Publications by authors named "Rupali Das"

52 Publications

Proposed Mitigation and Adaptation Strategies Related to Climate Change: Guidance for OEM Professionals.

J Occup Environ Med 2021 Sep;63(9):e650-e656

American College of Occupational and Environmental Medicine, Elk Grove, Illinois.

Climate change is an urgent challenge amplified by socioeconomic factors that demands thoughtful public health responses from OEM professionals. This guidance statement from the American College of Occupational and Environmental Medicine focuses on the different strategies that these health professionals can implement to protect workers from health impacts associated with climate change hazards, foster workplace resilience in the face of rapidly changing environments, and take the necessary steps to mitigate the effects of global climate change.
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http://dx.doi.org/10.1097/JOM.0000000000002321DOI Listing
September 2021

Na/H Exchanger Regulatory Factor 1 Mediates the Pathogenesis of Airway Inflammation in a Murine Model of House Dust Mite-Induced Asthma.

J Immunol 2021 05 5;206(10):2301-2311. Epub 2021 May 5.

Department of Physiology, Michigan State University, East Lansing, MI

Na/H exchanger regulatory factor 1 (NHERF1), a class I PDZ-binding protein, regulates G protein-coupled receptor signaling in some cell types. NHERF1 also functions as a scaffolding protein and activates non-G protein-coupled receptor signaling pathways, thereby contributing to the pathogenesis of various diseases. Although we have previously shown that NHERF1 regulates mast cell functions, there is little information regarding the role of NHERF1 in other immune cells. How NHERF1 regulates the pathogenesis of allergic disease such as asthma also remains unknown. In the current study, we show that NHERF1 promotes allergic airway inflammation in a house dust mite extract (HDME)-induced mouse model of asthma. Specifically, HDME-specific serum IgE levels, airway leukocyte numbers, and goblet cell hyperplasia were reduced in NHERF1 mice as compared with NHERF1 mice. Interestingly, the gene expression of inflammatory (IL-17a, IL-25, and IL-33) as well as T helper 2 (Th2) cytokines (IL-4, IL-5, and IL-13) and several chemokines that recruit eosinophils, neutrophils, and lymphocytes were also decreased in the lungs of NHERF1 mice exposed to HDME. Consistent with these observations, microRNAs regulating mucus production, inflammation, Th2 effector functions, and IL-13 expression were increased in the lungs of HDME-treated NHERF1 mice. Overall, our studies reveal a unique role for NHERF1 in regulating asthma pathogenesis, and further elucidation of the mechanisms through which NHERF1 modulates allergic inflammation will lead to the development of new therapeutic strategies for asthma.
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http://dx.doi.org/10.4049/jimmunol.2001199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113128PMC
May 2021

Workers' Compensation Elements in Different Jurisdictions in the United States.

J Occup Environ Med 2020 12;62(12):e760-e769

From the American College of Occupational and Environmental Medicine, Elk Grove, Illinois.

: Over the decades, the workers' compensation system has provided many injured workers with a significant guarantee of both medical and financial support when they have been injured on the job. To be effective, workers' compensation systems at a minimum should include principles that require the addressing of medical causation, determination of an individual's functional ability both pre- and post-injury to include activity restrictions, return-to-work capability and disability, meeting jurisdiction-specific reporting requirements of the workers' compensation reporting requirements, and having knowledge of other perspectives of the various authorities and jurisdictions present in the United States. ACOEM lays out a description of various aspects of workers' compensations systems in the United States, with recommendations for minimal standards and best practices. This paper limits itself to the discussion of jurisdictions within the United States and ACOEM strongly recommends that providers consult directly with the states in which they are working as there are state variations in workers' compensation.
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http://dx.doi.org/10.1097/JOM.0000000000002047DOI Listing
December 2020

Safely Returning America to Work: Part I: General Guidance for Employers.

J Occup Environ Med 2020 09;62(9):771-779

American College of Occupational and Environmental Medicine, Elk Grove Village, Illinois.

: Businesses are struggling to re-open as the world continues to deal with the coronavirus 2019 (COVID-19) pandemic. The reopening of businesses will require employers to implement safe return-to-work strategies through evaluation, testing, work modifications, and development of appropriate workplace policies. There will be unique challenges along the way as no one approach will be ideal for all workplaces and industries. This document is intended to provide return-to-work guidance for both employers and the occupational and environmental medicine physicians who will be supporting businesses in implementing safe return-to-work strategies.
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http://dx.doi.org/10.1097/JOM.0000000000001984DOI Listing
September 2020

Combination of NKT14m and Low Dose IL-12 Promotes Invariant Natural Killer T Cell IFN-γ Production and Tumor Control.

Int J Mol Sci 2020 Jul 18;21(14). Epub 2020 Jul 18.

Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes characterized by the expression of an invariant T cell receptor (iTCR) that recognizes glycolipid antigens presented by the MHC I-like CD1d molecule. Following antigenic stimulation, iNKT cells rapidly produce large amounts of cytokines that can trans-activate dendritic cells (DC) and promote the anti-tumor functions of cytotoxic lymphocytes, such as natural killer (NK) and CD8 T cells. Additionally, iNKT cells can mediate robust and direct cytotoxicity against CD1d tumor targets. However, many tumors down-regulate CD1d and evade iNKT cell attack. To circumvent this critical barrier to iNKT cell anti-tumor activity, a novel monoclonal antibody (mAb), NKT14 has been recently developed. This agonistic antibody binds directly and specifically to the iTCR of murine iNKT cells. In the current study, we demonstrate that NKT14m mediates robust activation, cytokine production and degranulation of murine iNKT cells, in vitro. Consistently, NKT14m also promoted iNKT cell activation and immunomodulatory functions, in vivo. Finally, administration of NKT14m with low dose interleukin (IL)-12 further augmented iNKT cell IFN-γ production in vivo, and this combination conferred superior suppression of tumor cell growth compared to NKT14m or IL-12 alone. Together, these data demonstrate that a combination treatment consisting of low dose IL-12 and iTCR-specific mAb may be an attractive alternative to activate iNKT cell anti-tumor functions.
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http://dx.doi.org/10.3390/ijms21145085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404385PMC
July 2020

Cancer Immunotherapeutic Potential of NKTT320, a Novel, Invariant, Natural Killer T Cell-Activating, Humanized Monoclonal Antibody.

Int J Mol Sci 2020 Jun 17;21(12). Epub 2020 Jun 17.

Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.

Invariant natural killer T cells (iNKTs) directly kill tumor cells and trans-activate the anti-tumor functions of dendritic cells (DC), natural killer (NK) cells, and T and B cells. As such, iNKTs serve as a powerful tool for use in cell-based cancer immunotherapy. iNKT cell activation commonly requires engagement of the invariant T cell receptor (iTCR) by CD1d presenting glycolipid antigens. However, transformed cells often down-regulate CD1d expression, which results in a reduction of iNKT cell anti-tumor functions. One approach to circumvent this critical barrier to iNKT cell activation is to develop an agonistic antibody that binds directly to the iTCR without the requirement for CD1d-mediated antigen presentation. To this end, we have characterized the iNKT cell stimulatory properties of NKTT320, a novel, recombinant, humanized, monoclonal antibody that binds selectively and with high affinity to human iTCRs. Strikingly, immobilized NKTT320 mediated robust iNKT cell activation (upregulation of CD25 and CD69) and proliferation (carboxyfluorescein succinimidyl ester (CFSE) dilution), as well as Th1 and Th2 cytokine production. Additionally, iNKTs stimulated by plate-bound NKTT320 exhibited increased intracellular levels of granzyme B and degranulation (exposure of CD107 on the cell surface). Furthermore, both soluble and immobilized NKTT320 induced iNKT cell-mediated activation of bystander immune cells, suggesting that this novel anti-iTCR antibody facilitates both direct and indirect iNKT cell cytotoxicity. These studies are significant, as they provide a framework by which iNKT cell anti-cancer functions could be enhanced for therapeutic purposes.
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http://dx.doi.org/10.3390/ijms21124317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352964PMC
June 2020

CD2 Regulates Pathogenesis of Asthma Induced by House Dust Mice Extract.

Front Immunol 2020 12;11:881. Epub 2020 May 12.

College of Human Medicine, Michigan State University, East Lansing, MI, United States.

Characteristic of allergic asthma, CD4+Th2 lymphocytes secrete Th2 cytokines, interleukin (IL)-4, IL-13, and IL-5 that mediate the inflammatory immune response. Surface expression of CD2 and its ligand, CD58, is increased on the monocytes and eosinophils of asthma patients, which correlate with elevated serum IgE levels, suggesting that CD2 may contribute to allergic airway inflammation. Using a murine model of asthma, we observed that house dust mice extract (HDME)-exposed Balb/c mice have increased airway hyperresponsiveness (AHR), lung inflammation, goblet cell hyperplasia, and elevated levels of Th2 cytokines in the lungs, as well as increased serum IgE levels as compared to the control mice. In contrast, with the exception of serum IgE levels, all the other parameters were significantly reduced in HDME-treated mice. Interestingly, but not or gene expression in the lungs was dramatically decreased in HDME-exposed mice. Of note, the gene expression of IL-13 downstream targets (Muc5b and Muc5ac) and high affinity IL-13Rα2 were upregulated in the lungs of HDME-exposed Balb/c mice but were significantly reduced in HDME-exposed mice. Consistently, gene expression of microRNAs regulating mucin production, inflammation, airway smooth muscle cell proliferation and IL-13 transcripts were increased in the lungs of HDME-exposed mice. Given the established role of IL-13 in promoting goblet cell hyperplasia, lung inflammation and AHR in allergic asthma, our studies reveal a unique role for CD2 in the regulation of Th2-associated allergic asthma.
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http://dx.doi.org/10.3389/fimmu.2020.00881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235426PMC
April 2021

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses.

Front Immunol 2020 24;11:703. Epub 2020 Apr 24.

Department of Physiology, Michigan State University, East Lansing, MI, United States.

