Publications by authors named "Ashish Sharma"

733 Publications

TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.

PLoS Pathog 2021 Sep 24;17(9):e1009941. Epub 2021 Sep 24.

Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1β-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the proinflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received at least 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1β were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates is associated with IL-1β-mediated proinflammatory eicosanoid signaling in pulmonary TB disease. These findings support host metabolic remodeling as a key driver of pathologic inflammation in human TB disease.
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http://dx.doi.org/10.1371/journal.ppat.1009941DOI Listing
September 2021

The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination.

Nat Immunol 2021 Sep 23. Epub 2021 Sep 23.

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4 T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC + Alum, those immunized with ALVAC + MF59, the regimen in the HVTN702 trial that showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants that trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.
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http://dx.doi.org/10.1038/s41590-021-01026-9DOI Listing
September 2021

Biosimilars for Retinal Diseases- Understanding the Phase 3 Clinical Trial Design.

Ophthalmology 2021 Sep 14. Epub 2021 Sep 14.

Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2021.09.008DOI Listing
September 2021

"Extra-cranial proximal pica aneurysm - a rare and surreptious cause of posterior fossa sah: case report and review of literature".

Br J Neurosurg 2021 Sep 15:1-5. Epub 2021 Sep 15.

Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India.

Background: Extra-cranial posterior inferior cerebellar artery (PICA) aneurysms are rare with only 22 cases been reported so far. Intra-dural type of extra-cranial PICA aneurysm is even rarer with few case reports available. We report a previously unreported type of proximal PICA aneurysm in which the PICA aneurysm had intra-dural location at the C2 vertebral level.

Case Description: A 51 year old gentleman presented with sub-arachnoid haemorrhage and intra-ventricular haemorrhage, predominantly involving the fourth ventricle and had no focal neurological deficit. CT angiogram was negative however a dedicated four vessel angiogram demonstrated an abnormal extracranial origin of right PICA at C1-C2 level, with associated aneurysm in its proximal segment. A C1 posterior arch excision with partial C2 laminectomy and clipping of the aneurysm was done.

Conclusion: Aneurysm associated with extracranial intra-dural PICA origin is a rare cause of SAH, and may not be detected with CT angiography. Such cases often require dedicated four vessel angiography, with careful study for any possibility of extra-cranial aneurysm. This variant has important surgical implication and requires preservation of the Lateral spinal artery (LSA-PICA communication), and that such aneurysm approached only with posterior cervical exposure without the need of a craniotomy. Such cases remind us the need to have an in-depth understanding of the variations of the posterior circulation.
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http://dx.doi.org/10.1080/02688697.2021.1970112DOI Listing
September 2021

Efficacy of facemasks in mitigating respiratory exposure to submicron aerosols.

J Hazard Mater 2021 Aug 8;422:126783. Epub 2021 Aug 8.

Global Centre for Clean Air Research (GCARE), Department of Civil and Environmental Engineering, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford GU2 7XH, United Kingdom. Electronic address:

We designed a novel experimental set-up to pseudo-simultaneously measure size-segregated filtration efficiency (η), breathing resistance (η) and potential usage time (t) for 11 types of face protective equipment (FPE; four respirators; three medical; and four handmade) in the submicron range. As expected, the highest η was exhibited by respirators (97 ± 3%), followed by medical (81 ± 7%) and handmade (47 ± 13%). Similarly, the breathing resistance was highest for respirators, followed by medical and handmade FPE. Combined analysis of efficiency and breathing resistance highlighted trade-offs, i.e. respirators showing the best overall performance across these two indicators, followed by medical and handmade FPE. This hierarchy was also confirmed by quality factor, which is a performance indicator of filters. Detailed assessment of size-segregated aerosols, combined with the scanning electron microscope imaging, revealed material characteristics such as pore density, fiber thickness, filter material and number of layers influence their performance. η and η showed an inverse exponential decay with time. Using their cross-over point, in combination with acceptable breathability, allowed to estimate t as 3.2-9.5 h (respirators), 2.6-7.3 h (medical masks) and 4.0-8.8 h (handmade). While relatively longer t of handmade FPE indicate breathing comfort, they are far less efficient in filtering virus-laden submicron aerosols compared with respirators.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126783DOI Listing
August 2021

A Multicenter Cohort Study of Indian Centers on Reoccurring SARS-CoV-2 Infections in Kidney Transplant Recipients.

Exp Clin Transplant 2021 Sep 8. Epub 2021 Sep 8.

From the Department of Nephrology, Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad, India.

Objectives: There is scarcity of data on reoccurrence of SARS-CoV-2 infections in kidney transplant recipients.

Materials And Methods: We conducted a retrospective multicenter cohort study and identified 13 kidney transplant recipients (10 living and 3 deceased donors) with recurrent COVID-19, and here we report demographics, immunosuppression regimens, clinical profiles, treatments, and outcomes.

