controls. Comorbidities were associated with adverse disease features, but more research is needed on their impact on longitudinal outcomes such as treatment response, work productivity and mortality.
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http://dx.doi.org/10.1007/s00296-020-04775-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835184PMC
February 2021

Highly potent anti-malarial activity of benzopyrano(4,3-b)benzopyran derivatives and interaction analysis with putative target lactate dehydrogenase.

J Biomol Struct Dyn 2021 Jan 8:1-16. Epub 2021 Jan 8.

Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.

Malaria infection caused by is majorly responsible for millions of deaths in humans every year. Moreover, a rapid increase in resistance to existing drugs has posed an urgent need for new anti-malarials. Herein, we report the highly potent anti-malarial activity of benzopyrano(4,3-b)benzopyran derivatives, inspired from naturally occurring dependensin against chloroquine (CQ) sensitive and resistant strains. Chemically synthesized, four dependensin analogs exhibited growth inhibition at nanomolar concentrations ranging from 63.96 to 725.8 nM by blocking the parasite development at the ring and early trophozoite stages. The growth inhibitory activity of dependensin analogs was correlated with their anti-plasmodial lactate dehydrogenase activity by computational analysis. Molecular docking, 50 ns simulation and a 2D-Quantitative Structure-Activity Relationship (2D-QSAR) modelling revealed the interaction with their putative target lactate dehydrogenase (PfLDH). Here, developing the predictive 2D descriptors such as thermodynamic, spatial, electronic, and topological with multiple linear regression analysis (MLRA), the structural requirements for potent and selective PfLDH inhibitory activity has been identified. The strong binding of compound to the catalytic Nicotinamide adenine dinucleotide (NADH) binding pocket of the PfLDH further supported the PfLDH targeting potential of dependensin analogs. Overall, this study revealed a highly potent anti-malarial activity of benzopyrano(4,3-b)benzopyran derivatives with their putative anti-PfLDH activity.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1868336DOI Listing
January 2021

Deciphering LncRNA-protein interactions using docking complexes.

J Biomol Struct Dyn 2020 Dec 7:1-8. Epub 2020 Dec 7.

Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research (BISR), Jaipur, India.

Deciphering RNA-protein interactions are important to study principal biological mechanisms including transcription and translation regulation, gene silencing, among others. Predicting RNA molecule interaction with the target protein could allow us to understand important cellular processes and design novel treatment therapies for various diseases. As non-coding RNAs do not have coding potential our knowledge about their functions is still limited. Therefore, RNA-binding proteins of non-coding RNAs regulating functions, including cellular maturation, nuclear export and stability may play a very important role. Keeping in view of the need for refined methods to understand protein-RNA interactions, we have attempted a docking model to infer binding sites between lncRNA NONHSAT02007 and protein KIF13A for a rare disease phenotype that we are studying in our lab.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1850354DOI Listing
December 2020

A Pilot Study on the Whole Exome Sequencing of Prostate Cancer in the Indian Phenotype Reveals Distinct Polymorphisms.

Front Genet 2020 25;11:874. Epub 2020 Aug 25.

Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur, India.

Prostate cancer (PCa) is the third most common cancer among men in India, and no next-generation sequencing (NGS) studies have been attempted earlier. Recent advances in NGS have heralded the discovery of biomarkers from Caucasian/European and Chinese ancestry, but not much is known about the Indian phenotype/variant of PCa. In a pilot study using the whole exome sequencing of benign/PCa patients, we identified characteristic mutations specific to the Indian sub-population. We observed a large number of mutations in DNA repair genes, helicases, TP53, and BRCA besides the variants of unknown significance with a possibly damaging rare variant (rs730881069/chr19:55154172C/TR136Q) in the TNNI3 gene that has been previously reported as a semi-conservative amino acid substitution. Our pilot study attempts to bring an understanding of PCa prognosis and recurrence for the Indian phenotype.
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http://dx.doi.org/10.3389/fgene.2020.00874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477354PMC
August 2020

Corrigendum to "Effect of weather on COVID-19 spread in the US: A prediction model for India in 2020" [Sci. Total Environ. 728 (2020) 1-8/138860].

Sci Total Environ 2020 Dec 6;748:142577. Epub 2020 Oct 6.

