Publications by authors named "Pooja Jain"

138 Publications

Can Soluble Immune Checkpoint Molecules on Exosomes Mediate Inflammation?

J Neuroimmune Pharmacol 2021 Oct 25. Epub 2021 Oct 25.

Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA.

Immune checkpoints (ICPs) are major co-signaling pathways that trigger effector functions in immune cells, with isoforms that are either membrane bound, engaging in direct cell to cell activation locally, or soluble, acting at distant sites by circulating freely or potentially via extracellular vesicles (EVs). Exosomes are small EVs secreted by a variety of cells carrying various proteins and nucleic acids. They are distributed extensively through biological fluids and have major impacts on infectious diseases, cancer, and neuroinflammation. Similarly, ICPs play key roles in a variety of disease conditions and have been extensively utilized as a prognostic tool for various cancers. Herein, we explored if the association between exosomes and ICPs could be a significant contributor of inflammation, particularly in the setting of cancer, neuroinflammation and viral infections, wherein the up regulation in both exosomal proteins and ICPs correlate with immunosuppressive effects. The detailed literature review of existing data highlights the significance and complexity of these two important pathways in mediating cancer and potentiating neuroinflammation via modulating overall immune response. Cells increasingly secret exosomes in response to intracellular signals from invading pathogens or cancerous transformations. These exosomes can carry a variety of cargo including proteins, nucleic acids, cytokines, and receptors/ligands that have functional consequences on recipient cells. Illustration generated using BioRender software.
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http://dx.doi.org/10.1007/s11481-021-10018-3DOI Listing
October 2021

Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers.

Cancers (Basel) 2021 Oct 10;13(20). Epub 2021 Oct 10.

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.

The mitogen-activated protein kinase (MAPK) pathway, consisting of the Ras-Raf-MEK-ERK signaling cascade, regulates genes that control cellular development, differentiation, proliferation, and apoptosis. Within the cascade, multiple isoforms of Ras and Raf each display differences in functionality, efficiency, and, critically, oncogenic potential. According to the NCI, over 30% of all human cancers are driven by genes. This dysfunctional signaling is implicated in a wide variety of leukemias and solid tumors, both with and without viral etiology. Due to the strong evidence of Ras-Raf involvement in tumorigenesis, many have attempted to target the cascade to treat these malignancies. Decades of unsuccessful experimentation had deemed Ras undruggable, but recently, the approval of Sotorasib as the first ever KRas inhibitor represents a monumental breakthrough. This advancement is not without novel challenges. As a G12C mutant-specific drug, it also represents the issue of drug target specificity within Ras pathway; not only do many drugs only affect single mutational profiles, with few pan-inhibitor exceptions, tumor genetic heterogeneity may give rise to drug-resistant profiles. Furthermore, significant challenges in targeting downstream Raf, especially the BRaf isoform, lie in the paradoxical activation of wild-type BRaf by BRaf mutant inhibitors. This literature review will delineate the mechanisms of Ras signaling in the MAPK pathway and its possible oncogenic mutations, illustrate how specific mutations affect the pathogenesis of specific cancers, and compare available and in-development treatments targeting the Ras pathway.
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http://dx.doi.org/10.3390/cancers13205059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534156PMC
October 2021

Role of MRI in diagnosing the primary site of origin in indeterminate cases of uterocervical carcinomas: a systematic review and meta-analysis.

Br J Radiol 2021 Oct 8:20210428. Epub 2021 Oct 8.

Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India.

Objective: To perform a literature review assessing role of MRI in predicting origin of indeterminate uterocervical carcinomas with emphasis on sequences and imaging parameters.

Methods: Electronic literature search of PubMed was performed from its inception until May 2020 and PICO model used for study selection; population was female patients with known/clinical suspicion of uterocervical cancer, intervention was MRI, comparison was by histopathology and outcome was differentiation between primary endometrial and cervical cancers.

Results: Eight out of 9 reviewed articles reinforced role of MRI in uterocervical primary determination. T2 and Dynamic contrast were the most popular sequences determining tumor location, morphology, enhancement, and invasion patterns. Role of DWI and MR spectroscopy has been evaluated by even fewer studies with significant differences found in both apparent diffusion coefficient values and metabolite spectra. The four studies eligible for meta-analysis showed a pooled sensitivity of 88.4% (95% confidence interval 70.6 to 96.1%) and a pooled specificity of 39.5% (95% confidence interval 4.2 to 90.6%).

Conclusions: MRI plays a pivotal role in uterocervical primary determination with both conventional and newer sequences assessing important morphometric and functional parameters. Socioeconomic impact of both primaries, different management guidelines and paucity of existing studies warrants further research. Prospective multicenter trials will help bridge this gap. Meanwhile, individual patient database meta-analysis can help corroborate existing data.

Advances In Knowledge: MRI with its classical and functional sequences helps in differentiation of the uterine 'cancer gray zone' which is imperative as both primary endometrial and cervical tumors have different management protocols.
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http://dx.doi.org/10.1259/bjr.20210428DOI Listing
October 2021

Concurrent versus sequential chemoradiotherapy for unresectable locally advanced stage III non-small cell lung cancer: Retrospective analysis in a single United Kingdom cancer centre.

Cancer Treat Res Commun 2021 Sep 28;29:100460. Epub 2021 Sep 28.

St James's Institute of Oncology, The Leeds Teaching Hospitals Trust, Leeds, LS9 7TF, United Kingdom.

Introduction: Stage III unresectable locally advanced non-small cell lung cancer (NSCLC) is a complex disease group with poor long-term survival. Clinical data suggests curative intent concurrent chemoradiotherapy (CCRT) is superior to a sequential (SCRT) approach but comes with additional toxicities. We report real world data regarding overall survival and toxicity to aid clinical decision making in balancing optimal management and treatment tolerability.