Results: COVID-19 second infection rate was 0.9% (13/1350) in kidney transplant recipients with a median age of 46 years; median time interval from transplant to first episode of COVID-19 diagnosis was 9.2 months (interquartile range, 2.2-46.5 months). The most common comorbidities were hypertension (84%) and diabetes (23%). Fever was significantly less common with recurrent COVID-19. COVID-19 severity ranged from asymptomatic (23%), mild (31%), and moderate (46%) during the first infection and asymptomatic (8%), mild (46%), and severe (46%) in the second infection. All 6 kidney transplant recipients with severe second infections died. The median interval between the 2 episodes based upon reverse transcriptase polymerase chain reaction COVID-19- positive tests was 135 days (interquartile range, 71-274 days) without symptoms. Statistically signi - ficant risk factors for mortality were dyspnea (P = .04), disease severity (P = .004), allograft dysfunction (P < .05), higher levels of neutrophil-to-lymphocyte ratio (P = .05), and intensive care unit/ventilator requirement (P = .004). Although our limited resources did not allow for molecular diagnostics and typing, we suggest that these second episodes were reinfections with SARS-CoV-2.

Conclusions: To our knowledge, this is the largest study of kidney transplant recipients with reoccurring SARS-CoV-2 infection, and we observed 46% mortality.
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http://dx.doi.org/10.6002/ect.2021.0284DOI Listing
September 2021

D614G mutation eventuates in all VOI and VOC in SARS-CoV-2: Is it part of the positive selection pioneered by Darwin?

Mol Ther Nucleic Acids 2021 Dec 1;26:237-241. Epub 2021 Sep 1.

College of Pharmacy and Health Care, Tajen University, Yanpu, Pingtung 907, Taiwan.

Recently, several emerging variants of SARS-CoV-2 have originated from the Wuhan strain and spread throughout the globe within one and a half years. One mutation, D614G, is very prominent in all VOI and VOC in SARS-CoV-2. This mutation might help to increase the viral fitness in all emerging variants where the mutation is present. With the help of this mutation (D614G), the SARS-CoV-2 variants have gained viral fitness to enhance viral replication and increase transmission. This paper attempts to answer the question of whether the mutation (D614G) occurs due to positive selection or not.
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http://dx.doi.org/10.1016/j.omtn.2021.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408019PMC
December 2021

Recent research progress on circular RNAs: Biogenesis, properties, functions, and therapeutic potential.

Mol Ther Nucleic Acids 2021 Sep 4;25:355-371. Epub 2021 Jun 4.

Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Barasat-Barrackpore Road, Jagannathpur, Kolkata, West Bengal 700126, India.

Circular RNAs (circRNAs), an emerging family member of RNAs, have gained importance in research due to their new functional roles in cellular physiology and disease progression. circRNAs are usually available in a wide range of cells and have shown tissue-specific expression as well as developmental specific expression. circRNAs are characterized by structural stability, conservation, and high abundance in the cell. In this review, we discuss the different models of biogenesis. The properties of circRNAs such as localization, structure and conserved pattern, stability, and expression specificity are also been illustrated. Furthermore, we discuss the biological functions of circRNAs such as microRNA (miRNA) sponging, cell cycle regulation, cell-to-cell communication, transcription regulation, translational regulation, disease diagnosis, and therapeutic potential. Finally, we discuss the recent research progress and future perspective of circRNAs. This review provides an understanding of potential diagnostic markers and the therapeutic potential of circRNAs, which are emerging daily.
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http://dx.doi.org/10.1016/j.omtn.2021.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399087PMC
September 2021

Evolution, Mode of Transmission, and Mutational Landscape of Newly Emerging SARS-CoV-2 Variants.

mBio 2021 08 31;12(4):e0114021. Epub 2021 Aug 31.

Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon-si, Gangwon-do, Republic of Korea.

The recent emergence of multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a significant concern for public health worldwide. New variants have been classified either as variants of concern (VOCs) or variants of interest (VOIs) by the CDC (USA) and WHO. The VOCs include lineages such as B.1.1.7 (20I/501Y.V1 variant), P.1 (20J/501Y.V3 variant), B.1.351 (20H/501Y.V2 variant), and B.1.617.2. In contrast, the VOI category includes B.1.525, B.1.526, P.2, and B.1.427/B.1.429. The WHO provided the alert for last two variants (P.2 and B.1.427/B.1.429) and labeled them for further monitoring. As per the WHO, these variants can be reclassified due to their status at a particular time. At the same time, the CDC (USA) has marked these two variants as VOIs up through today. This article analyzes the evolutionary patterns of all these emerging variants, as well as their geographical distributions and transmission patterns, including the circulating frequency, entropy diversity, and mutational event diversity throughout the genomes of all SARS-CoV-2 lineages. The transmission pattern was observed highest in the B.1.1.7 lineage. Our frequency evaluation found that this lineage achieved 100% frequency in early October 2020. We also critically evaluated the above emerging variants mutational landscape and significant spike protein mutations (E484K, K417T/N, N501Y, and D614G) impacting public health. Finally, the effectiveness of vaccines against newly SARS-CoV-2 variants was also analyzed. Irrespective of the aggressive vaccination drive, the newly emerging multiple SARS-CoV-2 variants are causing havoc in several countries. As per the CDC (USA) and WHO, the VOCs include the B.1.1.7, P.1, B.1.351, and B.1.617.2 lineages, while the VOIs include the B.1.525, B.1.526, P.2, and B.1.427/B.1.429 lineages. This study analyzed the evolutionary patterns, geographical distributions and transmission patterns, circulating frequency, entropy diversity, and mutational event diversity throughout the genome of significant SARS-CoV-2 lineages. A higher transmission pattern was observed for the B.1.1.7 variant. The study also evaluated the mutational landscape and important spike protein mutations (E484K, K417T/N, N501Y, and D614G) of all of the above variants. Finally, a survey was performed on the efficacy of vaccines against these variants from the previously published literature. The results presented in this article will help design future countrywide pandemic planning strategies for the emerging variants, next-generation vaccine development using alternative wild-type antigens and significant viral antigens, and immediate planning for ongoing vaccination programs worldwide.
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http://dx.doi.org/10.1128/mBio.01140-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406297PMC
August 2021