Centre for Biomedical Engineering, IIT, Delhi, India; Department of Biomedical Engineering, AIIMS, Delhi, India. Electronic address:

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http://dx.doi.org/10.1016/j.scitotenv.2020.142577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537598PMC
December 2020

Paradoxical Role of AT-rich Interactive Domain 1A in Restraining Pancreatic Carcinogenesis.

Cancers (Basel) 2020 Sep 21;12(9). Epub 2020 Sep 21.

Department of Translational Molecular Pathology and Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

: ARID1A is postulated to be a tumor suppressor gene owing to loss-of-function mutations in human pancreatic ductal adenocarcinomas (PDAC). However, its role in pancreatic pathogenesis is not clear despite recent studies using genetically engineered mouse (GEM) models. We aimed at further understanding of its direct functional role in PDAC, using a combination of GEM model and PDAC cell lines. : Pancreas-specific mutant -driven GEM model (-Cre; ; or "KAC") was generated by crossing -Cre; ("KC") mice with mice and characterized histologically with timed necropsies. was also deleted using CRISPR-Cas9 system in established human and murine PDAC cell lines to study the immediate effects of Arid1a loss in isogenic models. Cell lines with or without Arid1a expression were developed from respective autochthonous PDAC GEM models, compared functionally using various culture assays, and subjected to RNA-sequencing for comparative gene expression analysis. DNA damage repair was analyzed in cultured cells using immunofluorescence and COMET assay. : Retention of Arid1a is critical for early progression of mutant -driven pre-malignant lesions into PDAC, as evident by lower Ki-67 and higher apoptosis staining in "KAC" as compared to "KC" mice. Enforced deletion of in established PDAC cell lines caused suppression of cellular growth and migration, accompanied by compromised DNA damage repair. Despite early development of relatively indolent cystic precursor lesions called intraductal papillary mucinous neoplasms (IPMNs), a subset of "KAC" mice developed aggressive PDAC in later ages. PDAC cells obtained from older autochthonous "KAC" mice revealed various compensatory ("escaper") mechanisms to overcome the growth suppressive effects of Arid1a loss. : Arid1a is an essential survival gene whose loss impairs cellular growth, and thus, its expression is critical during early stages of pancreatic tumorigenesis in mouse models. In tumors that arise in the setting of ARID1A loss, a multitude of "escaper" mechanisms drive progression.
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http://dx.doi.org/10.3390/cancers12092695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564752PMC
September 2020

Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer.

J Exp Med 2020 12;217(12)

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with an immunosuppressive microenvironment that is resistant to most therapies. IL17 is involved in pancreatic tumorigenesis, but its role in invasive PDAC is undetermined. We hypothesized that IL17 triggers and sustains PDAC immunosuppression. We inhibited IL17/IL17RA signaling using pharmacological and genetic strategies alongside mass cytometry and multiplex immunofluorescence techniques. We uncovered that IL17 recruits neutrophils, triggers neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from tumors. Additionally, IL17 blockade increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Inhibition of neutrophils or Padi4-dependent NETosis phenocopies IL17 neutralization. NMR spectroscopy revealed changes in tumor lactate as a potential early biomarker for IL17/PD-1 combination efficacy. Higher expression of IL17 and PADI4 in human PDAC corresponds with poorer prognosis, and the serum of patients with PDAC has higher potential for NETosis. Clinical studies with IL17 and checkpoint blockade represent a novel combinatorial therapy with potential efficacy for this lethal disease.
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http://dx.doi.org/10.1084/jem.20190354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953739PMC
December 2020

The prevalence and impact of depression in primary systemic vasculitis: a systematic review and meta-analysis.

Rheumatol Int 2020 Aug 4;40(8):1215-1221. Epub 2020 Jun 4.

Department of Academic Rheumatology, Liverpool University Hospitals, Liverpool, L9 7AL, UK.

Objective: To describe the prevalence of depression among patients with primary systemic vasculitides (PSV); compare prevalence according to vasculitis type and against controls; and examine the impact of depression on PSV outcomes.

Methods: We searched Medline, PubMed, Scopus and Web of Science using a predefined protocol in accordance with PRISMA guidelines. We included all studies that reported the prevalence or impact of depression in PSV. We also included polymyalgia rheumatica (PMR) given its association with giant cell arteritis (GCA). Meta-analyses of prevalence estimates were performed using random-effects models and reported as percentages (95% confidence interval).

