Publications by authors named "Mohammad Athar"

194 Publications

Predicting the Global Distribution of (Hymenoptera: Formicidae) under Climate Change Using the MaxEnt Model.

Insects 2021 Mar 8;12(3). Epub 2021 Mar 8.

Department of Biology, Kyung Hee University, Dongdaemun, Seoul 02447, Korea.

The tropical fire ant (Hymenoptera: Formicidae) is a serious invasive species that causes a decline in agricultural production, damages infrastructure, and harms human health. This study was aimed to develop a model using the maximum entropy (MaxEnt) algorithm to predict the current and future distribution of on a global scale for effective monitoring and management. In total, 669 occurrence sites of and six bioclimatic variables of current and future climate change scenarios for 2050 and 2100 were used for the modeling. The annual mean temperature, annual precipitation, and precipitation in the driest quarter were the key influential factors for determining the distribution of . Although the potential global distribution area of is predicted to decrease slightly under global warming, the distribution of favorable habitats is predicted to expand to high latitudes under climate scenarios. In addition, some countries in America and East Asia, such as Brazil, China, South Korea, the USA, and Uruguay, are predicted to be threatened by invasion under future climate change. These findings can facilitate the proactive management of . through monitoring, surveillance, and quarantine measures.
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http://dx.doi.org/10.3390/insects12030229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998871PMC
March 2021

Transcriptional circuitry atlas of genetic diverse unstimulated murine and human macrophages define disparity in population-wide innate immunity.

Sci Rep 2021 Apr 1;11(1):7373. Epub 2021 Apr 1.

Department of Biology, University of Alabama At Birmingham, 464 Campbell Hall, 1300 University Boulevard, Alabama, 35294, USA.

Macrophages are ubiquitous custodians of tissues, which play decisive role in maintaining cellular homeostasis through regulatory immune responses. Within tissues, macrophage exhibit extremely heterogeneous population with varying functions orchestrated through regulatory response, which can be further exacerbated in diverse genetic backgrounds. Gene regulatory networks (GRNs) offer comprehensive understanding of cellular regulatory behavior by unfolding the transcription factors (TFs) and regulated target genes. RNA-Seq coupled with ATAC-Seq has revolutionized the regulome landscape influenced by gene expression modeling. Here, we employ an integrative multi-omics systems biology-based analysis and generated GRNs derived from the unstimulated bone marrow-derived macrophages of five inbred genetically defined murine strains, which are reported to be linked with most of the population-wide human genetic variants. Our probabilistic modeling of a basal hemostasis pan regulatory repertoire in diverse macrophages discovered 96 TFs targeting 6279 genes representing 468,291 interactions across five inbred murine strains. Subsequently, we identify core and distinctive GRN sub-networks in unstimulated macrophages to describe the system-wide conservation and dissimilarities, respectively across five murine strains. Our study concludes that discrepancies in unstimulated macrophage-specific regulatory networks not only drives the basal functional plasticity within genetic backgrounds, additionally aid in understanding the complexity of racial disparity among the human population during stress.
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http://dx.doi.org/10.1038/s41598-021-86742-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016976PMC
April 2021

Citrullinated vimentin mediates development and progression of lung fibrosis.

Sci Transl Med 2021 Mar;13(585)

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

The mechanisms by which environmental exposures contribute to the pathogenesis of lung fibrosis are unclear. Here, we demonstrate an increase in cadmium (Cd) and carbon black (CB), common components of cigarette smoke (CS) and environmental particulate matter (PM), in lung tissue from subjects with idiopathic pulmonary fibrosis (IPF). Cd concentrations were directly proportional to citrullinated vimentin (Cit-Vim) amounts in lung tissue of subjects with IPF. Cit-Vim amounts were higher in subjects with IPF, especially smokers, which correlated with lung function and were associated with disease manifestations. Cd/CB induced the secretion of Cit-Vim in an Akt1- and peptidylarginine deiminase 2 (PAD2)-dependent manner. Cit-Vim mediated fibroblast invasion in a 3D ex vivo model of human pulmospheres that resulted in higher expression of CD26, collagen, and α-SMA. Cit-Vim activated NF-κB in a TLR4-dependent fashion and induced the production of active TGF-β1, CTGF, and IL-8 along with higher surface expression of TLR4 in lung fibroblasts. To corroborate ex vivo findings, mice treated with Cit-Vim, but not Vim, independently developed a similar pattern of fibrotic tissue remodeling, which was TLR4 dependent. Moreover, wild-type mice, but not and TLR4 mutant (MUT) mice, exposed to Cd/CB generated high amounts of Cit-Vim, in both plasma and bronchoalveolar lavage fluid, and developed lung fibrosis in a stereotypic manner. Together, these studies support a role for Cit-Vim as a damage-associated molecular pattern molecule (DAMP) that is generated by lung macrophages in response to environmental Cd/CB exposure. Furthermore, PAD2 might represent a promising target to attenuate Cd/CB-induced fibrosis.
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http://dx.doi.org/10.1126/scitranslmed.aba2927DOI Listing
March 2021

Dietary table grape protects against ultraviolet photodamage in humans: 2. molecular biomarker studies.

J Am Acad Dermatol 2021 Jan 20. Epub 2021 Jan 20.

Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.01.036DOI Listing
January 2021

Dietary table grape protects against ultraviolet photodamage in humans: 1. clinical evaluation.

J Am Acad Dermatol 2021 Jan 20. Epub 2021 Jan 20.

Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.01.035DOI Listing
January 2021

Prevalence of the Factor V Leiden Mutation Arg534Gln in Western Region of Saudi Arabia: Functional Alteration and Association Study With Different Populations.

Clin Appl Thromb Hemost 2021 Jan-Dec;27:1076029620978532

Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.