Magnetic optical rotary dispersion and magnetic circular dichroism in methylammonium lead halide perovskites.

Chirality 2021 Oct 31;33(10):610-617. Epub 2021 Aug 31.

ARC Centre of Excellence in Exciton Science, School of Chemistry, University of Sydney, Sydney, NSW, Australia.

Large magnetic optical rotary dispersion (Faraday rotation) has been demonstrated recently in methylammonium lead bromide. Here, we investigate the prospect of extending the active spectral range by altering the halogen. We also investigate the origins of large Faraday rotation in these diamagnetic materials using magnetic circular dichroism (MCD) spectroscopy and the Kramers-Kronig relations. We find that, while MAPbCl (MA = methylammonium) single crystals exhibit a large Verdet constant in the blue, no appreciable Faraday rotation is observed in the red/near infra-red for MAPbI single crystals. However, in all film samples, we find clear evidence of large MCD resulting from the Zeeman splitting of the highly resonant 1s exciton state. Our Kramers-Kronig calculations of Faraday rotation based on MCD data matches well with the dispersion of our experimental data for MAPbCl and MAPbBr , with some deviation in magnitude-demonstrating the excitonic nature of Faraday rotation in these materials. However, our calculations predict significant Faraday rotation in MAPbI , contrary to our experimental results, indicating a potential discrepancy between the properties of the thin film and single crystal.
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http://dx.doi.org/10.1002/chir.23346DOI Listing
October 2021

Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment.

Cancers (Basel) 2021 Aug 20;13(16). Epub 2021 Aug 20.

Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), University of Zurich (UZH), CH-8091 Zurich, Switzerland.

Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.
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http://dx.doi.org/10.3390/cancers13164200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391410PMC
August 2021

Pentacene-Bridge Interactions in an Axially Chiral Binaphthyl Pentacene Dimer.

J Phys Chem A 2021 Aug 16;125(33):7226-7234. Epub 2021 Aug 16.

ARC Centre of Excellence in Exciton Science, School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.

Molecular chirality can be exploited as a sensitive reporter of the nature of intra- and interchromophore interactions in π-conjugated systems. In this report, we designed an intramolecular singlet fission (iSF)-based pentacene dimer with an axially chiral binaphthyl bridge (2,2'-(2,2'-dimethoxy-[1,1'-binaphthalene]-3,3'-diyl) -octyl-di-isopropyl silylethynyl dipentacene, ) to utilize its chiroptical response as a marker of iSF chromophore-bridge-chromophore (SFC-β-SFC) interactions. The axial chirality of the bridge enforces significant one-handed excitonic coupling of the pentacene monomer units; as such, exhibits significant chiroptical response in the ground and excited states. We analyzed the chiroptical response of using the exciton coupling method and quadratic response density functional theory calculations to reveal that higher energy singlet transitions in involve significant delocalization of the electronic density on the bridging binaphthyl group. Our results highlight the promising application of chiroptical techniques to investigate the nature of SFC-β-SFC interactions that impact singlet fission dynamics.
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http://dx.doi.org/10.1021/acs.jpca.1c05254DOI Listing
August 2021

Commentary: Acute central serous chorioretinopathy - Treat early, observe longer.

Indian J Ophthalmol 2021 09;69(9):2347-2348

Department of Vitreo-Retina, Lotus Eye Hospital and Institute, Coimbatore, Tamil Nadu, India.

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http://dx.doi.org/10.4103/ijo.IJO_789_21DOI Listing
September 2021

A DICOM Framework for Machine Learning and Processing Pipelines Against Real-time Radiology Images.

J Digit Imaging 2021 Aug 17;34(4):1005-1013. Epub 2021 Aug 17.

Emory University, GA, 30306, Atlanta, USA.