Methods: Retrospective analysis of survival data, treatment toxicities, and rates of treatment completion were performed for 241 patients who underwent chemoradiotherapy for unresectable stage III NSCLC within Leeds Cancer Centre from January 2011 to December 2014.

Results: Median survival was 18.8 months following SCRT compared to 22.7 months following CCRT HR 0.90 (95% CI 0.67-1.20, P = 0.46). Median follow up was 21 months. The clinical benefit rate for CCRT compared to SCRT was 22.7% versus 24%. In the CCRT group 63.8% patients completed treatment compared to 46% in the SCRT arm (P < 0.01). 90-day mortality rates were low in CCRT and SCRT cohorts at 4.3% and 1% respectively. There was greater pulmonary toxicity following CCRT versus SCRT (13.5% versus 1.0%, P < 0.01).

Conclusion: This study provides real world data regarding the radical treatment of unresectable stage III NSCLC. Increased hospital admissions and pneumonitis toxicities did not adversely affect treatment completion for those undergoing CCRT; this was likely due to careful patient selection based on performance status. SCRT still remains an important treatment modality for patients who cannot tolerate the upfront CCRT approach but could still be treated with curative intent.
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http://dx.doi.org/10.1016/j.ctarc.2021.100460DOI Listing
September 2021

Periodontitis and Systemic Disorder-An Overview of Relation and Novel Treatment Modalities.

Pharmaceutics 2021 Jul 30;13(8). Epub 2021 Jul 30.

Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi 110062, India.

Periodontitis, a major oral disease, affects a vast majority of the population but has been often ignored without realizing its long-fetched effects on overall human health. A realization in recent years of its association with severe diseases such as carditis, low birth weight babies, and preeclampsia has instigated dedicated research in this area. In the arena of periodontal medicines, the studies of past decades suggest a link between human periodontal afflictions and certain systemic disorders such as cardiovascular diseases, diabetes mellitus, respiratory disorders, preterm birth, autoimmune disorders, and cancer. Although, the disease appears as a locoregional infection, the periodontal pathogens, in addition their metabolic products and systemic mediators, receive access to the bloodstream, thereby contributing to the development of systemic disorders. Mechanism-based insights into the disease pathogenesis and association are highly relevant and shall be useful in avoiding any systemic complications. This review presents an update of the mechanisms and relationships between chronic periodontal infection and systemic disorders. Attention is also given to highlighting the incidence in support of this relationship. In addition, an attempt is made to propose the various periodonto-therapeutic tools to apprise the readers about the availability of appropriate treatment for the disease at the earliest stage without allowing it to progress and cause systemic adverse effects.
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http://dx.doi.org/10.3390/pharmaceutics13081175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398110PMC
July 2021

Risk Factors Associated with the Clinical Outcomes of COVID-19 and Its Variants in the Context of Cytokine Storm and Therapeutics/Vaccine Development Challenges.

Vaccines (Basel) 2021 Aug 23;9(8). Epub 2021 Aug 23.

Department of Microbiology and Immunology, Drexel University College of Medicine Philadelphia, 2900 Queen Lane, Philadelphia, PA 19129, USA.

The recent appearance of SARS-CoV-2 is responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic and has brought to light the importance of understanding this highly pathogenic agent to prevent future pandemics. This virus is from the same single-stranded positive-sense RNA family, Coronaviridae, as two other epidemic-causing viruses, SARS-CoV-1 and MERS-CoV. During this pandemic, one crucial focus highlighted by WHO has been to understand the risk factors that may contribute to disease severity and predict COVID-19 outcomes. In doing so, it is imperative to understand the virology of SARS-CoV-2 and the immunological response eliciting the clinical manifestation and progression of COVID-19. In this review, we provide clinical data-based analyses of how multiple risk factors (such as sex, race, HLA genotypes, blood groups, vitamin D deficiency, obesity, smoking, and asthma) contribute to the inflammatory overactivation and cytokine storm (frequently seen in COVID-19 patients) with a focus on the IL-6 pathway. We also draw comparisons to the virulence and pathophysiology of SARS and MERS to establish parallels in immune response and discuss the potential for therapeutic approaches that may limit disease progression in patients with higher risk profiles than others. Moreover, we cover the latest information on approved or upcoming COVID-19 vaccines. This paper also provides perspective on emerging variants and associated opportunistic infections such as black molds and fungus that have added to mortality in some parts of the world, such as India. This compilation of existing COVID-19 studies and data will provide an excellent referencing tool for the research, clinical, and public health communities.
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http://dx.doi.org/10.3390/vaccines9080938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402745PMC
August 2021

Permanent visual impairment in dengue fever following platelet transfusion: A series of 5 cases.

Ann Acad Med Singap 2021 Jul;50(7):588-592

Department of Uveitis and Ocular Immunology, Narayana Nethralaya, Bengaluru, India.

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July 2021

Defining the Role of Cellular Immune Signatures in Diagnostic Evaluation of Suspected Tuberculosis.

J Infect Dis 2021 Jul 31. Epub 2021 Jul 31.

TB Research Centre, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Background: Diagnosis of paucibacillary tuberculosis (TB) including extrapulmonary TB is a significant challenge, particularly in high-income, low-incidence settings. Measurement of Mycobacterium tuberculosis (Mtb)-specific cellular immune signatures by flow cytometry discriminates active TB from latent TB infection (LTBI) in case-control studies; however, their diagnostic accuracy and clinical utility in routine clinical practice is unknown.