The rare Gln534 (Factor V Leiden; FVL) allele (1:169,519,049 T>C) is associated with an increased risk of venous thrombosis. The purpose of this study was to measure the prevalence of Factor V Leiden mutation in thrombophilia patients with deep vein thrombosis. Also, we investigated the functional and structural characteristics of this mutation p.(Arg534Gln) to be examined the cumulative impact on venous thrombosis risk as well correlated with different populations by Genome Wide Association Studies (GWAS). A total of 108 patients with idiopathic deep vein thrombosis were examined for Factor V Leiden gene mutation. Our preliminary data show that about 10% of patients were detected with the heterozygous and homozygous form of the Factor V Leiden mutation. An association analysis confirmed that the SNP variant (rs6025) was highly associated (-value 4.91 x10-^ -39) with an increased risk of venous thrombosis. Also, we found that the recognized SNP was important among HapMap populations. Our results indicated that among the 3 populations (Asian, African, and American) studied, this association was highest in the African population based on the r(2) significant threshold (-value 5e-190). In addition, this mutation was located at the domain F5/8 type A 2, which can disturb this domain and abolish its function. Because of aspartic acid nearby wild type position as form in the salt bridge due to this discharge will disturb the ionic interaction made by the wild type residue Arg534. This residue was not found to be in contact with other domains of which the function was known. However, contact with other molecules or domains (THPH2: MIM: 188055) were still possible and might be affected by this mutation that may cause thrombophilia due to activated protein C resistance.
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http://dx.doi.org/10.1177/1076029620978532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812389PMC
January 2021

Epigenetic regulation in the pathogenesis of non-melanoma skin cancer.

Semin Cancer Biol 2020 Nov 23. Epub 2020 Nov 23.

UAB Research Center of Excellence in Arsenicals, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address:

Understanding of cancer with the help of ever-expanding cutting edge technological tools and bioinformatics is revolutionizing modern cancer research by broadening the space of discovery window of various genomic and epigenomic processes. Genomics data integrated with multi-omics layering have advanced cancer research. Uncovering such layers of genetic mutations/modifications, epigenetic regulation and their role in the complex pathophysiology of cancer progression could lead to novel therapeutic interventions. Although a plethora of literature is available in public domain defining the role of various tumor driver gene mutations, understanding of epigenetic regulation of cancer is still emerging. This review focuses on epigenetic regulation association with the pathogenesis of non-melanoma skin cancer (NMSC). NMSC has higher prevalence in Caucasian populations compared to other races. Due to lack of proper reporting to cancer registries, the incidence rates for NMSC worldwide cannot be accurately estimated. However, this is the most common neoplasm in humans, and millions of new cases per year are reported in the United States alone. In organ transplant recipients, the incidence of NMSC particularly of squamous cell carcinoma (SCC) is very high and these SCCs frequently become metastatic and lethal. Understanding of solar ultraviolet (UV) light-induced damage and impaired DNA repair process leading to DNA mutations and nuclear instability provide an insight into the pathogenesis of metastatic neoplasm. This review discusses the recent advances in the field of epigenetics of NMSCs. Particularly, the role of DNA methylation, histone hyperacetylation and non-coding RNA such as long-chain noncoding (lnc) RNAs, circular RNAs and miRNA in the disease progression are summarized.
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http://dx.doi.org/10.1016/j.semcancer.2020.11.009DOI Listing
November 2020

EGFRvIII expression and isocitrate dehydrogenase mutations in patients with glioma.

Oncol Lett 2020 Dec 23;20(6):384. Epub 2020 Oct 23.

Department of Radiation Oncology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.

Molecular pathology and personalized medicine are still being evolved in Saudi Arabia, and genetic testing for the detection of mutations as cancer markers have not been established in the diagnostics laboratories in Saudi Arabia. The aim of the present study was to determine the prevalence of isocitrate dehydrogenase (IDH1 and IDH2) mutations and epidermal growth factor receptor variant (EGFRv)III transcript expression in Saudi Arabian patients with glioma. Out of 117 brain tumors tested by reverse transcription-quantitative PCR for EGFRvIII, 41 cases tested positive. In the glioblastoma (GBM) category, 28/55 tumors were positive, in astrocytoma tumors 5/22, and in oligodendrogliomas 4/13 cases were positive respectively. EGFRvIII transcript was sequenced by capillary electrophoresis to demonstrate the presence of EGFRvIII-specific junction where exons 2-7 were deleted. In the present study 106 tumors were sequenced for IDH1 exon-4 mutations using the capillary sequencing method. The most common substitution missense mutation c.395G>A was found in 16 tumors. In the case of adamantinomatous craniopharyngioma, a novel missense mutation in c.472C>T was detected in IDH2 gene. Using next-generation sequencing (NGS), 74 tumors were sequenced for the IDH1 gene, and a total of 8 missense variants were identified in 36 tumors in a population of Saudi Arabia. The missense mutation (c.395G>A) was detected in 29/36 of tumors. A novel intronic mutation in c.414+9T>A was found in 13 cases in the IDH1 gene. In addition, one case exhibited a novel synonymous mutation in c.369A>G. Eleven tumors were found to have compound mutations in the IDH1 gene. In IDH2 gene, out of a total of 16 variants found in 6 out of 45 tumors, nine were missense, five were synonymous and one was intronic. This is the first report from Saudi Arabian laboratories analyzing glioma tumors for EGFRvIII expression, and the first study from Saudi Arabia to analyze IDH mutations in gliomas using the capillary and NGS methods.
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http://dx.doi.org/10.3892/ol.2020.12247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656109PMC
December 2020

Regulatory T Cells Play an Important Role in the Prevention of Murine Melanocytic Nevi and Melanomas.

Cancer Prev Res (Phila) 2020 Nov 4. Epub 2020 Nov 4.

Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.