Real-time execution of machine learning (ML) pipelines on radiology images is difficult due to limited computing resources in clinical environments, whereas running them in research clusters requires efficient data transfer capabilities. We developed Niffler, an open-source Digital Imaging and Communications in Medicine (DICOM) framework that enables ML and processing pipelines in research clusters by efficiently retrieving images from the hospitals' PACS and extracting the metadata from the images. We deployed Niffler at our institution (Emory Healthcare, the largest healthcare network in the state of Georgia) and retrieved data from 715 scanners spanning 12 sites, up to 350 GB/day continuously in real-time as a DICOM data stream over the past 2 years. We also used Niffler to retrieve images bulk on-demand based on user-provided filters to facilitate several research projects. This paper presents the architecture and three such use cases of Niffler. First, we executed an IVC filter detection and segmentation pipeline on abdominal radiographs in real-time, which was able to classify 989 test images with an accuracy of 96.0%. Second, we applied the Niffler Metadata Extractor to understand the operational efficiency of individual MRI systems based on calculated metrics. We benchmarked the accuracy of the calculated exam time windows by comparing Niffler against the Clinical Data Warehouse (CDW). Niffler accurately identified the scanners' examination timeframes and idling times, whereas CDW falsely depicted several exam overlaps due to human errors. Third, with metadata extracted from the images by Niffler, we identified scanners with misconfigured time and reconfigured five scanners. Our evaluations highlight how Niffler enables real-time ML and processing pipelines in a research cluster.
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http://dx.doi.org/10.1007/s10278-021-00491-wDOI Listing
August 2021

Looking for pathways related to COVID-19: confirmation of pathogenic mechanisms by SARS-CoV-2-host interactome.

Cell Death Dis 2021 08 12;12(8):788. Epub 2021 Aug 12.

National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, Rome, Italy.

In the last months, many studies have clearly described several mechanisms of SARS-CoV-2 infection at cell and tissue level, but the mechanisms of interaction between host and SARS-CoV-2, determining the grade of COVID-19 severity, are still unknown. We provide a network analysis on protein-protein interactions (PPI) between viral and host proteins to better identify host biological responses, induced by both whole proteome of SARS-CoV-2 and specific viral proteins. A host-virus interactome was inferred, applying an explorative algorithm (Random Walk with Restart, RWR) triggered by 28 proteins of SARS-CoV-2. The analysis of PPI allowed to estimate the distribution of SARS-CoV-2 proteins in the host cell. Interactome built around one single viral protein allowed to define a different response, underlining as ORF8 and ORF3a modulated cardiovascular diseases and pro-inflammatory pathways, respectively. Finally, the network-based approach highlighted a possible direct action of ORF3a and NS7b to enhancing Bradykinin Storm. This network-based representation of SARS-CoV-2 infection could be a framework for pathogenic evaluation of specific clinical outcomes. We identified possible host responses induced by specific proteins of SARS-CoV-2, underlining the important role of specific viral accessory proteins in pathogenic phenotypes of severe COVID-19 patients.
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http://dx.doi.org/10.1038/s41419-021-03881-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357963PMC
August 2021

Deceased Donor Renal Transplantation: A Single Center Experience.

Indian J Nephrol 2021 May-Jun;31(3):254-260. Epub 2021 Apr 10.

Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Introduction: Deceased donor kidney transplant are still not common across India. This study was done to assess various measures taken at a single center level to increase organ donation rate and to analyse the outcomes of transplants performed from these donors.

Methods: All deceased donor renal transplants performed from November 2011 to February 2017 were analysed for patient and death censored graft survival, rate of delayed graft function, rate of rejection and mortality. Kaplan Meir analysis for Survival Curves was used.

Results: Organ donation rate at our center improved from one donation every alternate year in 2004 to a peak of 44 donations in 2017. Patient survival was 93.42%, 89.44%, 85.53%, and death censored graft survival was 94.07%, 88.21%, and 82.86% at 1, 2 and 3 years respectively. Mean duration of hemodialysis pre transplantation was 34.6 ± 27.43 months.

Conclusions: This study has shown that steps taken at a single center level alone can also significantly improve organ donation rates. Employment of dedicated professionals including transplant surgeons and coordinators, developing a protocol-based approach for referral, and early counseling in triage along with regular audits can help to establish deceased donor program with acceptable outcomes elsewhere in the country.
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http://dx.doi.org/10.4103/ijn.IJN_66_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330647PMC
April 2021

Semaglutide and the risk of diabetic retinopathy-current perspective.

Eye (Lond) 2021 Aug 9. Epub 2021 Aug 9.

University Vita-Salute, Scientific Institute San Raffaele, Milano, Italy.

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http://dx.doi.org/10.1038/s41433-021-01741-5DOI Listing
August 2021

Mesenchymal Stem Cells Alter MicroRNA Expression and Attenuate Thoracic Aortic Aneurysm Formation.

J Surg Res 2021 Aug 6;268:221-231. Epub 2021 Aug 6.