Methods: Using a nested case-control study design within a prospective multicenter cohort of patients presenting with suspected TB in England, we assessed diagnostic accuracy of signatures in 134 patients who tested interferon-gamma release assay (IGRA)-positive and had final diagnoses of TB or non-TB diseases with coincident LTBI. Cellular signatures were measured using flow cytometry.

Results: All signatures performed less well than previously reported. Only signatures incorporating measurement of phenotypic markers on functional Mtb-specific CD4 T cells discriminated active TB from non-TB diseases with LTBI. The signatures measuring HLA-DR+IFNγ + CD4 T cells and CD45RA-CCR7-CD127- IFNγ -IL-2-TNFα + CD4 T cells performed best with 95% positive predictive value (95% confidence interval, 90-97) in the clinically challenging subpopulation of IGRA-positive but acid-fast bacillus (AFB) smear-negative TB suspects.

Conclusions: Two cellular immune signatures could improve and accelerate diagnosis in the challenging group of patients who are IGRA-positive, AFB smear-negative, and have paucibacillary TB.
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http://dx.doi.org/10.1093/infdis/jiab311DOI Listing
July 2021

Eugenol as a potential drug candidate: A review.

Curr Top Med Chem 2021 Jul 1. Epub 2021 Jul 1.

Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India.

Eugenol is a bioactive compound widely available in many herbs like clove, cinnamon, tulsi, pepper etc. The compound is known for its antioxidant, antimicrobial, anaesthetic, anti-inflammatory, neuroprotective, anti-diabetic, and anti-cancer activities. In pharmaceutical analysis, eugenol is used as a marker for single drugs and drug products. Dental care, household, and personal hygiene products are other areas where it has established its potential. In the food industry, eugenol is used as a flavouring agent in non-alcoholic beverages, baked foods, and chewing gums. Considering the huge potential of eugenol, this review is an attempt to collate the regulatory information, physico-chemical properties, toxicity profile, marketed conventional and novel formulations, analytical methods, extraction procedures, recent patents and clinical trials of the moiety. Based on the literature survey, a schematic diagram of the mechanism of action has also been made.
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http://dx.doi.org/10.2174/1568026621666210701141433DOI Listing
July 2021

Upper limb arterial pattern: clinical correlation and embryological perspective.

J Vasc Bras 2021 Jun 11;20:e20210008. Epub 2021 Jun 11.

Lady Hardinge Medical College - LHMC, Department of Anatomy, Connaught Place, New Delhi, India.

Background: Variations in the upper limb arterial pattern are commonplace and necessitate complete familiarity for successful surgical and interventional procedures. Variance in the vascular tree may involve any part of the axis artery of the upper limb, including the axillary artery and brachial artery or its branches, in the form of radial and ulnar arteries, which eventually supply the hand via anastomosing arches.

Objectives: To study the peculiarities of the arterial pattern of the upper limb and to correlate them with embryological development.

Methods: The entire arterial branching of forty-two upper limbs of formalin fixed adult human cadavers was examined during routine dissection for educational purposes, conducted over a 3-year period in the Department of Anatomy, Lady Hardinge Medical College, New Delhi.

Results: The study found: 1) One case in which a common trunk arose from the third part of the axillary artery, which immediately splayed into four branches (2.4%); 2) High division of the brachial artery into ulnar and radial arteries, in 3 cases (7.1%); 3) Pentafurcation of the brachial artery into ulnar, interosseus, radial, and radial recurrent arteries and a muscular twig to the brachioradialis in 1/42 cases (2.4%); 4) Incomplete Superficial Palmar arch in 3/42 cases (7.1%); and 5) Presence of a median artery in 2/42 case(4.8%).

Conclusions: This study observed and described the varied arterial patterns of the upper limb and identified the various anomalous patterns, supplementing the surgeon's armamentarium in various surgical procedures, thereby helping to prevent complications or failures of reconstructive surgeries, bypass angiography, and many similar procedures.
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http://dx.doi.org/10.1590/1677-5449.210008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210643PMC
June 2021

3D printing technology in healthcare: applications, regulatory understanding, IP repository and clinical trial status.

J Drug Target 2021 Jun 10:1-20. Epub 2021 Jun 10.

Department of Pharmaceutics, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India.

Mass consumerization of three-dimensional (3D) printing innovation has revolutionised admittance of 3D-printing in an expansive scope of ventures. When utilised predominantly for industrial manufacturing, 3D-printing strategies have rapidly attained acquaintance in different parts of health care industry. 3D-printing is a moderately new technology that has discovered promising applications in the medication conveyance and clinical areas. This review intends to explore different parts of 3D- printing innovation concerning pharmaceutical and clinical applications. Review on pharmaceutical products like tablets, caplets, films, polypills, microdots, biodegradable patches, medical devices (uterine and subcutaneous), patient specific implants, cardiovascular stents, etc. and prosthetics/anatomical structures, surgical models, organs and tissues created utilising 3D-printing is being presented. In addition, the regulatory understanding and current IP and clinical trial status pertaining to 3D fabricated products/medical applications have also been funnelled, garnering information from different web portals of regulatory agencies and databases. It is additionally certain that for such new innovations, there would be difficulties and questions before these are acknowledged as protected and viable. The circumstance demands purposeful and wary endeavours to acquire regulations which would at last prompt the accomplishment of this progressive innovation, thus various regulatory challenges faced have been conscientiously discussed.
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http://dx.doi.org/10.1080/1061186X.2021.1935973DOI Listing
June 2021

Preparation and quality by design assisted (Qb-d) optimization of bioceramic loaded microspheres for periodontal delivery of doxycycline hyclate.

Saudi J Biol Sci 2021 May 21;28(5):2677-2685. Epub 2021 Mar 21.

Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.

PLGA (Lactic- co-glycolic acid) coated chitosan microspheres loaded with hydroxyapatite and doxycycline hyclate complex were developed in the present study for periodontal delivery. A modified single emulsion method was adopted for the development of microspheres. Formulation was optimized on the basis of particle size, drug loading and encapsulation efficiency with the central composite design using 2 factorial design. Microspheres were optimized and electron microscopy revealed their spherical shape and porous nature. study showed initial burst and then sustained release behavior of the formulation for 14 days. Further, antibacterial study performed on E. coli (ATCC-25922) and S. aureus (ATCC-29213) revealed concentration dependent activity. Also, cyto-toxicity assessment ensures biocompatibility of the formulation with the fibroblast's cells. Overall, the quality by design assisted PLGA microspheres, demonstrated the desired attributes and were found suitable for periodontal drug delivery.
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http://dx.doi.org/10.1016/j.sjbs.2021.03.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117247PMC
May 2021

Clinical therapies and nano drug delivery systems for urinary bladder cancer.

Pharmacol Ther 2021 Oct 27;226:107871. Epub 2021 Apr 27.

Department of Pharmaceutics, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, Maharashtra, India. Electronic address:

Bladder cancer is the 10 most commonly occurring malignancy worldwide with a 75% of 5-year survival rate, while it ranks 13 among the deaths occurring due to cancer. The majority of bladder cancer cases are diagnosed at an early stage and 70% are of non-invasive grade. However, 70% of these cases develop chemoresistance and progress to the muscle invasive stage. Conventional chemotherapy treatments are unsuccessful in curbing chemoresistance, bladder cancer progression while having an adverse side effect, which is mainly due to off-target drug distribution. Therefore, new drug delivery strategies, new therapeutics and therapies or their combination are being explored to develop better treatments. In this regard, nanotechnology has shown promise in the targeted delivery of therapeutics to bladder cancer cells. This review discusses the recent discovery of new therapeutics (chemotherapeutics, immunotherapeutic, and gene therapies), recent developments in the delivery of therapeutics using nano drug delivery systems, and the combination treatments with FDA-approved therapies, i.e., hyperthermia and photodynamic therapy. We also discussed the potential of other novel drug delivery systems that are minimally explored in bladder cancer. Lastly, we discussed the clinical status of therapeutics and therapies for bladder cancer. Overall, this review can provide a summary of available treatments for bladder cancer, and also provide opportunities for further development of drug delivery systems for better management of bladder cancer.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107871DOI Listing
October 2021

Phenotypic and Functional Analyses Guiding Combination Immune Checkpoint Immunotherapeutic Strategies in HTLV-1 Infection.

Front Immunol 2021 9;12:608890. Epub 2021 Mar 9.

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, United States.

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in 1-5% of HTLV-1-infected individuals. Previous studies by us and others have shown that the expression of negative immune checkpoint receptors (NCRs) is significantly increased on CD8 T cells in various chronic viral infections and are associated with poor anti-viral immunity. We have previously identified the differential expression of NCRs on CD8 T cells in blood from patients with HAM/TSP and in central nervous system (CNS) tissues of HTLV-1 infected humanized mice and defined the association with neurological complications. In this study, we determined the co-expression patterns of several key NCRs (PD-1, TIGIT, TIM-3, and LAG-3) and their cognate ligands in HTLV-1 infection and assessed how combination strategies targeting these pathways would impact HTLV-1-specific CD8 T-cell effector functions as an approach to reduce CNS disease outcomes. We found that global CD8 T cells from HAM/TSP patients co-express multiple NCRs at significantly higher frequencies than asymptomatic carriers (AC). Moreover, NCR ligands (PVR and PD-LI) on both plasmacytoid and myeloid dendritic cells were also expressed at higher frequencies in HAM/TSP compared to AC. In both AC and HAM/TSP subjects, combination dual PD-L1/TIGIT or triple PD-L1/TIGIT/TIM-3 blockade with monoclonal antibodies resulted in increases in intracellular cytokine expression in CD8 T cells after virus stimulation, particularly CD107a, a marker of degranulation, and TNF-α, a key cytokine that can directly inhibit viral replication. Interestingly, almost all blockade combinations resulted in reduced IL-2+ HTLV-1-specific CD8 T cell frequencies in HAM/TSP subjects, but not in AC. These results define a novel combinatorial NCR immunotherapeutic blockade strategy to reduce HAM/TSP disease burden.
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http://dx.doi.org/10.3389/fimmu.2021.608890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985073PMC
July 2021

Transcriptomic signatures for diagnosing tuberculosis in clinical practice: a prospective, multicentre cohort study.

Lancet Infect Dis 2021 03 25;21(3):366-375. Epub 2021 Jan 25.

Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK. Electronic address:

Background: Blood transcriptomic signatures for diagnosis of tuberculosis have shown promise in case-control studies, but none have been prospectively designed or validated in adults presenting with the full clinical spectrum of suspected tuberculosis, including extrapulmonary tuberculosis and common differential diagnoses that clinically resemble tuberculosis. We aimed to evaluate the diagnostic accuracy of transcriptomic signatures in patients presenting with clinically suspected tuberculosis in routine practice.

Methods: The Validation of New Technologies for Diagnostic Evaluation of Tuberculosis (VANTDET) study was nested within a prospective, multicentre cohort study in secondary care in England (IDEA 11/H0722/8). Patients (aged ≥16 years) suspected of having tuberculosis in the routine clinical inpatient and outpatient setting were recruited at ten National Health Service hospitals in England for IDEA and were included in VANTDET if they provided consent for genomic analysis. Patients had whole blood taken for microarray analysis to measure abundance of transcripts and were followed up for 6-12 months to determine final diagnoses on the basis of predefined diagnostic criteria. The diagnostic accuracy of six signatures derived from the cohort and three previously published transcriptomic signatures with potentially high diagnostic performance were assessed by calculating area under the receiver-operating characteristic curves (AUC-ROCs), sensitivities, and specificities.