Melanocytic nevi are benign proliferations of pigment cells that can occasionally develop into melanomas. There is a significant correlation between increased nevus numbers and melanoma development. Our previous reports revealed that 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced dysplastic nevi in C3H/HeN mice, with a potential to transform into melanomas. To understand the immune mechanisms behind this transformation, we applied increasing DMBA doses followed by TPA to the skin of C3H/HeN mice. We observed that increased doses of DMBA correlated well with increased numbers of nevi. The increased DMBA dose induced diminished immune responses and promoted the expansion of regulatory T cells (Treg) that resulted in increased IL10 and reduced IFNγ levels. Mice with increased nevus numbers had loss of p16 expression. These mice had increased migration of melanocytic cells to lymph nodes (LN) and a greater percent of LNs produced immortalized melanocytic cell lines. DMBA-induced immunosuppression was lost in CD4-knockout (KO) mice. Lymphocytes in the CD4KO mice produced less IL10 than CD8KO mice. Furthermore, CD4KO mice had significantly reduced nevus numbers and size compared with wild-type and CD8KO mice. These results suggest that Tregs play a vital role in the incidence of nevi and their progression to melanoma. PREVENTION RELEVANCE: There has been little progress in developing novel strategies for preventing premalignant dysplastic nevi from becoming melanomas. In this study in mice, regulatory-T cells enhanced progression of benign nevi to malignant melanomas; and by inhibiting their activity, melanomas could be retarded. The findings identify new possibilities for melanoma prevention in high risk individuals.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0360DOI Listing
November 2020

EZH2-Targeted Therapies in Cancer: Hype or a Reality.

Cancer Res 2020 12 25;80(24):5449-5458. Epub 2020 Sep 25.

Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama.

Next-generation genomic sequencing has identified multiple novel molecular alterations in cancer. Since the identification of DNA methylation and histone modification, it has become evident that genes encoding epigenetic modifiers that locally and globally regulate gene expression play a crucial role in normal development and cancer progression. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the enzymatic catalytic subunit of the polycomb-repressive complex 2 (PRC2) that can alter gene expression by trimethylating lysine 27 on histone 3 (H3K27). EZH2 is involved in global transcriptional repression, mainly targeting tumor-suppressor genes. EZH2 is commonly overexpressed in cancer and shows activating mutations in subtypes of lymphoma. Extensive studies have uncovered an important role for EZH2 in cancer progression and have suggested that it may be a useful therapeutic target. In addition, tumors harboring mutations in other epigenetic genes such as , and are highly sensitive to EZH2 inhibition, thus increasing its potential as a therapeutic target. Recent studies also suggest that inhibition of EZH2 enhances the response to tumor immunotherapy. Many small-molecule inhibitors have been developed to target EZH2 or the PRC2 complex, with some of these inhibitors now in early clinical trials reporting clinical responses with acceptable tolerability. In this review, we highlight the recent advances in targeting EZH2, its successes, and potential limitations, and we discuss the future directions of this therapeutic subclass.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2147DOI Listing
December 2020

5'-Cap‒Dependent Translation as a Potent Therapeutic Target for Lethal Human Squamous Cell Carcinoma.

J Invest Dermatol 2021 Apr 21;141(4):742-753.e10. Epub 2020 Sep 21.

UAB Research Center of Excellence in Arsenicals and Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA. Electronic address:

Skin squamous cell carcinomas (SCCs) are a major cause of death in patients who have undergone or will undergo organ transplantation. Moreover, these neoplasms cause significant disease and economic burden and diminish patients' life quality. However, no effective treatment or intervention strategies are available. In this study, we investigated the pathologic role of 5'-cap translation, which is regulated by the formation of a ternary initiation factor complex involving eIF4E, eIF4G, and eIF4A1. We detected increased expression of phosphorylated eIF4E, eIF4G, and eIF4A1 in human and murine skin SCCs. The increase in these ternary initiation factor complex proteins was associated with enhanced eIF4E translation targets cyclin D1 and c-Myc. Conversely, small interfering RNA-mediated depletion of eIF4E in human SCC cells (A431 and SCC-13) reduced eIF4G and proteins that regulate the cell cycle and proliferation. Notably, inhibition of Raf/MAPK/extracellular signal-regulated kinase signaling decreased eIF4E and phosphorylated eIF4E accumulation and significantly diminished cell-cycle gene expression and tumor volume of A431-derived xenograft tumors. Furthermore, disrupting the eIF4E with an allosteric inhibitor of eIF4E and eIF4G binding, 4EGI-1, decreased the eIF4E/eIF4G expression and reduced the proliferation. Finally, combined inhibition of the Raf/MAPK/extracellular signal-regulated kinase axis and eIF4E impaired 5'-cap‒dependent translation and abrogated tumor cell proliferation. These data demonstrate that 5'-cap‒dependent translation is a potential therapeutic target for abrogating lethal skin SCCs in patients who have undergone or will undergo organ transplantation.
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http://dx.doi.org/10.1016/j.jid.2020.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981283PMC
April 2021

The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers.

Adv Exp Med Biol 2020 ;1268:257-283

Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.

Nonmelanoma skin cancers including basal and squamous cell carcinomas (SCC and BCC) represent a significant clinical problem due to their relatively high incidence, imposing an economic burden to healthcare systems around the world. It is accepted that ultraviolet radiation (UVR: λ = 290-400 nm) plays a crucial role in the initiation and promotion of BCC and SCC with UVB (λ = 290-320 nm) having a central role in this process. On the other hand, UVB is required for vitamin D3 (D3) production in the skin, which supplies >90% of the body's requirement for this prohormone. Prolonged exposure to UVB can also generate tachysterol and lumisterol. Vitamin D3 itself and its canonical (1,25(OH)D3) and noncanonical (CYP11A1-intitated) D3 hydroxyderivatives show photoprotective functions in the skin. These include regulation of keratinocyte proliferation and differentiation, induction of anti-oxidative responses, inhibition of DNA damage and induction of DNA repair mechanisms, and anti-inflammatory activities. Studies in animals have demonstrated that D3 hydroxyderivatives can attenuate UVB or chemically induced epidermal cancerogenesis and inhibit growth of SCC and BCC. Genomic and non-genomic mechanisms of action have been suggested. In addition, vitamin D3 itself inhibits hedgehog signaling pathways which have been implicated in many cancers. Silencing of the vitamin D receptor leads to increased propensity to develop UVB or chemically induced epidermal cancers. Other targets for vitamin D compounds include 1,25D3-MARRS, retinoic orphan receptors α and γ, aryl hydrocarbon receptor, and Wnt signaling. Most recently, photoprotective effects of lumisterol hydroxyderivatives have been identified. Clinical trials demonstrated a beneficial role of vitamin D compounds in the treatment of actinic keratosis. In summary, recent advances in vitamin D biology and pharmacology open new exciting opportunities in chemoprevention and treatment of skin cancers.
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http://dx.doi.org/10.1007/978-3-030-46227-7_13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490773PMC
September 2020

Integrative Network Biology Framework Elucidates Molecular Mechanisms of SARS-CoV-2 Pathogenesis.

iScience 2020 Sep 3;23(9):101526. Epub 2020 Sep 3.