Department of Surgery, University of Florida, Gainesville, Florida. Electronic address:

Background: Thoracic aortic aneurysms (TAA) are a progressive disease characterized by inflammation, smooth muscle cell activation and matrix degradation. We hypothesized that mesenchymal stem cells (MSCs) can immunomodulate vascular inflammation and remodeling via altered microRNA (miRNAs) expression profile to attenuate TAA formation.

Materials And Methods: C57BL/6 mice underwent topical elastase application to form descending TAAs. Mice were also treated with MSCs on days 1 and 5 and aortas were analyzed on day 14 for aortic diameter. Cytokine array was performed in aortic tissue and total RNA was tagged and hybridized for miRNAs microarray analysis. Immunohistochemistry was performed for elastin degradation and leukocyte infiltration.

Results: Treatment with MSCs significantly attenuated aortic diameter and TAA formation compared to untreated mice. MSC administration also attenuated T-cell, neutrophil and macrophage infiltration and prevented elastic degradation to mitigate vascular remodeling. MSC treatment also attenuated aortic inflammation by decreasing proinflammatory cytokines (CXCL13, IL-27, CXCL12 and RANTES) and upregulating anti-inflammatory interleukin-10 expression in aortic tissue of elastase-treated mice. TAA formation demonstrated activation of specific miRNAs that are associated with aortic inflammation and vascular remodeling. Our results also demonstrated that MSCs modulate a different set of miRNAs that are associated with decrease leukocyte infiltration and vascular inflammation to attenuate the aortic diameter and TAA formation.

Conclusions: These results indicate that MSCs immunomodulate specific miRNAs that are associated with modulating hallmarks of aortic inflammation and vascular remodeling of aortic aneurysms. Targeted therapies designed using MSCs and miRNAs have the potential to regulate the growth and development of TAAs.
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http://dx.doi.org/10.1016/j.jss.2021.06.057DOI Listing
August 2021

Transcriptome profiling reveal key hub genes in co-expression networks involved in Iridoid glycosides biosynthetic machinery in Picrorhiza kurroa.

Genomics 2021 Sep 28;113(5):3381-3394. Epub 2021 Jul 28.

Department of Biotechnology, School of Engineering & Applied Sciences, Bennett University, Greater Noida, Uttar Pradesh 201310, India. Electronic address:

Picrorhiza kurroa is a medicinal herb rich in hepatoprotective iridoid glycosides, picroside-I (P-I) and picroside-II (P-II). The biosynthetic machinery of picrosides is poorly understood, therefore, 'no-direction' gene co-expression networks were used to extract linked/closed and separated interactions in terpenoid glycosides-specific sub-networks. Transcriptomes generated from different organs, varying for P-I and P-II contents such as shoots grown at 15 and 25 °C and nursery-grown shoots, stolons, and roots resulted in 47,726, 44,958, 40,117, 66,979, and 55,578 annotated transcripts, respectively. Occurrence of 2810 ± 136 nodes and 15,626 ± 696 edges in these networks indicated intense, co-expressed, closed loop interactions. Either deregulation/inhibition of abscisic acid (ABA) biosynthesis/signaling or constitutive degradation of ABA resulted in organ-specific accumulation of P-I and P-II. Biosynthesis, condensation and glucosylation of isoprene units may occur in shoots, roots or stolons; but addition of phenylpropanoid moiety and further modification/s of the iridoid backbone occurs mainly inside vacuoles in roots.
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http://dx.doi.org/10.1016/j.ygeno.2021.07.024DOI Listing
September 2021

Recent developments and strategies of Ebola virus vaccines.

Curr Opin Pharmacol 2021 Jul 27;60:46-53. Epub 2021 Jul 27.

Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon-si, 24252, Gangwon-do, Republic of Korea. Electronic address:

The Filovirus family member, Ebola virus (EBOV), is a highly infectious pathogen responsible for viral hemorrhagic fever. EBOV has a fatality rate in the range 50%-90% in primates. The lethal viral hemorrhagic attack in 2014 by EBOV has forced the human race to look for rapid countermeasures. Fortunately, owing to continuous efforts and several vaccine platforms, few potential vaccine candidates are emerging, such as replicative and non-replicative vectored vaccines, polyepitopic or monovalent vaccines, and DNA vaccines. This article reviewed various kinds of EBOV vaccines in different clinical trial phases and their approval status. Updated knowledge of vaccine development progress might stimulate the researchers to look for more potent and effective vaccine candidates against EBOV.
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http://dx.doi.org/10.1016/j.coph.2021.06.008DOI Listing
July 2021

A prospective longitudinal study to evaluate bone health, implication of FRAX tool and impact on quality of life (FACT-P) in advanced prostate cancer patients.

Am J Clin Exp Urol 2021 15;9(3):211-220. Epub 2021 Jun 15.

King George's Medical University Lucknow, India.

Background: Androgen-deprivation therapy (ADT) as a treatment modality in advanced prostate cancer has deleterious effect on bone mineral density (BMD) and quality of life (QOL). Using FRAX (Fracture Risk Assessment) model, candidates at high risk of fractures can be predicted and appropriate treatment can be initiated at early step to prevent skeletal-related events. Objectives of the present study were to evaluate bone health, implication of FRAX tool in advanced prostate cancer and to see the impact of ADT and Bone-directed therapy (BDT) on FRAX and FACT-P QOL scores.