Findings: Between Nov 25, 2011, and Dec 31, 2013, 1162 participants were enrolled. 628 participants (aged ≥16 years) were included in the analysis, of whom 212 (34%) had culture-confirmed tuberculosis, 89 (14%) had highly probable tuberculosis, and 327 (52%) had tuberculosis excluded. The novel signature with highest performance for identifying all active tuberculosis gave an AUC-ROC of 0·87 (95% CI 0·81-0·92), sensitivity of 77% (66-87), and specificity of 84% (74-91). The best-performing published signature gave an AUC-ROC of 0·83 (0·80-0·86), sensitivity of 78% (73-83), and specificity of 76% (70-80). For detecting highly probable tuberculosis, the best novel signature yielded results of 0·86 (0·71-0·95), 77% (56-94%), and 77% (57-95%). None of the relevant cohort-derived or previously published signatures achieved the WHO-defined targets of paired sensitivity and specificity for a non-sputum-based diagnostic test.

Interpretation: In a clinically representative cohort in routine practice in a low-incidence setting, transcriptomic signatures did not have adequate accuracy for diagnosis of tuberculosis, including in patients with highly probable tuberculosis where the unmet need is greatest. These findings suggest that transcriptomic signatures have little clinical utility for diagnostic assessment of suspected tuberculosis.

Funding: National Institute for Health Research.
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http://dx.doi.org/10.1016/S1473-3099(20)30928-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907671PMC
March 2021

Can dosimetry affect local control and survival in patients with early-stage lung cancer treated with Stereotactic Ablative Radiotherapy (SABR)? An analysis of the UK's largest cohort of lung SABR patients.

Acta Oncol 2021 Apr 24;60(4):505-512. Epub 2021 Jan 24.

Department of Medical Physics, Leeds Teaching Hospitals, NHS trust, Leeds, UK.

Purpose/objectives: A recent study has shown that tight conformity of lung Stereotactic Ablative Radiotherapy (SABR) plans might worsen loco-regional control and can predict distant metastases. The study aims to report overall survival (OS), progression-free survival (PFS), local recurrence free survival (LRFS), and dosimetry of early-stage lung cancer patients treated with SABR and to try to explore any dosimetric predictor of outcomes.

Material And Methods: Patients treated in our institute (May 2009-August 2018) were included. Electronic medical records were reviewed for baseline characteristics, treatment details, and outcomes. Dosimetric data were extracted from Xio and Monaco software. Patients were treated according to the United Kingdom (UK) SABR consortium guidelines. Kaplan-Meier's analysis with log-rank test was used for survival analysis. The univariate and multivariable Cox regression model was used for correlating dosimetric variables and outcomes.

Results: We treated 1266 patients with median age of 75 years and 47.4% were male. Median follow up was 56 months. Median OS was 36 months with 1, 2, and 5 years OS of 84.2%, 64.5%, and 31.5%, respectively. Median for PFS and LRFS was not reached. One, 2, and 5 years PFS were 87.4%, 78.4%, and 72.5%, respectively. One, 2, and 5 years LRFS were 98.2%, 95.1%, and 92.5%, respectively. Planning target volume (PTV), dose to 99% volume of PTV (D99), and R50 (volume receiving the 50% dose/volume (PTV)) were significantly associated with OS. PTV, mean lung dose (MLD), V20 (volume of lung minus gross tumour volume (GTV) receiving 20 Gy), V12.5 (volume of lung minus GTV receiving 12.5 Gy), and dose fractionation were significantly associated with PFS. Nothing was associated with LRFS on univariate analysis. R100 of >1.1 was associated with better OS, PFS, and LRFS compared to R100 ≤ 1.1.

Conclusion: SABR achieves good clinical outcomes in patients with early-stage lung cancer; even in elderly patients with multiple comorbidities. In the largest UK early lung cancer cohort treated with SABR, we found that dosimetry correlates with clinical outcomes. Further validation of these results is needed to guide future optimisation of SABR delivery.
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http://dx.doi.org/10.1080/0284186X.2021.1874617DOI Listing
April 2021

Imaging of primary testicular lymphoma with unusual intraabdominal spread along the spermatic cord and gonadal vein.

Radiol Case Rep 2021 Mar 17;16(3):419-424. Epub 2020 Dec 17.

Department of Radiodiagnosis and Interventional Radiology, VMMC and Safdarjung Hospital, Ring Road, New Delhi 110029, India.

Primary testicular lymphoma (PTL) is a rare Testicular neoplasm found in elderly patients. Imaging features in PTL presenting with contiguous involvement of spermatic cord and extension along gonadal vein have been rarely detailed before. We describe a case of a 50-year-old male who presented with complaints of scrotal swelling and abdominal discomfort. Imaging, which included Ultrasonography and contrast-enhanced computed tomography of chest-abdomen, showed features of aggressive-looking bilateral testicular mass lesions with the distinctive feature of contiguous spread along the spermatic cord and gonadal vein till retroperitoneum and disseminated chest and abdominal metastases. The distinctive feature of contiguous extension along the spermatic cord and gonadal vein can help suggest a diagnosis of PTL on imaging.
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http://dx.doi.org/10.1016/j.radcr.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750148PMC
March 2021

Clinical and dosimetric predictors of radiation pneumonitis in early-stage lung cancer treated with Stereotactic Ablative radiotherapy (SABR) - An analysis of UK's largest cohort of lung SABR patients.