Department of Biology, University of Alabama at Birmingham, 464 Campbell Hall, 1300 University Boulevard, AL 35294, USA.

COVID-19 (coronavirus disease 2019) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the pathophysiology of this virus is complex and largely unknown, we employed a network-biology-fueled approach and integrated transcriptome data pertaining to lung epithelial cells with human interactome to generate Calu-3-specific human-SARS-CoV-2 interactome (CSI). Topological clustering and pathway enrichment analysis show that SARS-CoV-2 targets central nodes of the host-viral network, which participate in core functional pathways. Network centrality analyses discover 33 high-value SARS-CoV-2 targets, which are possibly involved in viral entry, proliferation, and survival to establish infection and facilitate disease progression. Our probabilistic modeling framework elucidates critical regulatory circuitry and molecular events pertinent to COVID-19, particularly the host-modifying responses and cytokine storm. Overall, our network-centric analyses reveal novel molecular components, uncover structural and functional modules, and provide molecular insights into the pathogenicity of SARS-CoV-2 that may help foster effective therapeutic design.
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http://dx.doi.org/10.1016/j.isci.2020.101526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468341PMC
September 2020

Protective role of HO-1 against acute kidney injury caused by cutaneous exposure to arsenicals.

Ann N Y Acad Sci 2020 11 3;1480(1):155-169. Epub 2020 Sep 3.

UAB Research Center of Excellence in Arsenicals, Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.

Lewisite and many other similar arsenicals are warfare vesicants developed and weaponized for use in World Wars I and II. These chemicals, when exposed to the skin and other epithelial tissues, cause rapid severe inflammation and systemic damage. Here, we show that topically applied arsenicals in a murine model produce significant acute kidney injury (AKI), as determined by an increase in the AKI biomarkers NGAL and KIM-1. An increase in reactive oxygen species and ER stress proteins, such as ATF4 and CHOP, correlated with the induction of these AKI biomarkers. Also, TUNEL staining of CHOP-positive renal tubular cells suggests CHOP mediates apoptosis in these cells. A systemic inflammatory response characterized by a significant elevation in inflammatory mediators, such as IL-6, IFN-α, and COX-2, in the kidney could be the underlying cause of AKI. The mechanism of arsenical-mediated inflammation involves activation of AMPK/Nrf2 signaling pathways, which regulate heme oxygenase-1 (HO-1). Indeed, HO-1 induction with cobalt protoporphyrin (CoPP) treatment in arsenical-treated HEK293 cells afforded cytoprotection by attenuating CHOP-associated apoptosis and cytokine mRNA levels. These results demonstrate that topical exposure to arsenicals causes AKI and that HO-1 activation may serve a protective role in this setting.
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http://dx.doi.org/10.1111/nyas.14475DOI Listing
November 2020

Moving Immune Therapy Forward Targeting TME.

Physiol Rev 2021 Apr 13;101(2):417-425. Epub 2020 Aug 13.

Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.

The host immune system shapes the fate of tumor progression. Hence, manipulating patients' immune system to activate host immune responses against cancer pathogenesis is a promising strategy to develop effective therapeutic interventions for metastatic and drug-resistant cancers. Understanding the dynamic mechanisms within the tumor microenvironment (TME) that contribute to heterogeneity and metabolic plasticity is essential to enhance the patients' responsiveness to immune targeted therapies. Riera-Domingo et al. (Riera-Domingo C, Audige A, Granja S, Cheng WC, Ho PC, Baltazar F, Stockmann C, Mazzone, M. 100: 1-102, 2020) describe the immune landscape within the TME and highlight the significance of metabolic and hypoxic signatures that impact immune function and response to immunotherapy strategies. Current literature in this field confirms that targeting tumor metabolism and the acidic microenvironment commonly associated with tumors may present viable strategies to modulate the host immune system in favor of response to immune targeted therapies. However, development of better tools to understand tumor-immune interactions and identify mechanisms driving nonresponders, more innovative clinical trial design, and new therapies will need to be identified to move the field forward. Personalized immune therapies incorporating metabolic and microbiome-based gene signatures to influence the therapeutic response and novel methods to generate immunologically "hot" tumors are at the forefront of immunotherapy currently. The combination of these approaches with clinically approved immunotherapies will be valuable moving forward.
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http://dx.doi.org/10.1152/physrev.00008.2020DOI Listing
April 2021

COVID-19 and Vitamin D: A lesson from the skin.

Exp Dermatol 2020 09 9;29(9):885-890. Epub 2020 Sep 9.

Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.

The negative outcomes of COVID-19 diseases respiratory distress (ARDS) and the damage to other organs are secondary to a "cytokine storm" and to the attendant oxidative stress. Active hydroxyl forms of vitamin D are anti-inflammatory, induce antioxidative responses, and stimulate innate immunity against infectious agents. These properties are shared by calcitriol and the CYP11A1-generated non-calcemic hydroxyderivatives. They inhibit the production of pro-inflammatory cytokines, downregulate NF-κΒ, show inverse agonism on RORγ and counteract oxidative stress through the activation of NRF-2. Therefore, a direct delivery of hydroxyderivatives of vitamin D deserves consideration in the treatment of COVID-19 or ARDS of different aetiology. We also recommend treatment of COVID-19 patients with high-dose vitamin D since populations most vulnerable to this disease are likely vitamin D deficient and patients are already under supervision in the clinics. We hypothesize that different routes of delivery (oral and parenteral) will have different impact on the final outcome.
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http://dx.doi.org/10.1111/exd.14170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436895PMC
September 2020

Integrative Network Biology Framework Elucidates Molecular Mechanisms of SARS-CoV-2 Pathogenesis.