Material & Method: We conducted a prospective longitudinal study of 83 localized and metastatic prostate cancer patients from March 2017 to Dec 2020. FRAX tool using BMD femoral neck (GE-Lunar) was used to compute the probability of 10-year Major osteoporotic fracture (MOF) and hip fracture risk %. Patients who received monthly Zolendronic acid with or without Vitamin-D/calcium supplementation were classified as BDT group. FRAX and FACT-P were measured at baseline and 12 months follow-up and compared between different therapeutic modalities to see the impact on clinical outcomes.

Results: Majority of patients had skeletal metastasis (78.3%) and high-grade disease at presentation. Secondary osteoporosis was the most commonly (82.05%) observed clinical risk factor (CRF) followed by smoking (19.23%). Hip fracture risk ≥3% accounted for larger proportion of patients than did MOF risk ≥20% (21.2% and 2.5%, respectively). Statistically significant reduction was observed in both MOF and hip fracture risk in BDT group, while worsening on ADT. ADT duration correlated positively with both MOF and hip fracture risk (R=0.148, P<0.001 and R=0.164, P<0.001, respectively). FRAX score accurately predict future fracture events in majority (80%) of high-risk patients. Statistically and clinically significant worsening in PWB, EWB, PCS, FACT-P Total, FACT-P TOI and FAPSI scores were observed in patients on ADT. Statistically and clinically significant improvement was noted in physical well-being in BDT group. However, other QOL domains and FACT-P total scores remained stable.

Conclusions: ADT caused duration depended worsening of FRAX and FACT-P score in these patients while improvements of FRAX were seen on BDT. FRAX tool is advantageous in identifying the patients who require early intervention or therapy to decrease skeletal-related events.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303024PMC
June 2021

A rare case of toxocariasis presenting with hypereosinophilic pericardial effusion and mycotic aneurysm.

Trop Doct 2021 Jul 29:494755211034327. Epub 2021 Jul 29.

Department of Pediatrics, Post Graduate Institute of Medical Sciences and Research, Chandigarh, India.

Parasitic infections are the leading cause of hypereosinophilia in the paediatric population in tropical countries. We report an unusual case of infection in an eight-year-old boy who presented with intermittent fever, hypereosinophilia complicated by massive pericardial effusion and a mycotic aneurysm. This child received treatment with four weeks of albendazole and steroids.
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http://dx.doi.org/10.1177/00494755211034327DOI Listing
July 2021

Maresin 1 activates LGR6 signaling to inhibit smooth muscle cell activation and attenuate murine abdominal aortic aneurysm formation.

FASEB J 2021 08;35(8):e21780

Department of Surgery, University of Florida, Gainesville, FL, USA.

The specialized pro-resolving lipid mediator maresin 1 (MaR1) is involved in the resolution phase of tissue inflammation. It was hypothesized that exogenous administration of MaR1 would attenuate abdominal aortic aneurysm (AAA) growth in a cytokine-dependent manner via LGR6 receptor signaling and macrophage-dependent efferocytosis of smooth muscle cells (SMCs). AAAs were induced in C57BL/6 wild-type (WT) mice and smooth muscle cell specific TGF-β2 receptor knockout (SMC-TGFβr2 ) mice using a topical elastase AAA model. MaR1 treatment significantly attenuated AAA growth as well as increased aortic SMC α-actin and TGF-β2 expressions in WT mice, but not SMC-TGFβr2 mice, compared to vehicle-treated mice. In vivo inhibition of LGR6 receptors obliterated MaR1-dependent protection in AAA formation and SMC α-actin expression. Furthermore, MaR1 upregulated macrophage-dependent efferocytosis of apoptotic SMCs in murine aortic tissue during AAA formation. In vitro studies demonstrate that MaR1-LGR6 interaction upregulates TGF-β2 expression and decreases MMP2 activity during crosstalk of macrophage-apoptotic SMCs. In summary, these results demonstrate that MaR1 activates LGR6 receptors to upregulate macrophage-dependent efferocytosis, increases TGF-β expression, preserves aortic wall remodeling and attenuate AAA formation. Therefore, this study demonstrates the potential of MaR1-LGR6-mediated mitigation of vascular remodeling through increased efferocytosis of apoptotic SMCs via TGF-β2 to attenuate AAA formation.
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http://dx.doi.org/10.1096/fj.202100484RDOI Listing
August 2021

Does Socioeconomic Status Have an Association with Cranio-vertebral Anomalies: A Step Toward Healing the Curse!

J Pediatr Neurosci 2021 Jan-Mar;16(1):44-48. Epub 2021 Jun 25.

Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.

Background: The etiological or causal factors of pediatric craniovertebral junction anomalies (CVJA) are still unknown. The disease bears a major proportion of economic and social burdens over a developing country like ours. This article aims to highlight an important modifiable factor that may prove to have a critical causal relationship with disease incidence.