Mast cells are tissue-resident innate immune cells known for their prominent role in mediating allergic reactions. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a promiscuous G-protein coupled receptor (GPCR) expressed on mast cells that is activated by several ligands that share cationic and amphipathic properties. Interestingly, MRGPRX2 ligands include certain FDA-approved drugs, antimicrobial peptides, and neuropeptides. Consequently, this receptor has been implicated in causing mast cell-dependent pseudo-allergic reactions to these drugs and chronic inflammation associated with asthma, urticaria and rosacea in humans. In the current study we examined the role of osthole, a natural plant coumarin, in regulating mast cell responses when activated by the MRGPRX2 ligands, including compound 48/80, the neuropeptide substance P, and the cathelicidin LL-37. We demonstrate that osthole attenuates both the early (Ca mobilization and degranulation) and delayed events (chemokine/cytokine production) of mast cell activation via MRGPRX2 . Osthole also inhibits MrgprB2- (mouse ortholog of human MRGPRX2) dependent inflammation in mouse models of pseudo-allergy. Molecular docking analysis suggests that osthole does not compete with the MRGPRX2 ligands for interaction with the receptor, but rather regulates MRGPRX2 activation via allosteric modifications. Furthermore, flow cytometry and confocal microscopy experiments reveal that osthole reduces both surface and intracellular expression levels of MRGPRX2 in mast cells. Collectively, our data demonstrate that osthole inhibits MRGPRX2/MrgprB2-induced mast cell responses and provides a rationale for the use of this natural compound as a safer alternative treatment for pseudo-allergic reactions in humans.
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http://dx.doi.org/10.3389/fimmu.2020.00703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194083PMC
March 2021

NCOA5 deficiency promotes a unique liver protumorigenic microenvironment through p21 overexpression, which is reversed by metformin.

Oncogene 2020 05 20;39(19):3821-3836. Epub 2020 Mar 20.

Department of Physiology, Michigan State University, East Lansing, Michigan, 48824, USA.

Prevention and treatment options for hepatocellular carcinoma (HCC) are presently limited, underscoring the necessity for further elucidating molecular mechanisms underlying HCC development and identifying new prevention and therapeutic targets. Here, we demonstrate a unique protumorigenic niche in the livers of Ncoa5 mouse model of HCC, which is characterized by altered expression of a subset of genes including p21 and proinflammatory cytokine genes, increased putative hepatic progenitors, and expansions of activated and tissue-resident memory (TRM) CD8+ T lymphocytes, myeloid-derived suppressor cells (MDSCs), and alternatively activated M2 macrophages. Importantly, prophylactic metformin treatment reversed these characteristics including aberrant p21 expression and subsequently reduced HCC incidence in Ncoa5 male mice. Heterozygous deletion of the p21 gene alleviated the key features associated with the protumorigenic niche in the livers of Ncoa5 male mice. Moreover, transcriptomic analysis reveals that preneoplastic livers of Ncoa5 mice are similar to the livers of nonalcoholic steatohepatitis patients as well as the adjacent noncancerous liver tissues of a subset of HCC patients with a relatively poor prognosis. Together, our results suggest that p21 overexpression is essential in the development of protumorigenic microenvironment induced by NCOA5 deficiency and metformin prevents HCC development via alleviating p21 overexpression and protumorigenic microenvironment.
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http://dx.doi.org/10.1038/s41388-020-1256-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210077PMC
May 2020

SLAM-SAP-Fyn: Old Players with New Roles in iNKT Cell Development and Function.

Int J Mol Sci 2019 Sep 27;20(19). Epub 2019 Sep 27.

Department of Physiology, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA.

Invariant natural killer T (iNKT) cells are a unique T cell lineage that develop in the thymus and emerge with a memory-like phenotype. Accordingly, following antigenic stimulation, they can rapidly produce copious amounts of Th1 and Th2 cytokines and mediate activation of several immune cells. Thus, it is not surprising that iNKT cells play diverse roles in a broad range of diseases. Given their pivotal roles in host immunity, it is crucial that we understand the mechanisms that govern iNKT cell development and effector functions. Over the last two decades, several studies have contributed to the current knowledge of iNKT cell biology and activity. Collectively, these studies reveal that the thymic development of iNKT cells, their lineage expansion, and functional properties are tightly regulated by a complex network of transcription factors and signaling molecules. While prior studies have clearly established the importance of the SLAM-SAP-Fyn signaling axis in iNKT cell ontogenesis, recent studies provide exciting mechanistic insights into the role of this signaling cascade in iNKT cell development, lineage fate decisions, and functions. Here we summarize the previous literature and discuss the more recent studies that guide our understanding of iNKT cell development and functional responses.
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http://dx.doi.org/10.3390/ijms20194797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801923PMC
September 2019

Enhancing the antitumor functions of invariant natural killer T cells using a soluble CD1d-CD19 fusion protein.

Blood Adv 2019 03;3(5):813-824

Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN.