Radiother Oncol 2021 03 14;156:153-159. Epub 2020 Dec 14.

Department of Medical Physics, St James's University Hospital, Leeds, UK.

Background: Stereotactic Ablative Radiotherapy (SABR) is the standard treatment for early-stage medically inoperable lung cancer. Predictors of radiation pneumonitis (RP) in patients treated with SABR are poorly defined. In this study, we investigate clinical and dosimetric parameters, which can predict symptomatic RP in early-stage lung cancer patients treated with SABR.

Materials And Methods: Patients treated with lung SABR between May 2009 and August 2018, in a single United Kingdom (UK) radiotherapy center were included. The patient's baseline characteristics, treatment details, and toxicity were retrieved from the electronic medical record. Dosimetric data was extracted from Xio and Monaco treatment planning systems. Patients were treated according to the UK SABR consortium guidelines. RP was graded retrospectively using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, based on available clinical and imaging information. Univariate and multivariate binary logistic regression was performed to determine predictive factors for grade ≥ 2 radiation pneumonitis, using Statistical Package for the Social Sciences (SPSS) statistics version 21 software. The goodness of fit was assessed using the Hosmer and Lemeshow test. The optimal diagnostic threshold was tested using the Receiver operating characteristics (ROC) curve. The chi-square test was carried out to test the different risk factors against the likelihood of developing grade ≥ 2 pneumonitis.

Results: A total of 1266 patients included in the analysis. The median age of patients was 75 years. Six hundred sixty-six patients (52.6%) were female. Median follow up was 56 months. Sixty-five percent of patients received 55 Gy in 5 fractions. Forty-three percent of patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 and 16.2% had PS of 3. The Median Charlson comorbidity index was 6 (range 2-11). Median Standardized Uptake Value (SUV) max of the tumor was 6.5. Four hundred two patients (31.8%) had confirmed histological diagnosis; other patients were treated based on a radiological diagnosis. The median tumor size was 20 mm (range 4 mm-63 mm). Median Planning Target Volume (PTV) was 30.3 cc. Median values of R100, R50, and D2cm were 1.1, 5.6, 32.8 Gy. The median value of mean lung dose, V20, and V12.5 were 3.9 Gy, 5 %and 9.3% respectively. Eighty-five (6.7%) patients developed symptomatic RP (grade ≥ 2) with only 5(0.4%) developing grade 3 RP. Five percent of patients developed rib fractures but only 28% of these were symptomatic. On univariate analysis lower lobe tumor location, larger tumor size, PTV, mean lung dose, lung V20Gy, and V12.5 Gy were significantly associated with grade ≥ 2 RP. On multivariate analysis, only mean lung dose was associated with grade ≥ 2 pneumonitis. ROC curve analysis showed optimal diagnostic threshold for tumour size, PTV, mean lung dose, V20 and V12.5; are 22.5 mm ((Area Under Curve (AUC)-0.565)), 27.15 cc (AUC-0.58), 3.7 Gy (AUC-0.633), 4.6% (AUC-0.597), 9.5% (AUC-0.616). The incidence of ≥grade 2 RP was significantly high for values higher than the ROC threshold.

Conclusion: SABR treatment resulted in a very low rate of grade 3 pneumonitis. Lower lobe tumor location, larger tumor size, PTV, mean lung dose, V20, and V12.5 were found to be significant predictors of symptomatic radiation pneumonitis.
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http://dx.doi.org/10.1016/j.radonc.2020.12.015DOI Listing
March 2021

pH-Sensitive Nanodrug Carriers for Codelivery of ERK Inhibitor and Gemcitabine Enhance the Inhibition of Tumor Growth in Pancreatic Cancer.

Mol Pharm 2021 01 24;18(1):87-100. Epub 2020 Nov 24.

Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, North Dakota 58108, United States.

Pancreatic ductal adenocarcinoma (PDAC), a metabolic disorder, remains one of the leading cancer mortality sources worldwide. An initial response to treatments, such as gemcitabine (GEM), is often followed by emergent resistance reflecting an urgent need for alternate therapies. The PDAC resistance to GEM could be due to ERK1/2 activity. However, successful ERKi therapy is hindered due to low ligand efficiency, poor drug delivery, and toxicity. In this study, to overcome these limitations, we have designed pH-responsive nanoparticles (NPs) with a size range of 100-150 nm for the simultaneous delivery of ERKi (SCH 772984) and GEM with tolerable doses. These NPs are polyethylene glycol (PEG)-containing amphiphilic polycarbonate block copolymers with tertiary amine side chains. They are systemically stable and capable of improving and drug delivery at the cellular environment's acidic pH. The functional analysis indicates that the nanomolar doses of ERKi or GEM significantly decreased the 50% growth inhibition (IC) of PDAC cells when encapsulated in NPs compared to free drugs. The combination of ERKi with GEM displayed a synergistic inhibitory effect. Unexpectedly, we uncover that the minimum effective dose of ERKi significantly promotes GEM activities on PDAC cells. Furthermore, we found that NP-encapsulated combination therapy of ERKi with GEM was superior to unencapsulated combination drug therapy. Our findings, thus, reveal a simple, yet efficient, drug delivery approach to overcome the limitations of ERKi for clinical applications and present a new model of sensitization of GEM by ERKi with no or minimal toxicity.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00499DOI Listing
January 2021

Quality by design (Qbd) assisted development of phytosomal gel of aloe vera extract for topical delivery.

J Liposome Res 2021 Dec 19;31(4):381-388. Epub 2020 Nov 19.

Faculty of Pharmacy, Al Hawash Private University, Homs, Syria.