Materials And Methods: This is a cross-sectional, single-institutional study, wherein the socioeconomic status (SES) of all the operated pediatric patients of CVJA, between 2014 and 2019, was studied. Variables including the patient's age, sex, residence status (rural or urban), perioperative data, length of stay, follow-up, and the time between revision surgery (if required) and clinical presentation were noted. Data regarding average household and type of family (nuclear or joint) were also enquired.

Results: Sixty-six patients (M:F 56:10) with a mean age of 13.14 ± 3.44 years were included. The mean annual family income was 11.1 ± 12.1 thousands. 43.9% belonged to joint family; according to Kuppuswami and Prasad scale, 42.4% of patients belong to lower class, while 20 patients belong to lower middle class, and 14 patients belong to the below poverty line category. Neither the SES of patient nor rural-urban background affected the surgical outcome. The mean follow-up of patients in our study was 42.3 ± 23.0 months and 83.3% had a good outcome.

Discussion: Patients operated for CVJ anomaly in the authors' institution mainly come from the lower socioeconomic groups. The present study raises several important questions like nutritional deficiencies in reproductive age group females leading to a cascade of events as a causal factor.
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http://dx.doi.org/10.4103/jpn.JPN_49_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276953PMC
June 2021

From COVID-19 to Cancer mRNA Vaccines: Moving From Bench to Clinic in the Vaccine Landscape.

Front Immunol 2021 7;12:679344. Epub 2021 Jul 7.

Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-do, South Korea.

Recently, mRNA vaccines have become a significant type of therapeutic and have created new fields in the biopharmaceutical industry. mRNA vaccines are promising next-generation vaccines that have introduced a new age in vaccinology. The recent approval of two COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) has accelerated mRNA vaccine technology and boosted the pharmaceutical and biotechnology industry. These mRNA vaccines will help to tackle COVID-19 pandemic through immunization, offering considerable hope for future mRNA vaccines. Human trials with data both from mRNA cancer vaccines and mRNA infectious disease vaccines have provided encouraging results, inspiring the pharmaceutical and biotechnology industries to focus on this area of research. In this article, we discuss current mRNA vaccines broadly in two parts. In the first part, mRNA vaccines in general and COVID-19 mRNA vaccines are discussed. We presented the mRNA vaccine structure in general, the different delivery systems, the immune response, and the recent clinical trials for mRNA vaccines (both for cancer mRNA vaccines and different infectious diseases mRNA vaccines). In the second part, different COVID-19 mRNA vaccines are explained. Finally, we illustrated a snapshot of the different leading mRNA vaccine developers, challenges, and future prospects of mRNA vaccines.
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http://dx.doi.org/10.3389/fimmu.2021.679344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293291PMC
August 2021

Health System Building Blocks and Organ Transplantation in India.

Transplantation 2021 08;105(8):1631-1634

George Institute for Global Health, UNSW, New Delhi, India.

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http://dx.doi.org/10.1097/TP.0000000000003685DOI Listing
August 2021

Lessons Learned from Cutting-Edge Immunoinformatics on Next-Generation COVID-19 Vaccine Research.

Int J Pept Res Ther 2021 Jul 10:1-9. Epub 2021 Jul 10.

Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon-si, 24252 Gangwon-do Republic of Korea.

Presently, immunoinformatics and bioinformatics approaches are contributing actively to COVID-19 vaccine research. The first immunoinformatics-based vaccine construct against SARS-CoV-2 was published in February 2020. Following this, immunoinformatics and bioinformatics approaches have created a new direction in COVID-19 vaccine research. Several researchers have designed the next-generation COVID-19 vaccines using these approaches. Presently, immunoinformatics has accelerated immunology research immensely in the area of COVID-19. Hence, we have tried to depict the current scenario of immunoinformatics and bioinformatics in COVID-19 vaccine research.

Supplementary Information: The online version contains supplementary material available at 10.1007/s10989-021-10254-4.
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http://dx.doi.org/10.1007/s10989-021-10254-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272614PMC
July 2021

AI-DRIVEN QUANTIFICATION OF GROUND GLASS OPACITIES IN LUNGS OF COVID-19 PATIENTS USING 3D COMPUTED TOMOGRAPHY IMAGING.

medRxiv 2021 Jul 8. Epub 2021 Jul 8.

Objectives: Ground-glass opacity (GGO) - a hazy, gray appearing density on computed tomography (CT) of lungs - is one of the hallmark features of SARS-CoV-2 in COVID-19 patients. This AI-driven study is focused on segmentation, morphology, and distribution patterns of GGOs.

Method: We use an AI-driven unsupervised machine learning approach called PointNet++ to detect and quantify GGOs in CT scans of COVID-19 patients and to assess the severity of the disease. We have conducted our study on the "MosMedData", which contains CT lung scans of 1110 patients with or without COVID-19 infections. We quantify the morphologies of GGOs using Minkowski tensors and compute the abnormality score of individual regions of segmented lung and GGOs.