SSRN 2020 May 5:3581857. Epub 2020 May 5.

Department of Biology, 464 Campbell Hall, 1300 University Boulevard, University of Alabama at Birmingham, Alabama 35294, USA.

COVID-19 (Coronavirus disease 2019) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the pathophysiology of this deadly virus is complex and largely unknown, we employ a network biology-fueled approach and integrate multiomics data pertaining to lung epithelial cells-specific co-expression network and human interactome to generate Calu-3-specific human-SARS-CoV-2 nteractome (CSI). Topological clustering and pathway enrichment analysis show that SARS-CoV-2 target central nodes of host-viral network that participate in core functional pathways. Network centrality analyses discover 28 high-value SARS-CoV-2 targets, which are possibly involved in viral entry, proliferation and survival to establish infection and facilitate disease progression. Our probabilistic modeling framework elucidates critical regulatory circuitry and molecular events pertinent to COVID-19, particularly the host modifying responses and cytokine storm. Overall, our network centric analyses reveal novel molecular components, uncover structural and functional modules, and provide molecular insights into SARS-CoV-2 pathogenicity that may foster effective therapeutic design. Funding: This work was supported by the National Science Foundation (IOS-1557796) to M.S.M., and U54 ES 030246 from NIH/NIEHS to M. A. Conflict of Interest: The authors declare no competing interests. The authors also declare no financial interests.
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http://dx.doi.org/10.2139/ssrn.3581857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366800PMC
May 2020

Topical delivery of nordihydroguaretic acid for attenuating cutaneous damage caused by arsenicals.

J Drug Deliv Sci Technol 2020 Aug 12;58. Epub 2020 May 12.

Dept of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA, 30341, USA.

This study evaluated the topical delivery of nordihydroguaretic acid (NDGA), a molecule that can potentially alleviate cutaneous damage caused by exposure to arsenic warfare chemicals. N-acetylcysteine (NAC 0.2% w/v) was added as an antioxidant, preventing the oxidation of NDGA to toxic quinones. A 24 h study was performed to arrive at a minimum concentration of NDGA needed to deliver maximum drug. A solution of 3% w/v delivered the maximum amount of drug at the end of 24 h (37.45 ± 4.32 μg). Short duration studies were carried out to determine the time needed to saturate skin with NDGA. There was no significant difference in the skin concentrations for 24 h and 8 h (14.89 ± 2.36 μg), due to skin saturation. However, there was significant difference in the amount of drug delivered to the epidermis (12.29 ± 1.87 μg) and dermis (2.54 ± 0.56 μg) at the end of 8 h. Solution of NDGA was applied on UV treated skin to assess changes in drug delivery. In vivo studies revealed that 3% NDGA was non-toxic for topical administration.
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http://dx.doi.org/10.1016/j.jddst.2020.101773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367059PMC
August 2020

Comparative foliar anatomical and pollen morphological studies of Acanthaceae using light microscope and scanning electron microscope for effective microteaching in community.

Microsc Res Tech 2020 Sep 8;83(9):1103-1117. Epub 2020 Jul 8.

Department of Plant Sciences, Quaid-i-Azam University, Islamabad, Pakistan.

In this study, foliar anatomy and pollen morphology of 10 species of Acanthaceae has been investigated using light and scanning electron microscopy. The study was aimed to highlight the role of microscopy in microteaching at community for proper characterization of plants using palyno-anatomical characters including pollen type, exine sculpturing, shape of epidermal cells, pattern of anticlinal wall, type and size of stomata, and trichome. Most of the species have polygonal cell shapes but some species have irregular, tetragonal, and pentagonal shape of epidermal cells. The largest epidermal cell length on adaxial and abaxial surface were observed in Asystasia gangetica 66.95 and 87.40 μm whereas least was observed on adaxial surface in Justicia adhatoda 36.9 μm and on abaxial surface in Barleria cristata 35.65 μm. In anatomy, species have diacytic type of stomata, whereas stomata of paracytic type observed in two species, while in A. gangetica cyclocytic type of stomata are present. Quantitively on abaxial surface, largest stomata length 29.9 μm and width 24.30 μm was noted in B. cristata. While shortest stomata length was observed in Ruellia prostrata 25.95 μm whereas minimum width of stomata was examined in Barleria acanthoides 2.05 μm. The diversity of trichomes are present in all species except in Ruellia brittoniana. Acanthaceae can be characterized by exhibiting different pollen morphology having five types of pollen shapes, prolate, spheroidal, perprolate, subprolate, and oblate spheroidal. Exine peculiarities showing variations such as reticulate, granulate, coarsely reticulate, lophoreticulate, perforate tectate, and granulate surface were examined.
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http://dx.doi.org/10.1002/jemt.23502DOI Listing
September 2020

Xanthomas Can Be Misdiagnosed and Mistreated in Homozygous Familial Hypercholesterolemia Patients: A Call for Increased Awareness Among Dermatologists and Health Care Practitioners.

Glob Heart 2020 02 28;15(1):19. Epub 2020 Feb 28.

Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah Al Mukarramah, SA.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant inherited genetic disorder and results in the development of coronary artery disease (CAD). Clinical diagnosis of homozygous HH patients is usually straightforward because persistent hypercholesterolemia can produce xanthoma and corneal arcus. However, xanthoma may also be misdiagnosed as skin lesions and could therefore be mistreated. The aim of this case study report is to highlight the plight of patients with FH as means of raising awareness of the condition among dermatologists and health care practitioners, also to determine the genotype-phenotype correlation in severely affected homozygous FH proband patients.

Methods: Genetic screening of FH associated genes was performed by Ion Torrent next-generation sequencing and cascade screening by capillary sequencing.

Results: We present two clinical cases with prominent skin lesions seen in a dermatology clinic that were referred to plastic surgery for excision. Genetic testing was performed later, and confirmed common single nucleotide deletion variant (c.2027delG) in the alleles consequent to a frameshift mutation p.(G676Afs*33). In addition to the variant, two possibly damaging variants p.(L3313I) and p.(L1212M) and three damaging variants p.(R19*), p.(G83Q) and p.(S474*) in and genes respectively were identified. The gene variant p.(G83Q) was found to be novel, while others have been previously reported. Both patients were refractory to pharmacological therapies and are currently on lipoprotein apheresis (LA).