Invariant natural killer T (iNKT) cells comprise a unique lineage of CD1d-restricted lipid-reactive T lymphocytes that potently kill tumor cells and exhibit robust immunostimulatory functions. Optimal tumor-directed iNKT cell responses often require expression of the antigen-presenting molecule CD1d on tumors; however, many tumor cells downregulate CD1d and thus evade iNKT cell recognition. We generated a soluble bispecific fusion protein designed to direct iNKT cells to the site of B-cell cancers in a tumor antigen-specific but CD1d-independent manner. This fusion protein is composed of a human CD1d molecule joined to a single chain antibody FV fragment specific for CD19, an antigen widely expressed on B-cell cancers. The CD1d-CD19 fusion protein binds specifically to CD19-expressing, but not CD19-negative cells. Once loaded with the iNKT cell lipid agonist α-galactosyl ceramide (αGC), the CD1d-CD19 fusion induces robust in vitro activation of and cytokine production by human iNKT cells. iNKT cells stimulated by the αGC-loaded CD1d-CD19 fusion also strongly transactivate T-, B-, and NK-cell responses and promote dendritic cell maturation. Importantly, the αGC-loaded fusion induces robust lysis of CD19CD1d Epstein-Barr virus immortalized human B-lymphoblastoid cell lines that are otherwise resistant to iNKT cell killing. Consistent with these findings; administration of the αGC-loaded fusion protein controlled the growth of CD19CD1d tumors in vivo, suggesting that it can "link" iNKT cells and CD19CD1d targets in a therapeutically beneficial manner. Taken together, these preclinical studies demonstrate that this B cell-directed fusion protein can be used to effectively induce iNKT cell antitumor responses in vitro and in vivo
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http://dx.doi.org/10.1182/bloodadvances.2018028886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418505PMC
March 2019

Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice.

J Am Chem Soc 2018 12 19;140(48):16596-16609. Epub 2018 Nov 19.

School of Chemistry & Biochemistry and School of Biological Sciences , Georgia Institute of Technology , Atlanta , Georgia 30332 , United States.

Human mucin-1 (MUC1) is a highly attractive antigen for the development of anticancer vaccines. However, in human clinical trials of multiple MUC1 based vaccines, despite the generation of anti-MUC1 antibodies, the antibodies often failed to exhibit much binding to tumor presumably due to the challenges in inducing protective immune responses in the immunotolerant environment. To design effective MUC1 based vaccines functioning in immunotolerant hosts, vaccine constructs were first synthesized by covalently linking the powerful bacteriophage Qβ carrier with MUC1 glycopeptides containing 20-22 amino acid residues covering one full length of the tandem repeat region of MUC1. However, IgG antibodies elicited by these first generation constructs in tolerant human MUC1 transgenic (Tg) mice did not bind tumor cells strongly. To overcome this, a peptide array has been synthesized. By profiling binding selectivities of antibodies, the long MUC1 glycopeptide was found to contain immunodominant but nonprotective epitopes. Critical insights were obtained into the identity of the key protective epitope. Redesign of the vaccine focusing on the protective epitope led to a new Qβ-MUC1 construct, which was capable of inducing higher levels of anti-MUC1 IgG antibodies in MUC1.Tg mice to react strongly with and kill a wide range of tumor cells compared to the construct containing the gold standard protein carrier, i.e., keyhole limpet hemocyanin. Vaccination with this new Qβ-MUC1 conjugate led to significant protection of MUC1.Tg mice in both metastatic and solid tumor models. The antibodies exhibited remarkable selectivities toward human breast cancer tissues, suggesting its high translational potential.
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http://dx.doi.org/10.1021/jacs.8b08473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470043PMC
December 2018

Rhodium nanocubes and nanotripods for highly sensitive ultraviolet surface-enhanced Raman spectroscopy.

Authors:
Rupali Das R K Soni

Analyst 2018 May;143(10):2310-2322

Department of Physics, Indian Institute of Technology Delhi, New Delhi 110016, India.

We report the shape- and wavelength-dependent ultrasensitive label-free detection of adenine on rhodium cube- and tripod-star-like nanoparticles (Rh NPs) using ultraviolet surface-enhanced Raman scattering (UV-SERS). Rh NPs immobilized on a silane-treated glass substrate probed at near-resonant and non-resonant wavelengths served as the SERS platform for the highly reproducible, stable, and real-time detection of adsorbed adenine molecules in the femtomolar region. The sensitivity of SERS-active Rh NPs displaying LSPR in the UV region was exploited for the 266 nm (DUV), 325 nm (UV) and 532 nm (visible) Raman excitation wavelengths. With the 266 nm and 325 nm DUV-UV excitation lines, for the Rh tripod geometry near or pre-resonant excitation being closer to the analyte absorption band combined with the intrinsic UV-LSPR resonant energy produced a SERS enhancement factor as high as 105 and accelerated photoinduced degradations compared to 532 nm for our substrates. Computational results consistent with the experiment clearly demonstrated that the NP SERS enhancement was sensitive to both the intrinsic optical properties of Rh in the UV region and the excitation closer to the LSPR peak producing larger EM enhancements. The wavelength-dependent correlations between the optical properties of the shape-tailored Rh NPs and SERS enhancements envisage the merit and demerit of DUV-UV excitation over visible excitation for Raman measurements. The as-fabricated SERS substrate could also be efficiently recycled using O2 plasma for the detection of other biomolecules. The use of oxide-free transition metal Rh and DUV-UV excitation thereby extends the improved generality of the SERS technique for ultrasensitive bimolecular detection and for gaining a comprehensive understanding of UV-SERS-based applications.
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http://dx.doi.org/10.1039/c8an00341fDOI Listing
May 2018

Roles of NHERF Family of PDZ-Binding Proteins in Regulating GPCR Functions.