Results: PointNet++ detects GGOs with the highest evaluation accuracy (98%), average class accuracy (95%), and intersection over union (92%) using only a fraction of 3D data. On average, the shapes of GGOs in the COVID-19 datasets deviate from sphericity by 15% and anisotropies in GGOs are dominated by dipole and hexapole components. These anisotropies may help to quantitatively delineate GGOs of COVID-19 from other lung diseases.

Conclusion: The PointNet++ and the Minkowski tensor based morphological approach together with abnormality analysis will provide radiologists and clinicians with a valuable set of tools when interpreting CT lung scans of COVID-19 patients. Implementation would be particularly useful in countries severely devastated by COVID-19 such as India, where the number of cases has outstripped available resources creating delays or even breakdowns in patient care. This AI-driven approach synthesizes both the unique GGO distribution pattern and severity of the disease to allow for more efficient diagnosis, triaging and conservation of limited resources.

Key Points: Our approach to GGO analysis has four distinguishing features:We combine an unsupervised computer vision approach with convex hull and convex points algorithms to segment and preserve the actual structure of the lung.To the best of our knowledge, we are the first group to use PointNet++ architecture for 3D visualization, segmentation, classification, and pattern analysis of GGOs.We make abnormality predictions using a deep network and Cox proportional hazards model using lung CT images of COVID-19 patients.We quantify the shapes and sizes of GGOs using Minkowski tensors to understand the morphological variations of GGOs within the COVID-19 cohort.
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http://dx.doi.org/10.1101/2021.07.06.21260109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282108PMC
July 2021

NOTTO COVID-19 Vaccine Guidelines for Transplant Recipients.

Indian J Nephrol 2021 Mar-Apr;31(2):89-91. Epub 2021 Apr 20.

Director General of Health Services, New Delhi, India.

In December 2019, novel coronavirus (SARS-CoV-2) infection started in Wuhan and resulted in a pandemic within a few weeks' time. Organ transplant recipients being at a risk for more severe COVID-19 if they get SARS CoV-2 viral infection, COVID-19 vaccine has a significant role in these patients. The vaccine is a safer way to help build protection and would either prevent COVID-19 infection or at least diminish the severity of the disease. It would also reduce the risk of the continuing transmission and enhance herd immunity. Immuno-compromised patients should not receive live vaccines as they can cause vaccine-related disease and hence the guidelines suggest that all transplant recipients should receive age-appropriate 'inactivated vaccine' as recommended for general population. Though trials have not been undertaken on transplant recipients, efficacy and safety of COVID-19 vaccine have been scientifically documented for few vaccines among the general population.
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http://dx.doi.org/10.4103/ijn.IJN_64_21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240933PMC
April 2021

Fluid based visual prognostication in Type 3 macular neovascularization (MNV)- FLIP-3 Study.

Retina 2021 Jul 9. Epub 2021 Jul 9.

Department of Vitreoretina, Lotus Eye Hospital and Institute, Coimbatore, TN, India Singapore National Eye Center, Singapore Department of Ophthalmology, Bellvitge University Hospital, Feixa Llarga, s/n, 08907 L'Hospitalet de Llobregat, Barcelona Spain Ophthalmology Department, Gazi University School of Medicine, Besevler, Ankara, Turkey Division of Ophthalmology, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Israel Department of Ophthalmology; University Vita-Salute, Scientific Institute San Raffaele, Milano, Italy.

Purpose: To analyze the effect of fluid on visual acuity in cases of Type 3 macular neovascularization (MNV).

Methods: This multi-centric, retrospective cohort study included eyes with treatment-naïve Type 3 MNV. Analysis of fluid in different compartments was performed. Group A included eyes with isolated intraretinal fluid (IRF), while Group B included eyes with IRF in conjunction with sub retinal fluid (SRF) and/or sub retinal pigment epithelial fluid (Sub-RPEF).

Results: Eyes in Group A (31, 55.3%) had better BCVA of 20/50 snellen equivalent (0.42 ± 0.31 logMAR) at baseline and 20/50 snellen equivalent (0.40 ±0.28 logMAR) at complete resolution compared to Group B with visual acuity of 20/80 snellen equivalent (0.64 ± 0.35 logMAR) (p= 0.0181) at baseline and 20/100 snellen equivalent (0.70 ± 0.40 logMAR) (p= 0.0021) at complete resolution. Subfoveal atrophy was more in Group B (82.6% 19/23) at complete resolution in comparison to Group A ((16/31, 51.6%). Eyes in Group B needed more anti-VEGF injections (10.3±9.0) for complete resolution compared to Group A (5.7±4.8).

Conclusion: IRF might be associated with good visual acuity in Type 3 MNV in contrast to other forms of n-AMD. Furthermore, IRF in isolation might need fewer injections and could probably be associated with less subfoveal atrophy.
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http://dx.doi.org/10.1097/IAE.0000000000003261DOI Listing
July 2021
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