Results: We reviewed a total of 15 studies that described the prevalence of depression, categorised into small (n = 10) and large vessel vasculitis (n = 7). Pooled prevalence estimate for depression in a small vessel (predominantly ANCA-associated) vasculitis was 28% (95% CI 20-38%) with significant heterogeneity (I = 93%). Depression prevalence in large-vessel vasculitis (Takayasu and GCA/PMR) was 24% (95% CI 17-34%), again with significant heterogeneity (I = 96%). One study reported 56% prevalence of depression in medium vessel disease. The prevalence of depression in small vessel vasculitis was higher than healthy controls. In these patients, depression and depressive symptoms were associated with poorer quality of life, adherence, and work disability, but not disease activity or damage.

Conclusion: Depression is highly prevalent among patients with primary systemic vasculitis and associated with poorer outcomes across a range of measures in studies of small vessel disease. Further studies are needed for depression in medium and large vessel vasculitides.
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http://dx.doi.org/10.1007/s00296-020-04611-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316669PMC
August 2020

Effect of weather on COVID-19 spread in the US: A prediction model for India in 2020.

Sci Total Environ 2020 Aug 21;728:138860. Epub 2020 Apr 21.

Centre for Biomedical Engineering, IIT, Delhi, India; Department of Biomedical Engineering, AIIMS, Delhi, India. Electronic address:

The effect of weather on COVID-19 spread is poorly understood. Recently, few studies have claimed that warm weather can possibly slowdown the global pandemic, which has already affected over 1.6 million people worldwide. Clarification of such relationships in the worst affected country, the US, can be immensely beneficial to understand the role of weather in transmission of the disease in the highly populated countries, such as India. We collected the daily data of new cases in 50 US states between Jan 1-Apr 9, 2020 and also the corresponding weather information (i.e., temperature (T) and absolute humidity (AH)). Distribution modeling of new cases across AH and T, helped identify the narrow and vulnerable AH range. We validated the results for 10-day intervals against monthly observations, and also worldwide trends. The results were used to predict Indian regions which would be vulnerable to weather based spread in upcoming months of 2020. COVID-19 spread in the US is significant for states with 4 < AH < 6 g/m and number of new cases > 10,000, irrespective of the chosen time intervals for study parameters. These trends are consistent with worldwide observations, but do not correlate well with India so far possibly due the total cases reported per interval < 10,000. The results clarify the relationship between weather parameters and COVID-19 spread. The vulnerable weather parameters will help classify the risky geographic areas in different countries. Specifically, with further reporting of new cases in India, prediction of states with high risk of weather based spread will be apparent.
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http://dx.doi.org/10.1016/j.scitotenv.2020.138860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194548PMC
August 2020

Correction to: Enhanced uptake, high selective and microtubule disrupting activity of carbohydrate fused pyrano-pyranones derived from natural coumarins attributes to its anti-malarial potential.

Malar J 2020 03 24;19(1):122. Epub 2020 Mar 24.

Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.

Please note, following publication of the original article [1], the authors have advised of two errors that are present in the published article.
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http://dx.doi.org/10.1186/s12936-020-03179-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092511PMC
March 2020

Prevalence of extra-articular manifestations in psoriatic arthritis: a systematic review and meta-analysis.

Rheumatology (Oxford) 2020 09;59(9):2199-2206

Department of Academic Rheumatology, Liverpool University Hospitals.

Objective: To describe the prevalence of extra-articular manifestations-enthesitis, dactylitis, nail disease, uveitis and IBD-in PsA, and their impact on longitudinal disease outcomes.

Methods: We searched Medline, PubMed, Scopus and Web of Science using a predefined protocol in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies using imaging to define extra-articular manifestations (EAMs) were excluded. Where possible, we performed meta-analyses of prevalence estimates, reported as percentages (95% CI). Heterogeneity (I2 statistic) was examined according to study characteristics.

Results: We identified 65 studies amounting to a total of 163 299 PsA patients. Enthesitis was assessed in 29 studies with an average prevalence of 30% (95% CI: 24%, 38%). Dactylitis was reported in 35 studies with an average prevalence of 25% (95% CI: 20%, 31%). Nail disease was present in 60% (95% CI: 52%, 68%) across 26 studies, but definitions were often unclear. Uveitis (3.2%; 95% CI: 1.9%, 5.3%) and IBD (3.3%; 95% CI: 1.5%, 7.1%) were less common. Heterogeneity was high (>95%) in all meta-analyses, but could not be explained by study characteristics. No studies examined the impact of EAMs on longitudinal disease outcomes, except that dactylitis increases radiographic progression.