The aim of the current study was to develop the phytosomal gel of aloe vera extract for improved topical delivery. Aloe vera extract loaded phytosomal system was developed by fixing the amount of aloe vera extract and ethanol and by varying the concentration of lecithin (0.15-0.25% w/v) and speed of rotation (80-120 rpm). Different formulation batches were prepared as per the Design expert software. A 2 Factorial design was applied to optimize the formulation on the basis of vesicular size and entrapment efficiency. Developed formulations were evaluated for vesicular size, entrapment efficiency, PDI, zeta potential and release. Further stability studies were also performed. For the optimized formulation (F09), vesicular size, entrapment efficiency and PDI were found as 123.1 ± 1.44 nm, 95.67 ± 0.27% and 0.98 ± 0.06. Zeta potential of -11.9 mV and drug release of 56.91 ± 4.1% obtained in 24 h. Drug release kinetics from the phytosomes follows Higuchi model. TEM micrograph confirms the uniform structure of phytosomes. Phytosomal gel of optimized phytosomal formulation (F09) was developed with 1% Carbopol 934 and physically characterized on the basis of pH, viscosity, homogeneity and drug content. permeation study showed the better permeation and flux profile of phytosomal gel with the conventional aloe vera extract gel. Also, studies on phytosomal formulation and gel showed stability up-to 3 months. Thus overall, it can be concluded that the phytosomal gel is a good carrier for topical delivery of herbal extract such as aloe vera.
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http://dx.doi.org/10.1080/08982104.2020.1849279DOI Listing
December 2021

Maintained memory and long-term potentiation in a mouse model of Alzheimer's disease with both amyloid pathology and human tau.

Eur J Neurosci 2021 01 17;53(2):637-648. Epub 2020 Aug 17.

Centre for Discovery Brain Sciences and UK Dementia Research Institute, The University of Edinburgh, Edinburgh, UK.

One of the key knowledge gaps in the field of Alzheimer's disease research is the lack of understanding of how amyloid beta and tau cooperate to cause neurodegeneration. We recently generated a mouse model (APP/PS1 + Tau) that develops amyloid plaque pathology and expresses human tau in the absence of endogenous murine tau. These mice exhibit an age-related behavioural hyperactivity phenotype and transcriptional deficits which are ameliorated by tau transgene suppression. We hypothesized that these mice would also display memory and hippocampal synaptic plasticity deficits as has been reported for many plaque bearing mouse models which express endogenous mouse tau. We observed that our APP/PS1 + Tau model does not exhibit novel object memory or robust long-term potentiation deficits with age, whereas the parent APP/PS1 line with mouse tau did develop the expected deficits. These data are important as they highlight potential functional differences between mouse and human tau and the need to use multiple models to fully understand Alzheimer's disease pathogenesis and develop effective therapeutic strategies.
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http://dx.doi.org/10.1111/ejn.14918DOI Listing
January 2021

Human T-cell Leukemia Virus Type 1 and : Partners in Pathogenesis.

Pathogens 2020 Oct 29;9(11). Epub 2020 Oct 29.

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.

Infection with human T-cell leukemia/lymphoma virus type 1 (HTLV-1) has been associated with various clinical syndromes including co-infection with , which is an intestinal parasitic nematode and the leading cause of strongyloidiasis in humans. Interestingly, HTLV-1 endemic areas coincide with regions citing high prevalence of infection, making these communities optimal for elucidating the pathogenesis of co-infection and its clinical significance. HTLV-1 co-infection with has been observed for decades in a number of published patient cases and case series; however, the implications of this co-infection remain elusive. Thus far, data suggest that increases proviral load in patients co-infected with HTLV-1 compared to HTLV-1 infection alone. Furthermore, co-infection with HTLV-1 has been associated with shifting the immune response from Th2 to Th1, affecting the ability of the immune system to address the helminth infection. Thus, despite this well-known association, further research is required to fully elucidate the impact of each pathogen on disease manifestations in co-infected patients. This review provides an analytical view of studies that have evaluated the variation within HTLV-1 patients in susceptibility to infection, as well as the effects of strongyloidiasis on HTLV-1 pathogenesis. Further, it provides a compilation of available clinical reports on the epidemiology and pathology of HTLV-1 with parasitic co-infection as well as data from mechanistic studies suggesting possible immunopathogenic mechanisms. Furthermore, specific areas of potential future research have been highlighted to facilitate advancing understanding of the complex interactions between these two pathogens.
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http://dx.doi.org/10.3390/pathogens9110904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692131PMC
October 2020

Comprehending Meningioma Signaling Cascades Using Multipronged Proteomics Approaches & Targeted Validation of Potential Markers.

Front Oncol 2020 26;10:1600. Epub 2020 Aug 26.

Proteomics Lab, Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India.

Meningiomas are one of the most prevalent primary brain tumors. Our study aims to obtain mechanistic insights of meningioma pathobiology using mass spectrometry-based label-free quantitative proteome analysis to identifying druggable targets and perturbed pathways for therapeutic intervention. Label-free based proteomics study was done from peptide samples of 21 patients and 8 non-tumor controls which were followed up with Phosphoproteomics to identify the kinases and phosphorylated components of the perturbed pathways. approaches revealed perturbations in extracellular matrix remodeling and associated cascades. To assess the extent of influence of Integrin and PI3K-Akt pathways, we used an Integrin Linked Kinase inhibitor on patient-derived meningioma cell line and performed a transcriptomic analysis of the components. Furthermore, we designed a Targeted proteomics assay which to the best of our knowledge for very first-time enables identification of peptides from 54 meningioma patients via SRM assay to validate the key proteins emerging from our study. This resulted in the identification of peptides from CLIC1, ES8L2, and AHNK many of which are receptors and kinases and are difficult to be characterized using conventional approaches. Furthermore, we were also able to monitor transitions for proteins like NEK9 and CKAP4 which have been reported to be associated with meningioma pathobiology. We believe, this study can aid in designing peptide-based validation assays for meningioma patients as well as IHC studies for clinical applications.
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http://dx.doi.org/10.3389/fonc.2020.01600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482667PMC
August 2020

Exploration of Nanoethosomal Transgel of Naproxen Sodium for the Treatment of Arthritis.