Conclusions: The present report indicates the need for increased awareness of FH, among the public and healthcare practitioners and supports the need for diagnostic screening and cascade genetic testing of this high-risk condition, which could ultimately lead to better prevention of CHD in this lethal condition.
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http://dx.doi.org/10.5334/gh.759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218775PMC
February 2020

Photoprotective Properties of Vitamin D and Lumisterol Hydroxyderivatives.

Cell Biochem Biophys 2020 Jun 22;78(2):165-180. Epub 2020 May 22.

School of Molecular Sciences, The University of Western Australia, Perth, WA, Australia.

We have previously described new pathways of vitamin D3 activation by CYP11A1 to produce a variety of metabolites including 20(OH)D3 and 20,23(OH)D3. These can be further hydroxylated by CYP27B1 to produce their C1α-hydroxyderivatives. CYP11A1 similarly initiates the metabolism of lumisterol (L3) through sequential hydroxylation of the side chain to produce 20(OH)L3, 22(OH)L3, 20,22(OH)L3 and 24(OH)L3. CYP11A1 also acts on 7-dehydrocholesterol (7DHC) producing 22(OH)7DHC, 20,22(OH)7DHC and 7-dehydropregnenolone (7DHP) which can be converted to the D3 and L3 configurations following exposure to UVB. These CYP11A1-derived compounds are produced in vivo and are biologically active displaying anti-proliferative, anti-inflammatory, anti-cancer and pro-differentiation properties. Since the protective role of the classical form of vitamin D3 (1,25(OH)D3) against UVB-induced damage is recognized, we recently tested whether novel CYP11A1-derived D3- and L3-hydroxyderivatives protect against UVB-induced damage in epidermal human keratinocytes and melanocytes. We found that along with 1,25(OH)D3, CYP11A1-derived D3-hydroxyderivatives and L3 and its hydroxyderivatives exert photoprotective effects. These included induction of intracellular free radical scavenging and attenuation and repair of DNA damage. The protection of human keratinocytes against DNA damage included the activation of the NRF2-regulated antioxidant response, p53-phosphorylation and its translocation to the nucleus, and DNA repair induction. These data indicate that novel derivatives of vitamin D3 and lumisterol are promising photoprotective agents. However, detailed mechanisms of action, and the involvement of specific nuclear receptors, other vitamin D binding proteins or mitochondria, remain to be established.
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http://dx.doi.org/10.1007/s12013-020-00913-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347247PMC
June 2020

Noncalcemic Vitamin D Hydroxyderivatives Inhibit Human Oral Squamous Cell Carcinoma and Down-regulate Hedgehog and WNT/β-Catenin Pathways.

Anticancer Res 2020 May;40(5):2467-2474

Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, U.S.A.

Background/aim: The hormonally-active form of vitamin D, 1,25(OH)D, demonstrated activity against oral squamous cell carcinoma (OSCC). Cytochrome P450scc (CYP11A1)-derived vitamin D hydroxyderivatives, such as 20(OH)D and 1,20(OH)D, have overlapping beneficial effects with 1,25(OH)D without causing hypercalcemia. This study sought to determine (i) whether 20(OH)D and 1,20(OH)D exhibit antitumor effects against OSCC comparable to those of 1,25(OH)D and (ii) whether these effects may stem from down-regulation of sonic hedgehog (SHH) or WNT/β-catenin signaling pathways.

Materials And Methods: Effects on CAL-27 cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt and spheroid assays. Signaling pathways were assessed by immunofluorescence and western blotting.

Results: 20(OH)D and 1,20(OH)D inhibited the growth of CAL-27 and demonstrated inhibition of WNT/β-catenin and the SHH signaling as evidenced by down-regulation of nuclear translocation of glioma-associated oncogene 1(GLI1) and β-catenin.

Conclusion: Noncalcemic vitamin D hydroxyderivatives demonstrated antitumor activities against OSCC comparable to those of 1,25(OH)D Their activities against SHH and the WNT/β-catenin pathways provide insight for a possible target for OSCC treatment.
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http://dx.doi.org/10.21873/anticanres.14216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241289PMC
May 2020

Cutaneous lewisite exposure causes acute lung injury.

Ann N Y Acad Sci 2020 11 24;1479(1):210-222. Epub 2020 Apr 24.

Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Lewisite is a strong vesicating and chemical warfare agent. Because of the rapid transdermal absorption, cutaneous exposure to lewisite can also elicit severe systemic injury. Lewisite (2.5, 5.0, and 7.5 mg/kg) was applied to the skin of Ptch1 /SKH-1 mice and acute lung injury (ALI) was assessed after 24 hours. Arterial blood gas measurements showed hypercapnia and hypoxemia in the lewisite-exposed group. Histological evaluation of lung tissue revealed increased levels of proinflammatory neutrophils and a dose-dependent increase in structural changes indicative of injury. Increased inflammation was also confirmed by altered expression of cytokines, including increased IL-33, and a dose-dependent elevation of CXCL1, CXCL5, and GCSF was observed in the lung tissue. In the bronchoalveolar lavage fluid of lewisite-exposed animals, there was a significant increase in HMGB1, a damage-associated molecular pattern molecule, as well as elevated CXCL1 and CXCL5, which coincided with an influx of neutrophils to the lungs. Complete blood cell analysis revealed eosinophilia and altered neutrophil-lymphocyte ratios as a consequence of lewisite exposure. Mean platelet volume and RBC distribution width, which are predictors of lung injury, were also increased in the lewisite group. These data demonstrate that cutaneous lewisite exposure causes ALI and may contribute to mortality in exposed populations.
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http://dx.doi.org/10.1111/nyas.14346DOI Listing
November 2020

Abundance and Distribution of Korean Flower Flies (Diptera: Syrphidae): Dominant Influence of Latitude on Regional Distribution.