Conclusion: Enthesitis, dactylitis and nail disease are highly prevalent in PsA, but not uveitis and IBD. EAM patterns differ from axial SpA despite their shared disease mechanisms, which may help further understand differences between spondyloarthritides. More studies are needed on the impact of EAMs on disease outcomes such as response to treatment.
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http://dx.doi.org/10.1093/rheumatology/keaa062DOI Listing
September 2020

Simultaneous Immunization with Omp25 and L7/L12 Provides Protection against Brucellosis in Mice.

Pathogens 2020 Feb 24;9(2). Epub 2020 Feb 24.

Laboratory of Molecular Biology and Genetic Engineering, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.

Currently used vaccines, strain 19 and RB51, comprises of live attenuated strains and prevent infection in animals. However, these vaccines pose potential risks to recipient animals such as attenuation reversal and virulence in susceptible hosts on administration. In this context, recombinant subunit vaccines emerge as a safe and competent alternative in combating the disease. In this study, we formulated a divalent recombinant vaccine consisting of Omp25 and L7/L12 of and evaluated vaccine potential individually as well as in combination. Sera obtained from divalent vaccine (Omp25+L7/L12) immunized mice group exhibited enhanced IgG titers against both components and indicated specificity upon immunoblotting reiterating its authenticity. Further, the IgG1/IgG2a ratio obtained against each antigen predicted a predominant Th2 immune response in the Omp25+L7/L12 immunized mice group. Upon infection with virulent 544, Omp25+L7/L12 infected mice exhibited superior Log10 protection compared to individual vaccines. Consequently, this study recommends that simultaneous immunization of Omp25 and L7/L12 as a divalent vaccine complements and triggers a Th2 mediated immune response in mice competent of providing protection against brucellosis.
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http://dx.doi.org/10.3390/pathogens9020152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175130PMC
February 2020

A combined subunit vaccine comprising BP26, Omp25 and L7/L12 against brucellosis.

Pathog Dis 2019 11;77(8)

Molecular Biology and Genetic Engineering Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.

The current vaccines against brucellosis, namely Brucella abortus strains 19 and RB51, prevent infection in animals but pose potential risks like virulence and attenuation reversal. In this milieu, although subunit vaccination using a single potent immunogen of B. abortus, e.g. BP26 or Omp25 or L7/L12 etc., appears as a safer alternative, nonetheless it confers inadequate protection against the zoonosis compared to attenuated vaccines. Hence, we have investigated the prophylactic potential of a combined subunit vaccine (CSV) comprising the BP26, Omp25 and L7/L12 antigens of B. abortus, in mice model. Sera obtained from CSV immunized mice groups showed heightened IgG titers against all the three components and exhibited specificity upon immunoblotting, reiterating their authenticity. Further, the IgG1/IgG2a ratio obtained against each antigen revealed a predominant Th2 immune response in CSV immunized mice group. However, on assessing the levels of Th1-dependent (IFN-γ and TNF-α) and Th2-dependent (IL-4 and IL-10) cytokines in different formulations, prominent IFN-γ levels were elicited in CSV immunized mice. Further, upon infection with virulent B. abortus 544, the combined subunit vaccinated mice displayed superior degree of protection (Log10 reduction) than the individual vaccines; however, B. abortus S19 showed the highest protection. Altogether, this study suggests that co-immunization of three B. abortus immunogens as a CSV complements and triggers a mixed Th1/Th2 immune response leading to superior degree of protection against pathogenic B. abortus 544 infection.
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http://dx.doi.org/10.1093/femspd/ftaa002DOI Listing
November 2019

Pars-plana vitrectomy with phacofragmentation for hyperdense cataracts in eyes with severe microcornea and chorio-retinal coloboma: A novel approach.

Indian J Ophthalmol 2020 01;68(1):91-98

Center for Sight, New Delhi, India.

Purpose: To report the outcomes of pars-plana approach for the management of brunescent cataract in eyes with severe microcornea and associated chorio-retinal coloboma.