Adv Immunol 2017 11;136:353-385. Epub 2017 Jul 11.

Michigan State University, East Lansing, MI, United States. Electronic address:

Multicellular organisms are equipped with an array of G-protein-coupled receptors (GPCRs) that mediate cell-cell signaling allowing them to adapt to environmental cues and ultimately survive. This is mechanistically possible through complex intracellular GPCR machinery that encompasses a vast network of proteins. Within this network, there is a group called scaffolding proteins that facilitate proper localization of signaling proteins for a quick and robust GPCR response. One protein family within this scaffolding group is the PSD-95/Dlg/ZO-1 (PDZ) family which is important for GPCR localization, internalization, recycling, and downstream signaling. Although the PDZ family of proteins regulate the functions of several receptors, this chapter focuses on a subfamily within the PDZ protein family called the Na/H exchanger regulatory factors (NHERFs). Here we extensively review the predominantly characterized roles of NHERFs in renal phosphate absorption, intestinal ion regulation, cancer progression, and immune cell functions. Finally, we discuss the future perspectives and possible clinical application of targeting NHERFs in several disorders.
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http://dx.doi.org/10.1016/bs.ai.2017.05.008DOI Listing
May 2018

Canonical and Noncanonical Signaling Roles of β-Arrestins in Inflammation and Immunity.

Adv Immunol 2017 17;136:279-313. Epub 2017 Jun 17.

Michigan State University, East Lansing, MI, United States. Electronic address:

β-Arrestins are a highly conserved family of cytosolic adaptor proteins that contribute to many immune functions by orchestrating the desensitization and internalization of cell-surface G protein-coupled receptors (GPCRs) via well-studied canonical interactions. In cells of the innate and adaptive immune system, β-arrestins also subserve a parallel but less understood role in which they propagate, rather than terminate, intracellular signal transduction cascades. Because β-arrestins are promiscuous in their binding, they are capable of interacting with several different GPCRs and downstream effectors; in doing so, they vastly expand the repertoire of cellular responses evoked by agonist binding and the scope of responses that may contribute to inflammation during infectious and sterile insults. In this chapter, we attempt to provide an overview of the canonical and noncanonical roles of β-arrestins in inflammatory diseases.
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http://dx.doi.org/10.1016/bs.ai.2017.05.004DOI Listing
May 2018

mTORC2 regulates multiple aspects of NKT-cell development and function.

Eur J Immunol 2017 03 27;47(3):516-526. Epub 2017 Jan 27.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Invariant NKT (iNKT) cells bridge innate and adaptive immunity by rapidly secreting cytokines and lysing targets following TCR recognition of lipid antigens. Based on their ability to secrete IFN-γ, IL-4 and IL-17A, iNKT-cells are classified as NKT-1, NKT-2, and NKT-17 subsets, respectively. The molecular pathways regulating iNKT-cell fate are not fully defined. Recent studies implicate Rictor, a required component of mTORC2, in the development of select iNKT-cell subsets, however these reports are conflicting. To resolve these questions, we used Rictor CD4cre mice and found that Rictor is required for NKT-17 cell development and normal iNKT-cell cytolytic function. Conversely, Rictor is not absolutely required for IL-4 and IFN-γ production as peripheral iNKT-cells make copious amounts of these cytokines. Overall iNKT-cell numbers are dramatically reduced in the absence of Rictor. We provide data indicating Rictor regulates cell survival as well as proliferation of developing and mature iNKT-cells. Thus, mTORC2 regulates multiple aspects of iNKT-cell development and function.
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http://dx.doi.org/10.1002/eji.201646343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656007PMC
March 2017

Environmental Chemicals in an Urban Population of Pregnant Women and Their Newborns from San Francisco.

Environ Sci Technol 2016 11 26;50(22):12464-12472. Epub 2016 Oct 26.

Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California , San Francisco, California 94143, United States.

Exposures to environmental pollutants in utero may increase the risk of adverse health effects. We measured the concentrations of 59 potentially harmful chemicals in 77 maternal and 65 paired umbilical cord blood samples collected in San Francisco during 2010-2011, including polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), hydroxylated PBDEs (OH-PBDEs), and perfluorinated compounds (PFCs) in serum and metals in whole blood. Consistent with previous studies, we found evidence that concentrations of mercury (Hg) and lower-brominated PBDEs were often higher in umbilical cord blood or serum than in maternal samples (median cord:maternal ratio > 1), while for most PFCs and lead (Pb), concentrations in cord blood or serum were generally equal to or lower than their maternal pair (median cord:maternal ratio ≤ 1). In contrast to the conclusions of a recent review, we found evidence that several PCBs and OCPs were also often higher in cord than maternal serum (median cord:maternal ratio > 1) when concentrations are assessed on a lipid-adjusted basis. Our findings suggest that for many chemicals, fetuses may experience higher exposures than their mothers and highlight the need to characterize potential health risks and inform policies aimed at reducing sources of exposure.
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http://dx.doi.org/10.1021/acs.est.6b03492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681912PMC
November 2016

Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis.