Insects 2020 Mar 29;11(4). Epub 2020 Mar 29.

Department of Biology, Kyung Hee University, Dongdaemun, Seoul 02447, Korea.

Studies on abundance and distribution at different scales are rare. We examined whether the abundance of flower flies at a site in South Korea was related to the national occupancy and global distribution (distributional extent or range size) and whether the national occupancy was related to global distribution. In global distribution, the influence of two dimensions (latitude and longitude) was analyzed separately. Flower flies were collected by malaise and pitfall traps at a forest gap in South Korea. Data regarding national occupancy and global distribution were obtained from a Korean Flower Fly Atlas. We collected 46 species from the field survey and obtained a list of 119 species from the Korean Flower Fly Atlas. Our results showed that abundance at a site was positively correlated with national occupancy, but not global distribution, and the national occupancy was positively correlated with global distribution, mainly by the latitudinal range size. Finally, our results indicated that the regional distribution of flower flies was influenced by its one-dimensional global distribution.
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http://dx.doi.org/10.3390/insects11040213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240411PMC
March 2020

Association of functional variants and protein-to-protein physical interactions of human MutY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome.

Noncoding RNA Res 2019 Dec 4;4(4):155-173. Epub 2019 Dec 4.

Bircham University, Av. Sierra, 2, 28691 Villanueva de la Canada, Madrid, Spain.

The human gene codes for a DNA glycosylase involved in the repair of oxidative DNA damage. Faulty MUTYH protein activity causes the accumulation of G→T transversions due to unrepaired 8-G:A mismatches. germ-line mutations in humans are linked with a recessive form of Familial Adenomatous Polyposis (FAP) and colorectal cancer predisposition. We studied the repair capacity of variants identified in MUTYH-associated polyposis (MAP) patients. MAP is inherited in an autosomal recessive type due to mutations in MUTYH (Y165C, G382D, P54S, A22V, Q63R, G45D, S136P and N43S), indicating that both copies of the gene become inactivated. However, the parents of an individual with an autosomal recessive condition may serve as carriers, each harboring one copy of the mutated gene without showing signs or symptoms of MAP. Six protein partners have been associated with MUTYH, four via direct physical interactions, namely hMSH6, hPCNA, hRPA1, and hAPEX1. We examined, for the first time, specific interactions of these protein partners with MAP-associated MUTYH mutants using molecular dynamics simulations. The approach provided tools for exploration of the conformational energy landscape accessible to protein partners. The investigation also determined the impact before and after energy minimization of protein-protein interaction and binding affinities of MUTYH wild type and mutant forms, as well as the interactions with other proteins. Taken together, this study provided new insights into the role of MUTYH and its interacting proteins in MAP.
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http://dx.doi.org/10.1016/j.ncrna.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012779PMC
December 2019

Morphological characterization of Hypnaceae (Bryopsida, Hypnales): Investigating four genera from Western Himalayas by using LM and SEM techniques.

Microsc Res Tech 2020 Jun 16;83(6):676-690. Epub 2020 Feb 16.

Department of Plant Sciences, Quaid-i-Azam University Islamabad, Islamabad, Pakistan.

The Hypnaceae is one of the largest and diversified family among the pleurocarpous mosses which consists of nearly 60 genera and 1,000 species around the world. In Pakistan, it is represented by 15 species and 8 genera. The current research article provides the detail morphological investigation of four different species (genera) of the family Hypnaceae that is, Gollania clarescens, Hypnum revolutum, Homomallium andoi, and Taxiphyllum taxirameum in the Western Himalayas, Pakistan. The research article reports the first SEM study of the leaf surfaces of the studied taxa, along with comprehensive morphological characters of the four species. The main objective of the research project is to present the comparative light and scanning electron microscopic study to discuss the morphology in detail because previously the family is just reported in different bryophyte checklists of the Western Himalayas. Based on results, morphological characters, micromorphological observations, qualitative and quantitative attributes, taxonomic keys for the studied taxa, distribution, and habitat are described. Stereoscope was used to analyze different qualitative characters, and light microscope was used to observe and measure the laminal and alar cells of the leaf. The SEM study reveals many important surface features like cell shape and cell wall. The laminal cells were mostly linear and elongated with thin cell walls. The specimens used for the SEM were air dried, so the laminal cells were somewhat constricted and concaved. The current study project will help to make the contribution in the taxonomy and morphology of this family.
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http://dx.doi.org/10.1002/jemt.23458DOI Listing
June 2020

Autocrine/paracrine actions of growth hormone in human melanoma cell lines.

Biochem Biophys Rep 2020 Mar 18;21:100716. Epub 2019 Dec 18.

Department of Medicine Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA.

Melanoma is the most aggressive skin cancer. Its aggressiveness is most commonly attributed to ERK pathway mutations leading to constitutive signaling. Though initial tumor regression results from targeting this pathway, resistance often emerges. Interestingly, interrogation of the NCI-60 database indicates high growth hormone receptor (GHR) expression in melanoma cell lines. To further characterize melanoma, we tested responsiveness to human growth hormone (GH). GH treatment resulted in GHR signaling and increased invasion and migration, which was inhibited by a GHR monoclonal antibody (mAb) antagonist in WM35, SK-MEL 5, SK-MEL 28 and SK-MEL 119 cell lines. We also detected GH in the conditioned medium (CM) of human melanoma cell lines. GHR, JAK2 and STAT5 were basally phosphorylated in these cell lines, consistent with autocrine/paracrine GH production. Together, our results suggest that melanomas are enriched in GHR and produce GH that acts in an autocrine/paracrine manner. We suggest that GHR may constitute a therapeutic target in melanoma.
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http://dx.doi.org/10.1016/j.bbrep.2019.100716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928330PMC
March 2020

Combined mTORC1/mTORC2 inhibition blocks growth and induces catastrophic macropinocytosis in cancer cells.

Proc Natl Acad Sci U S A 2019 12 15;116(49):24583-24592. Epub 2019 Nov 15.

Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294;

The mammalian target of rapamycin (mTOR) pathway, which plays a critical role in regulating cellular growth and metabolism, is aberrantly regulated in the pathogenesis of a variety of neoplasms. Here we demonstrate that dual mTORC1/mTORC2 inhibitors OSI-027 and PP242 cause catastrophic macropinocytosis in rhabdomyosarcoma (RMS) cells and cancers of the skin, breast, lung, and cervix, whereas the effects are much less pronounced in immortalized human keratinocytes. Using RMS as a model, we characterize in detail the mechanism of macropinocytosis induction. Macropinosomes are distinct from endocytic vesicles and autophagosomes in that they are single-membrane bound vacuoles formed by projection, ruffling, and contraction of plasma membranes. They are positive for EEA-1 and LAMP-1 and contain watery fluid but not organelles. The vacuoles then merge and rupture, killing the cells. We confirmed the inhibition of mTORC1/mTORC2 as the underpinning mechanism for macropinocytosis. Exposure to rapamycin, an mTORC1 inhibitor, or mTORC2 knockdown alone had little or reduced effect relative to the combination. We further demonstrate that macropinocytosis depends on MKK4 activated by elevated reactive oxygen species. In a murine xenograft model, OSI-027 reduced RMS tumor growth. Molecular characterization of the residual tumors was consistent with the induction of macropinocytosis. Furthermore, relative to the control xenograft tumors, the residual tumors manifested reduced expression of cell proliferation markers and proteins that drive the epithelial mesenchymal transition. These data indicate a role of mTORC2 in regulating tumor growth by macropinocytosis and suggest that dual inhibitors could help block refractory or recurrent RMS and perhaps other neoplasms and other cancer as well.
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http://dx.doi.org/10.1073/pnas.1911393116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900636PMC
December 2019

Molecular Dynamics Simulation Reveals Exposed Residues in the Ligand-Binding Domain of the Low-Density Lipoprotein Receptor that Interacts with Vesicular Stomatitis Virus-G Envelope.

Viruses 2019 11 15;11(11). Epub 2019 Nov 15.

Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia.

Familial hypercholesterolemia (FH) is an autosomal dominant disease most often caused by mutations in the low-density lipoprotein receptor (LDLR) gene, which consists of 18 exons spanning 45 kb and codes for a precursor protein of 860 amino acids. Mutations in the LDLR gene lead to a reduced hepatic clearance of LDL as well as a high risk of coronary artery disease (CAD) and sudden cardiac death (SCD). Recently, LDLR transgenes have generated interest as potential therapeutic agents. However, LDLR packaging using a lentiviral vector (LVV) system pseudotyped with a vesicular stomatitis virus (VSV)-G envelope is not efficient. In this study, we modified the LVV system to improve transduction efficiency and investigated the LDLR regions responsible for transduction inhibition. Transduction efficiency of 293T cells with a 5'-LDLReGFP-3' fusion construct was only 1.55% compared to 42.32% for the eGFP construct. Moreover, co-expression of LDLR affected eGFP packaging. To determine the specific region of the LDLR protein responsible for packaging inhibition, we designed constructs with mutations or sequential deletions at the 3' and 5' ends of LDLR cDNA. All constructs except one without the ligand-binding domain (LBD) (pWoLBD-eGFP) resulted in low transduction efficiency, despite successful packaging of viral RNA in the VSV envelope, as confirmed through RT-PCR. When we evaluated a direct interaction between LDLR and the VSV envelope glycoprotein using MD simulation and protein-protein interactions, we uncovered Val119, Thr120, Thr67, and Thr118 as exposed residues in the LDLR receptor that interact with the VSV protein. Together, our results suggest that the LBD of LDLR interacts with the VSV-G protein during viral packaging, which significantly reduces transduction efficiency.
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http://dx.doi.org/10.3390/v11111063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893590PMC
November 2019

Next generation DNA sequencing of atypical choroid plexus papilloma of brain: Identification of novel mutations in a female patient by Ion Proton.

Oncol Lett 2019 Nov 19;18(5):5063-5076. Epub 2019 Sep 19.

Department of Medical Genetics, Faculty of Medicine, Umm-Al-Qura University, Makkah 21955, Saudi Arabia.

Choroid plexus papilloma (CPP) is a rare benign tumor of the central nervous system that is usually confined to the cerebral ventricles. According to the World Health Organization, CPP corresponds to a grade I atypical CPP (a-CPP); however, it can become more aggressive and reach grade II, which can rarely undergo malignant transformation into a choroid plexus carcinoma (grade III). To the best of our knowledge, identification of these tumors mutations by next generation DNA sequencing (NGS) has not been yet reported. In the present study, NGS analysis of an a-CPP case was performed. Data were analyzed using Advaita Bioinformatics i-VariantGuide and Ion Reporter 5.6 programs. The results from NGS identified 12 novel missense mutations in the following genes: NOTCH1, ATM, STK36, MAGI1, DST, RECQL4, NUMA1, THBS1, MYH11, MALT1, SMARCA4 and CDH20. The PolyPhen score of six variants viz., DST, RECQL4, NUMA1, THBS1, MYHI1 and SMARCA4 were high, which suggested these variants represents pathogenic variants. Two novel insertions that caused frameshift were also found. Furthermore, two novel nonsense mutations and 14 novel intronic variants were identified in this tumor. The novel missense mutation detected in ATM gene was situated in c.5808A>T; p. (Leu1936Phe) in exon 39, and a known ATM mutation was in c.5948A>G; p. (Asn1983Ser). These novel mutations had not been reported in previous database. Subsequently, the quality statistics of these variants, including allele coverage, allele ratio, P-value, Phred quality score, sequencing coverage, PolyPhen score and alleles frequency was performed. For all variants, P-value was highly significant and the Phred quality score was high. In addition, the results from sequencing coverage demonstrated that 97.02% reads were on target and that 97.88% amplicons had at least 500 reads. These findings may serve at determining new strategies to distinguish the types of choroid plexus tumor, and at developing novel targeted therapies. Development of NGS technologies in the Kingdom of Saudi Arabia may be used in molecular pathology laboratories.
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http://dx.doi.org/10.3892/ol.2019.10882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781611PMC
November 2019