Methods: This was a retrospective, single center, interventional case series performed in a tertiary eyecare center in central Medical records of consecutive cases of microcornea with coloboma who underwent pars-plana vitrectomy with phacofragmentation (PF) between January 2015 and December 2017 were reviewed.

Results: The study group comprised of 30 eyes of 30 patients, of which 18 (60%) were males and 12 (40%) were females. The mean age of the patients was 41.9 years (range of 17-70 years). The mean corneal diameter was 6.7 mm with a range of 4-8 mm and all the eyes had dense cataract with nuclear sclerosis of grade 4 or more. The mean preoperative visual acuity was 1.97 (+/-0.067) Log MAR and the mean postoperative vision at 1 month was 1.6 (+/-0.39) Log MAR. Postoperatively, 21 patients (70%) gained ambulatory vision. The visual gain in all the patients was maintained over a mean follow-up period of 15.5 months.

Conclusion: Pars-plana vitrectomy with PF can be considered in eyes with severe microcornea and brunescent cataracts, where cataract surgery through the limbal (anterior) approach is not only difficult but at times impossible due to anatomical restraints.
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http://dx.doi.org/10.4103/ijo.IJO_405_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951206PMC
January 2020

Single Step Blending of PEDOT:PSS/SPGO Nanocomposite via Low Temperature Solid Phase Addition of Graphene Oxide for Effective Hole Transport Layer in Organic Solar Cells.

J Nanosci Nanotechnol 2020 Jun;20(6):3888-3895

Nanoscience and Nanotechnology Centre, Department of Chemistry, Kumaun University, Nainital 263001, Uttarakhand, India.

Herein, we report the modification of PEDOT:PSS by direct addition of graphene oxide powder processed by spray dryer (SPGO) for the enhancement in the performance of organic solar cell. The preparation of PEDOT:PSS/SPGO composite was done by direct incorporation of graphene oxide powder at lower temperature i.e., below 5 °C. Raman spectroscopy of the prepared PEDOT:PSS/SPGO nanocomposites at low temperature suggested that low temperature plays a vital role to improve the ability of these composite as hole transport layer by improving adhesive properties of the composite. Atomic force microscopy (AFM) analysis suggested that the adhesive ability of these composite decreased surface roughness and thus providing smoother path for the hole transportation. After the successful synthesis of PEDOT:PSS/SPGO nanocomposites, ITO/PEDOT:PSS/SPGO/PTB7:PC71BM/Al based organic solar cell was fabricated. The curves under AM 1.5G illumination (100 mW/cm²) of the PTB7:PCBM based OSCs using PEDOT:PSS/SPGO as a HTL exhibit = 0.67 V, = 17.3 mA, FF = 41.5%, PCE = 4.82%, and device with PEDOT:PSS as HTL exhibit = 0.68 V, = 16.0 mA/cm², FF = 38.7% and PCE = 4.04%. The enhance PCE in case of PEDOT:PSS/SPGO based devices depicted that the direct inclusion of graphene oxide in PEDOT:PSS increased the PCE almost 16%, which arises due the high conductivity and stable pi-pi stacking of the spray dryer processed graphene sheets with PEDOT:PSS which ease the charge carrier mobility, thus providing feasible path for charge transportation.
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http://dx.doi.org/10.1166/jnn.2020.17532DOI Listing
June 2020

Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts.

Elife 2019 11 1;8. Epub 2019 Nov 1.

Rutgers University, New Brunswick, United States.

Even though pancreatic ductal adenocarcinoma (PDAC) is associated with fibrotic stroma, the molecular pathways regulating the formation of cancer associated fibroblasts (CAFs) are not well elucidated. An epigenomic analysis of patient-derived and de-novo generated CAFs demonstrated widespread loss of cytosine methylation that was associated with overexpression of various inflammatory transcripts including . Co-culture of neoplastic cells with CAFs led to increased invasiveness that was abrogated by inhibition of CX. Metabolite tracing revealed that lactate produced by neoplastic cells leads to increased production of alpha-ketoglutarate (aKG) within mesenchymal stem cells (MSCs). In turn, aKG mediated activation of the demethylase TET enzyme led to decreased cytosine methylation and increased hydroxymethylation during de novo differentiation of MSCs to CAF. Co-injection of neoplastic cells with TET-deficient MSCs inhibited tumor growth in vivo. Thus, in PDAC, a tumor-mediated lactate flux is associated with widespread epigenomic reprogramming that is seen during CAF formation.
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http://dx.doi.org/10.7554/eLife.50663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874475PMC
November 2019

The remarkable morphological diversity of leaf shape in sweet potato (Ipomoea batatas): the influence of genetics, environment, and G×E.