Blood 2016 Mar 29;127(13):1666-75. Epub 2016 Jan 29.

Department of Oncology and.

Hemophagocytic lymphohistiocytosis (HLH) comprises an emerging spectrum of inherited and noninherited disorders of the immune system characterized by the excessive production of cytokines, including interferon-γ and interleukins 2, 6, and 10 (IL-2, IL-6, and IL-10). The Janus kinases (JAKs) transduce signals initiated following engagement of specific receptors that bind a broad array of cytokines, including those overproduced in HLH. Based on the central role for cytokines in the pathogenesis of HLH, we sought to examine whether the inhibition of JAK function might lessen inflammation in murine models of the disease. Toward this end, we examined the effects of JAK inhibition using a model of primary (inherited) HLH in which perforin-deficient (Prf1(-∕-)) mice are infected with lymphocytic choriomeningitis virus (LCMV) and secondary (noninherited) HLH in which C57BL/6 mice receive repeated injections of CpG DNA. In both models, treatment with the JAK1/2 inhibitor ruxolitinib significantly lessened the clinical and laboratory manifestations of HLH, including weight loss, organomegaly, anemia, thrombocytopenia, hypercytokinemia, and tissue inflammation. Importantly, ruxolitinib treatment also significantly improved the survival of LCMV-infectedPrf1(-∕-)mice. Mechanistic studies revealed that in vivo exposure to ruxolitinib inhibited signal transducer and activation of transcription 1-dependent gene expression, limited CD8(+)T-cell expansion, and greatly reduced proinflammatory cytokine production, without effecting degranulation and cytotoxic function. Collectively, these findings highlight the JAKs as novel, druggable targets for mitigating the cytokine-driven hyperinflammation that occurs in HLH. These observations also support the incorporation of JAK inhibitors such as ruxolitinib into future clinical trials for patients with these life-threatening disorders.
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http://dx.doi.org/10.1182/blood-2015-12-684399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817310PMC
March 2016

Exposures to environmental phenols in Southern California firefighters and findings of elevated urinary benzophenone-3 levels.

Environ Int 2016 Mar 25;88:281-287. Epub 2016 Jan 25.

Environmental Health Laboratory, California Department of Public Health, Richmond, CA, USA. Electronic address:

Firefighters are at increased risk for exposure to toxic chemicals compared to the general population, but few studies of this occupational group have included biomonitoring. We measured selected phenolic chemicals in urine collected from 101 Southern California firefighters. The analytes included bisphenol A (BPA), triclosan, benzophenone-3 (BP-3), and parabens, which are common ingredients in a range of consumer products. BP-3, BPA, triclosan, and methyl paraben were detected in almost all study subjects (94-100%). The BP-3 geometric mean for firefighters was approximately five times higher than for a comparable National Health and Nutrition Examination Survey (NHANES) subgroup. Demographic and exposure data were collected from medical records and via a questionnaire, and covariates were examined to assess associations with BP-3 levels. BP-3 levels were elevated across all firefighter age groups, with the highest levels observed in the 35 to 39year old group. Body fat percentage had a significant inverse association with BP-3 concentrations. Our results indicate pervasive exposure to BP-3, BPA, triclosan, and methyl paraben in this population of firefighters, consistent with studies of other populations. Further research is needed to investigate possible explanations for the higher observed BP-3 levels, such as occupational or California-specific exposures.
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http://dx.doi.org/10.1016/j.envint.2015.11.014DOI Listing
March 2016

Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1.

Sci Transl Med 2016 Jan;8(321):321ra7

Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy. School of Medicine, University Vita e Salute San Raffaele, 20132 Milan, Italy.

X-linked lymphoproliferative disease (XLP-1) is an often-fatal primary immunodeficiency associated with the exuberant expansion of activated CD8(+) T cells after Epstein-Barr virus (EBV) infection. XLP-1 is caused by defects in signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), an adaptor protein that modulates T cell receptor (TCR)-induced signaling. SAP-deficient T cells exhibit impaired TCR restimulation-induced cell death (RICD) and diminished TCR-induced inhibition of diacylglycerol kinase α (DGKα), leading to increased diacylglycerol metabolism and decreased signaling through Ras and PKCθ (protein kinase Cθ). We show that down-regulation of DGKα activity in SAP-deficient T cells restores diacylglycerol signaling at the immune synapse and rescues RICD via induction of the proapoptotic proteins NUR77 and NOR1. Pharmacological inhibition of DGKα prevents the excessive CD8(+) T cell expansion and interferon-γ production that occur in SAP-deficient mice after lymphocytic choriomeningitis virus infection without impairing lytic activity. Collectively, these data highlight DGKα as a viable therapeutic target to reverse the life-threatening EBV-associated immunopathology that occurs in XLP-1 patients.
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http://dx.doi.org/10.1126/scitranslmed.aad1565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918505PMC
January 2016

Effectiveness of Various Sensory Input Methods in Dental Health Education Among Blind Children- A Comparative Study.