Curr Drug Deliv 2020 ;17(10):885-897

Department of Pharmaceutics, Nanoformulation Research Lab, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.

Background: The present work aimed to develop an ethosomal gel of naproxen sodium for the amelioration of rheumatoid arthritis.

Objective: In the present work, we have explored the potential of ethosomes to deliver naproxen into deeper skin strata. Further, the anti-inflammatory efficacy of naproxen ethosomal formulation was assessed using the carrageenan-induced rat paw edema model.

Methods: Naproxen sodium nanoethosomes were prepared using different proportions of lipoid S100 (50mg-200mg), ethanol (20-50%) and water, and were further characterized on the basis of vesicle morphology, entrapment efficiency, zeta potential, in-vitro drug release and ex-vivo permeation studies.

Results: The optimized ethosomal formulation was found to have 129 ± 0.01 nm particle size, 0.295 Polydispersity Index (PDI), -3.29 mV zeta potential, 88% entrapment efficiency and 96.573% drug release in 24 hours. TEM and SEM analysis of the optimized formulation showed slightly smooth spherical structures. The Confocal laser scanning microscopy showed that ethosomes could easily infiltrate into deeper dermal layers (upto 104.9μm) whereas the hydroalcoholic solution of the drug could penetrate up to 74.9μm. Further, the optimized ethosomal formulation was incorporated into 1% carbopol 934 gel base and optimized wherein the transdermal flux was found to be approximately 10 times more than the hydroethanolic solution. Also, the in-vivo pharmacodynamic study of the optimized ethosomal gel exhibited a higher percentage inhibition of swelling paw edema than marketed diclofenac gel.

Conclusion: The ethosomal gel was successfully developed and has shown the potential to be a good option for the replacement of conventional therapies of rheumatoid arthritis.
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http://dx.doi.org/10.2174/1567201817666200724170203DOI Listing
January 2020

The National Lung Matrix Trial of personalized therapy in lung cancer.

Nature 2020 07 15;583(7818):807-812. Epub 2020 Jul 15.

Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.
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http://dx.doi.org/10.1038/s41586-020-2481-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116732PMC
July 2020

Apigenin Modulates Dendritic Cell Activities and Curbs Inflammation Via RelB Inhibition in the Context of Neuroinflammatory Diseases.

J Neuroimmune Pharmacol 2021 06 30;16(2):403-424. Epub 2020 Jun 30.

Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, 19102, USA.

Neuroinflammation leads to tissue injury causing many of the clinical symptoms of Multiple Sclerosis, an autoimmune disorder of the central nervous system (CNS). While T cells, specifically T1 and T17 cells, are the ultimate effectors of this disease, dendritic cells (DCs) mediate T cell polarization, activation, etc. In our previous study, Apigenin, a natural flavonoid, has been shown to reduce EAE disease severity through amelioration of demyelination in the CNS as well as the sequestering of DCs and other myeloid cells in the periphery. Here, we show that Apigenin exerts its effects possibly through shifting DC modulated T cell responses from T1 and T17 type towards T directed responses evident through the decrease in T-bet, IFN-γ (T1), IL-17 (T17) and increase in IL-10, TGF-β and FoxP3 (T) expression in cells from both normal human donors and EAE mice. RelB, an NF-κβ pathway protein is central to DC maturation, its antigen presentation capabilities and DC-mediated T cell activation. Apigenin reduced mRNA and protein levels of RelB and also reduced its nuclear translocation. Additionally, siRNA-mediated silencing of RelB further potentiated the RelB-mediated effects of Apigenin thus confirming its role in Apigenin directed regulation of DC biology. These results provide key information about the molecular events controlled by Apigenin in its regulation of DC activity marking its potential as a therapy for neuroinflammatory disease. Graphical Abstract.
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http://dx.doi.org/10.1007/s11481-020-09933-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772281PMC
June 2021

Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.

Genome Med 2020 03 2;12(1):25. Epub 2020 Mar 2.

Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada.

Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children.

Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung.

Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels.

Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
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http://dx.doi.org/10.1186/s13073-020-0716-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050134PMC
March 2020

Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease.

Cell Rep 2019 12;29(11):3592-3604.e5

The University of Edinburgh Centre for Discovery Brain Sciences, 1 George Square, Edinburgh EH8 9JZ, UK; UK Dementia Research Institute at Edinburgh, George Square, Edinburgh EH8 9JZ, UK. Electronic address:

A key knowledge gap blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aβ) peptide and pathological forms of the tau protein cooperate in causing disease phenotypes. Within a mouse tau-deficient background, we probed the molecular, cellular, and behavioral disruption triggered by the influence of wild-type human tau on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity behavioral phenotype and to cause downregulation of transcription of genes involved in synaptic function. In both our mouse model and human postmortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau reduction in the mice initiated after behavioral deficits emerge corrects behavioral deficits, reduces synaptic tau levels, and substantially reverses transcriptional perturbations, suggesting that lowering synaptic tau levels may be beneficial in AD.
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http://dx.doi.org/10.1016/j.celrep.2019.11.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915767PMC
December 2019
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