New Phytol 2020 03 28;225(5):2183-2195. Epub 2019 Nov 28.

Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI, 48105, USA.

Leaf shape, a spectacularly diverse plant trait, varies across taxonomic levels, geography and in response to environmental differences. However, comprehensive intraspecific analyses of leaf shape variation across variable environments is surprisingly absent. Here, we performed a multilevel analysis of leaf shape using diverse accessions of sweet potato (Ipomoea batatas), and uncovered the role of genetics, environment, and G×E on this important trait. We examined leaf shape using a variety of morphometric analyses, and complement this with a transcriptomic survey to identify gene expression changes associated with shape variation. Additionally, we examined the role of genetics and environment on leaf shape by performing field studies in two geographically separate common gardens. We showed that extensive leaf shape variation exists within I. batatas, and identified promising candidate genes associated with this variation. Interestingly, when considering traditional measures, we found that genetic factors are largely responsible for most of leaf shape variation, but that the environment is highly influential when using more quantitative measures via leaf outlines. This extensive and multilevel examination of leaf shape shows an important role of genetics underlying a potentially important agronomic trait, and highlights that the environment can be a strong influence when using more quantitative measures of leaf shape.
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http://dx.doi.org/10.1111/nph.16286DOI Listing
March 2020

Enhanced uptake, high selective and microtubule disrupting activity of carbohydrate fused pyrano-pyranones derived from natural coumarins attributes to its anti-malarial potential.

Malar J 2019 Oct 11;18(1):346. Epub 2019 Oct 11.

Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.

Background: Malaria is one of the deadliest infectious diseases caused by protozoan parasite of Plasmodium spp. Increasing resistance to anti-malarials has become global threat in control of the disease and demands for novel anti-malarial interventions. Naturally-occurring coumarins, which belong to a class of benzo-α-pyrones, found in higher plants and some essential oils, exhibit therapeutic potential against various diseases. However, their limited uptake and non-specificity has restricted their wide spread use as potential drug candidates.

Methods: Two series of carbohydrate fused pyrano[3,2-c]pyranone carbohybrids which were synthesized by combination of 2-C-formyl galactal and 2-C-formyl glucal, with various freshly prepared 4-hydroxycoumarins were screened against Plasmodium falciparum. The anti-malarial activity of these carbohybrids was determined by growth inhibition assay on P. falciparum 3D7 strain using SYBR green based fluorescence assay. Haemolytic activity of carbohybrid 12, which showed maximal anti-malarial activity, was determined by haemocompatibility assay. The uptake of the carbohybrid 12 by parasitized erythrocytes was determined using confocal microscopy. Growth progression assays were performed to determine the stage specific effect of carbohybrid 12 treatment on Pf3D7. In silico studies were conducted to explore the mechanism of action of carbohybrid 12 on parasite microtubule dynamics. These findings were further validated by immunofluorescence assay and drug combination assay.

Results: 2-C-formyl galactal fused pyrano[3,2-c]pyranone carbohybrid 12 exhibited maximum growth inhibitory potential against Plasmodium with IC value of 5.861 µM and no toxicity on HepG2 cells as well as no haemolysis of erythrocytes. An enhanced uptake of this carbohybrid compound was observed by parasitized erythrocytes as compared to uninfected erythrocytes. Further study revealed that carbohybrid 12 arrests the growth of parasite at trophozoite and schizonts stage during course of progression through asexual blood stages. Mechanistically, it was shown that the carbohybrid 12 binds to α,β-heterodimer of tubulin and affects microtubule dynamics.

Conclusion: These findings show carbohydrate group fusion to 4-hydroxycoumarin precursor resulted in pyrano-pyranones derivatives with better solubility, enhanced uptake and improved selectivity. This data confirms that, carbohydrate fused pyrano[3,2-c]pyranones carbohybrids are effective candidates for anti-malarial interventions against P. falciparum.
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http://dx.doi.org/10.1186/s12936-019-2971-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788091PMC
October 2019

YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma.