J Clin Diagn Res 2015 Oct 1;9(10):ZC75-8. Epub 2015 Oct 1.

Assistant Professor, Department of Oral Medicine and Radiology, Mallareddy Dental College for Women , Telangana, India .

Aim: The aim of the study is to evaluate effectiveness of various sensory input methods in dental health education among blind children. Oral hygiene status was assessed through visible plaque index and oral hygiene knowledge was assessed through questionnaire before and after oral health education.

Materials And Methods: The study involved of 200 blind children with the age range of 8 to 14 years of both genders from two blind schools similar in standard of teaching. The total study population (n=200) was randomized and divided into five Groups, comprising of 40 children in each Group. The first four were the experimental Groups who received dental health education through different modes, while the fifth Group served as control. Oral health related knowledge and plaque scores were assessed in all the study Groups before and after dental health education.

Results: After intervention, the mean knowledge scores and plaque scores were statistically significant in all the study Groups when compared to the baseline scores.

Conclusion: The present study proved that blind children can maintain an acceptable level of oral hygiene when taught with special customized methods like multisensory approach with creative use of other senses which was found to be effective than unisensory method.
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http://dx.doi.org/10.7860/JCDR/2015/15499.6686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625342PMC
October 2015

Antitumor Responses of Invariant Natural Killer T Cells.

J Immunol Res 2015 12;2015:652875. Epub 2015 Oct 12.

Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Natural killer T (NKT) cells are innate-like lymphocytes that were first described in the late 1980s. Since their initial description, numerous studies have collectively shed light on their development and effector function. These studies have highlighted the unique requirements for the activation of these lymphocytes and the functional responses that distinguish these cells from other effector lymphocyte populations such as conventional T cells and NK cells. This body of literature suggests that NKT cells play diverse nonredundant roles in a number of disease processes, including the initiation and propagation of airway hyperreactivity, protection against a variety of pathogens, development of autoimmunity, and mediation of allograft responses. In this review, however, we focus on the role of a specific lineage of NKT cells in antitumor immunity. Specifically, we describe the development of invariant NKT (iNKT) cells and the factors that are critical for their acquisition of effector function. Next, we delineate the mechanisms by which iNKT cells influence and modulate the activity of other immune cells to directly or indirectly affect tumor growth. Finally, we review the successes and failures of clinical trials employing iNKT cell-based immunotherapies and explore the future prospects for the use of such strategies.
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http://dx.doi.org/10.1155/2015/652875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620262PMC
August 2016

High levels of polybrominated diphenyl ethers in vacuum cleaner dust from California fire stations.

Environ Sci Technol 2015 Apr 7;49(8):4988-94. Epub 2015 Apr 7.

§Environmental Chemistry Laboratory, California Department of Toxic Substances Control, 700 Heinz Avenue, Berkeley, California 94710, United States.

Firefighters are exposed to chemicals during fire events and may also experience chemical exposure in their fire stations. Dust samples from used vacuum cleaner bags were collected from 20 fire stations in California and analyzed for polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs), and polychlorinated biphenyls (PCBs) using gas chromatography-mass spectrometry. Median dust concentrations were higher for PBDEs (e.g., 47 000 ng/g for BDE-209) than for PAHs (e.g., 220 ng/g for benzo[a]pyrene) or PCBs (e.g., 9.3 ng/g for PCB-180). BDE-209 concentrations in dust from California fire stations were among the highest of any previously documented homes or occupational settings in the world. We examined factors such as the frequency of emergency responses, the number of fire vehicles on site, and building age, but we could not account for the high levels of BDE-209 observed in fire station dust. Based on the findings of our pilot study, we hypothesize that possible sources of BDE-209 in fire stations include contaminated ash tracked back from fire events via boots, clothing, and other equipment as well as specialized equipment treated with BDE-209, including turnout gear and fire vehicles. We suggest possible follow-up studies to confirm these hypotheses.
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http://dx.doi.org/10.1021/es505463gDOI Listing
April 2015

Canal shaping with one shape file and twisted files: a comparative study.

J Clin Diagn Res 2014 Dec 5;8(12):ZF01-3. Epub 2014 Dec 5.

Professor, Department of Prosthodontics, Malla Reddy Dental College for Women , Hyderabad, India .

Aim: The aim of this study was to compare the shaping ability of two different rotary Nickel -Titanium (Ni-Ti) files, One shape file and Twisted files in a simulated artificial canals.

Materials And Methods: A total of 40 endodontic training blocks were used in this study and divided in two groups consisting of 20 each ( n = 20) and the shaping ability was accessed based on the left over ink stain in the artificial canal.

Results: Image proplus analysis software and stereomicroscope were used for analysing the shaping ability of the files and statistical analysis was done by SPSS software. Twisted files showed better shaping ability compared to one shape file both experimentally and statistically.

Conclusion: It can be concluded that twisted files shaped the canals better then one shape file.
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http://dx.doi.org/10.7860/JCDR/2014/11126.5333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4316365PMC
December 2014

High exposure of California firefighters to polybrominated diphenyl ethers.