JCI Insight 2019 11 1;4(21). Epub 2019 Nov 1.

Molecular and Cellular Oncology Department.

Transcriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and their correlation with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, the squamous subtype is relatively independent of oncogenic KRAS signaling and typically displays much more aggressive clinical behavior versus the progenitor subtype. Here, we identified that yes-associated protein 1 (YAP1) activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC cells. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and YAP1 activity in human PDAC and demonstrated that WNT5A overexpression led to YAP1 activation and recapitulated a YAP1-dependent but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A in driving PDAC malignancy through activation of the YAP pathway.
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http://dx.doi.org/10.1172/jci.insight.130811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948828PMC
November 2019

Is Pouch Specific to Colon and Not Ileum?

Curr Pediatr Rev 2019 ;15(4):259-264

Department of Pediatric Surgery, SMS Medical College, JLN Marg, Jaipur 302004 RJ, India.

Background: Congenital Pouch Colon (CPC) is an anorectal anomaly with an incidence of 3.5:1 in males and females, respectively. We have earlier reported CPC to be quite prevalent in north Indian tertiary care centers.

Objective: In this article, we deliberate on the possible causes associated with CPC bringing the manifestation of the disease. In addition, we throw insights on the effective role of this congenital anomaly in Colon and provide systems genomic evaluation by comparing our recent analysis to that of Colon and Ileum based on Next-Generation Sequencing (NGS) studies.

Conclusion: In this commentary article, we argue that a host of epigenetic factors could be the reason why the disease is manifested in colon alone. We further hypothesize on the few unmet challenges linking epigenetics to understand the genetic variants.
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http://dx.doi.org/10.2174/1573396315666190829155930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040526PMC
June 2020

Copper Bromide as an Efficient Solution-Processable Hole Transport Layer for Organic Solar Cells: Effect of Solvents.

ACS Omega 2019 Mar 29;4(3):6028-6034. Epub 2019 Mar 29.

Photovoltaic Metrology Section, Advanced Materials & Device Metrology Division, CSIR-National Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi 110012, India.

In this work, we report copper bromide (CuBr) as an efficient, inexpensive, and solution-processable hole transport layer (HTL) for organic solar cells (OSCs) for the first time. To examine the effectiveness of the material in general, three different solvents such as acetonitrile (MeCN), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF) are used for solution-processing thin-film deposition of CuBr. CuBr thin films deposited from different solvents show high transparency and no significant difference has been observed in absorption in the visible and near-IR range, whereas a slight difference has been found in the near-UV range by changing the solvents. Furthermore, two most studied combinations of the active layer such as PTB7/PCBM and PCDTBT:/PCBM are used for device fabrication with geometry of ITO/CuBr(HTL) active layer/Al. By using CuBr as a HTL in OSCs, the power conversion efficiencies (PCEs) have been achieved to up to 5.16 and 4.72% with PTB7/PCBM and PCDTBT/PCBM active layers, respectively. The CuBr film from DMF solvent shows highest PCE as compared to films deposited from DMSO and MeCN solvents. Different solvents used for HTL deposition have a major effect on the fill factor (FF), while very little difference on open circuit voltage ( ) and short circuit current ( ) has been observed. It may be mentioned here that a small difference of device parameters (PCE, FF, , and ) has been observed in the devices using the HTL deposited from DMF and DMSO solvents, whereas a significant difference of the device parameters has been found in devices using the HTL from MeCN solvent.
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http://dx.doi.org/10.1021/acsomega.8b03038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648316PMC
March 2019

Donor-Acceptor-Donor Copolymers with 3,4-Ethylenedioxythiophene Moiety: Electropolymerization and Effect on Optoelectronic and Electrochromic Properties.

ACS Omega 2019 Feb 18;4(2):3484-3492. Epub 2019 Feb 18.

Photovoltaic Metrology Section, Advanced Materials & Device Metrology Division, CSIR-National Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi 110012, India.

Three random copolymers , , and were obtained by electrochemical polymerization of donor-acceptor-donor monomers , , and with 3,4-ethylenedioxythiophene moiety, respectively, using a 1:1 molar ratio of the corresponding monomers, to find new properties and a more effective way to control the optoelectronic properties in conjugated system. For comparison purpose, polymers , , and were prepared from the corresponding monomer units -, respectively, by electrochemical polymerization. We also present efficient synthesis, characterization, and comparative density functional theory (DFT) calculations of the monomers - and polymers -. Cyclic voltammetry, spectroelectrochemistry, and electrochromic properties of all of the polymers - and copolymers , , and were carried out and a throughout comparison was made. We have shown that electrochemical copolymerization is a powerful strategy to tune the highest occupied molecular orbital energy level, band gap, and color of the copolymer. Thus, this finding clearly indicates that the copolymers show significantly different optoelectronic properties compared to their constituent polymers.
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http://dx.doi.org/10.1021/acsomega.8b02811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649091PMC
February 2019

Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer.

JCI Insight 2019 07 23;5. Epub 2019 Jul 23.

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Pancreatic ductal adenocarcinoma (PDAC) requires mitochondrial oxidative phosphorylation (OXPHOS) to fuel its growth, however, broadly inhibiting this pathway might also disrupt essential mitochondrial functions in normal tissues. PDAC cells exhibit abnormally fragmented mitochondria that are essential to its oncogenicity, but it was unclear if this mitochondrial feature was a valid therapeutic target. Here, we present evidence that normalizing the fragmented mitochondria of pancreatic cancer via the process of mitochondrial fusion reduces OXPHOS, which correlates with suppressed tumor growth and improved survival in preclinical models. Mitochondrial fusion was achieved by genetic or pharmacologic inhibition of dynamin related protein-1 (Drp1) or through overexpression of mitofusin-2 (Mfn2). Notably, we found that oral leflunomide, an FDA-approved arthritis drug, promoted a two-fold increase in Mfn2 expression in tumors and was repurposed as a chemotherapeutic agent, improving the median survival of mice with spontaneous tumors by 50% compared to vehicle. We found that the chief tumor suppressive mechanism of mitochondrial fusion was enhanced mitophagy, which proportionally reduced mitochondrial mass and ATP production. These data suggest that mitochondrial fusion is a specific and druggable regulator of pancreatic cancer growth that could be rapidly translated to the clinic.
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http://dx.doi.org/10.1172/jci.insight.126915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777817PMC
July 2019

Selective EGLN Inhibition Enables Ablative Radiotherapy and Improves Survival in Unresectable Pancreatic Cancer.

Cancer Res 2019 05;79(9):2327-2338

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

When pancreatic cancer cannot be removed surgically, patients frequently experience morbidity and death from progression of their primary tumor. Radiation therapy (RT) cannot yet substitute for an operation because radiation causes fatal bleeding and ulceration of the nearby stomach and intestines before achieving tumor control. There are no FDA-approved medications that prevent or reduce radiation-induced gastrointestinal injury. Here, we overcome this fundamental problem of anatomy and biology with the use of the oral EGLN inhibitor FG-4592, which selectively protects the intestinal tract from radiation toxicity without protecting tumors. A total of 70 KPC mice with autochthonous pancreatic tumors received oral FG-4592 or vehicle control ± ablative RT to a cumulative 75 Gy administered in 15 daily fractions to a limited tumor field. Although ablative RT reduced complications from local tumor progression, fatal gastrointestinal bleeding was observed in 56% of mice that received high-dose RT with vehicle control. However, radiation-induced bleeding was completely ameliorated in mice that received high-dose RT with FG-4592 (0% bleeding, < 0.0001 compared with vehicle). Furthermore, FG-4592 reduced epithelial apoptosis by half ( = 0.002) and increased intestinal microvessel density by 80% compared with vehicle controls. EGLN inhibition did not stimulate cancer growth, as treatment with FG-4592 alone, or overexpression of HIF2 within KPC tumors independently improved survival. Thus, we provide a proof of concept for the selective protection of the intestinal tract by the EGLN inhibition to enable ablative doses of cytotoxic therapy in unresectable pancreatic cancer by reducing untoward morbidity and death from radiation-induced gastrointestinal bleeding. SIGNIFICANCE: Selective protection of the intestinal tract by EGLN inhibition enables potentially definitive doses of radiation therapy. This might allow radiation to be a surgical surrogate for unresectable pancreatic cancer. http://cancerres.aacrjournals.org/content/canres/79/9/2327/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666414PMC
May 2019
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