Environ Sci Technol 2015 Mar 18;49(5):2948-58. Epub 2015 Feb 18.

Environmental Chemistry Laboratory, Department of Toxic Substances Control, California Environmental Protection Agency , Berkeley, California 94710, United States.

Concern about persistent organic pollutants (POPs) in Californians prompted the state's biomonitoring program to conduct a study in firefighters, who are occupationally exposed to high levels of POPs. In this work we present serum concentrations of several classes of POPs (polybrominated diphenyl ethers [PBDEs], polychlorinated biphenyls [PCBs], and organochlorine pesticides [OCPs]) in 101 Southern California firefighters. Despite recently reported declining trends of PBDEs in Californians, high levels were measured in firefighters' serum (Σ5PBDEs: median = 59.1 ng/(g of lipid); range = 18.8-714 ng/(g of lipid)) in comparison to other populations in California during the same period. In addition, nearly one-third of subjects had particularly high serum levels of decabromodiphenyl ether (BDE-209), consistent with other recent results in firefighters; this pattern may be a marker of recent firefighting activity. In contrast, serum levels of PCBs and OCPs measured in firefighters' sera were not elevated compared to U.S. levels. Multivariable analysis indicated that lower levels of serum PBDEs were associated with turnout gear cleaning and storage practices after fires. Our study supports the hypothesis that firefighting activities are likely to increase exposure to PBDEs and that good housekeeping and personal hygiene practices may reduce exposure to these compounds.
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http://dx.doi.org/10.1021/es5055918DOI Listing
March 2015

Biomonitoring in California firefighters: metals and perfluorinated chemicals.

J Occup Environ Med 2015 Jan;57(1):88-97

From the Environmental Health Investigations Branch (Ms Dobraca, Dr McNeel, Mr Voss, and Dr Das) and Environmental Health Laboratory (Drs Gajek, Barley, and She), California Department of Public Health, Richmond; Center for Occupational and Environmental Health (Dr Israel), University of California, Irvine; and Environmental Chemistry Laboratory (Drs Wang, Park, and Harwani), Department of Toxic Substances Control, California Environmental Protection Agency, Berkeley.

Objective: To assess California firefighters' blood concentrations of selected chemicals and compare with a representative US population.

Methods: We report laboratory methods and analytic results for cadmium, lead, mercury, and manganese in whole blood and 12 serum perfluorinated chemicals in a sample of 101 Southern California firefighters.

Results: Firefighters' blood metal concentrations were all similar to or lower than the National Health and Nutrition Examination Survey (NHANES) values, except for six participants whose mercury concentrations (range: 9.79 to 13.42 μg/L) were close to or higher than the NHANES reporting threshold of 10 μg/L. Perfluorodecanoic acid concentrations were elevated compared with NHANES and other firefighter studies.

Conclusions: Perfluorodecanoic acid concentrations were three times higher in this firefighter group than in NHANES adult males. Firefighters may have unidentified sources of occupational exposure to perfluorinated chemicals.
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http://dx.doi.org/10.1097/JOM.0000000000000307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274322PMC
January 2015

Invariant NKT cells: Killers and conspirators against cancer.

Oncoimmunology 2013 Dec 3;2(12):e27440. Epub 2014 Jan 3.

Division of Oncology; Children's Hospital of Philadelphia; Philadelphia, PA USA.

Although invariant natural killer T (iNKT) cells influence antitumor responses by secreting cytokines and promoting the cytolytic functions of T and NK cells, we find that iNKT cells mediate direct tumoricidal activity in vitro and significantly inhibit tumor growth in vivo even in the absence of other cytotoxic lymphocytes.
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http://dx.doi.org/10.4161/onci.27440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926875PMC
December 2013

iNKT cell cytotoxic responses control T-lymphoma growth in vitro and in vivo .

Cancer Immunol Res 2014 Jan;2(1):59-69

Invariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8+ T and NK cells. Although iNKT cells thereby act as potent cellular adjuvants, it is less clear whether they directly control the growth of tumors. To gain insights into the direct contribution of iNKT cells to tumor immune surveillance, we developed in vitro and in vivo systems to selectively examine the antitumor activity of iNKT cells in the absence of other cytolytic effectors. Using the EL4 T-lymphoma cell line as a model, we found that iNKT cells exert robust and specific lysis of tumor cells in vitro in a manner that is differentially induced by iNKT cell agonists of varying T-cell receptor (TCR) affinities, such as OCH, α-galactosyl ceramide, and PBS44. In vitro blockade of CD1d-mediated lipid antigen presentation, disruption of TCR signaling, or loss of perforin expression significantly reduce iNKT cell killing. Consistent with these findings, iNKT cell reconstitution of T, B, and NK cell–deficient mice slows EL4 growth in vivo via TCR-CD1d and perforin-dependent mechanisms. Together, these observations establish that iNKT cells are sufficient to control the growth of T lymphoma in vitro and in vivo. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d+ cancers, such as T lymphoma.
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http://dx.doi.org/10.1158/2326-6066.CIR-13-0104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927984PMC
January 2014
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