bluuebunny/crossref_metadata_2025 huggingface dataset:
Cilia and mitogen‐activated protein kinase signaling
Authors: Jivan Arif , Earnest Svetlana , Cobb Melanie H.
Published: June 2021

Our lab identified mouse Radial Spoke Protein 3 (RSP3) through a yeast two‐hybrid screen designed to identify interactors that have a higher affinity for the phosphorylated, active form of ERK2 (pERK2). RSP3 is a structural component of motile cilia and an A‐Kinase Anchoring Protein (AKAP) for cAMP‐dependent Protein Kinase (PKA). To confirm our finding, I showed that the human homolog, RSP3H, co‐immunoprecipitates with ERK2 in overexpression studies. Furthermore, I demonstrated, through immunoprecipitation kinase assays, that RSP3H is phosphorylated by pERK2. Additionally, I showed through RT‐PCR that an mRNA transcript of RSP3H is present in HEK293 and HeLa cells, neither of which are thought to contain motile cilia. I also performed immunofluorescence studies on overexpressed RSP3H, and discovered that not only does it localize to cilia‐like structures but also may induce the formation of multiple cilia‐like projections from the cell, thus functioning as a regulator of ciliogenesis. RSP3H may serve to localize ERK1/2 to cilia and function as a point of convergence of cAMP‐dependent and PKA‐mediated action upon ERK1/2 downstream signaling.
The Meyerhoff Scholars: A STEM diversity program that really works!
Authors: Summers Michael F
Published: June 2021

Although African Americans represent approximately 11 percent of all students enrolled in the nation's colleges and universities, and a greater percentage of African Americans begin college with interests in science, technology, engineering and mathematics (STEM) fields that their Caucasian peers, they earn less than seven percent of all STEM bachelor's degrees and less than two percent of the STEM doctoral degrees. The Meyerhoff Scholars Program was created at the University of Maryland Baltimore County (UMBC) in 1997 to address this retention problem. Since its inception, the Meyerhoff Scholars Program has supported more than 800 students (including ~260 currently enrolled undergraduates). Most of the graduates (87%) earned STEM undergraduate degrees, and of these, 41% matriculated to PhD or MD‐PhD programs, 22% to Masters programs, and 24% to professional programs. A Meyerhoff Gradaute Fellows program was initiated with NIH support about 12 years ago, and since that time, minority participation in biomedically related PhD programs at UMBC have increased from about 2% in 1995 to 17% today. Key elements of both the undergraduate and graduate programs that appear to be essential for successful student retention will be presented.
Effect of sesamol, a potent tyrosinase inhibitor, on melanin and melanin synthesizing melanoma cells
Authors: Kumar Mahendra C. , Sathisha Upparahalli V. , Dharmesh Shylaja M. , Rao Appu A. G. , Singh Sridevi Annapurna
Published: June 2021

The effect of lignans – sesamin, sesamolin and sesamol – from sesame seed (Sesamum indicum L.), known for their health promoting properties, on melanin synthesis was studied using mouse melanoma B16F10 cells. Sesamol inhibited the synthesis of melanin by 63%; sesamin and sesamolin had negligible effects (<2%). Reduction in melanin content of the cells was associated with the concomitant loss of viability and proliferation. The cell survivability could be attributed to the suppression of prooxidant effect of melanin in melanoma cells by the high antioxidant activity of sesamol (IC50 = 5.1 μg/mL). The hindered protective effect of melanin against UV induced skin damage and cancers (via its antioxidant property) in highly proliferative melanoma cells could probably be due to the presence of prooxidant short chain melanin polymers in the latter. To understand the role of lignans in inhibition of melanin synthesis, the effect of sesamol on tyrosinase (EC ), a copper containing oxygenase with mono and diphenolase activities was studied. Sesamol inhibited monophenolase and diphenolase activity in a noncompetitive and competitive manner with Ki values of 1.4 μM and 0.57 μM, respectively. This first ever report of the effect of lignans on melanin synthesis might help in validating the health benefits of sesame lignans.
Visualizing skin γδ T cell antigen expression during wound repair
Authors: Komori Heather Kiyomi , Teyton Luc , Havran Wendy L
Published: June 2021

Skin is the largest organ through which we experience the outside world and our first line of defense against environmental and pathogenic assault. Within the skin, dendritic epidermal T cells (DETC) are uniquely poised to monitor the tissue for damage and disease and play key roles in wound repair and homeostasis. Central to the role in wound repair is stimulation of the DETC through their invariant γδ TCR by an unknown antigen expressed on stressed keratinocytes. Characterizing ligands for the DETC TCR is crucial to understanding DETC activation and function. We developed soluble DETC TCR tetramers to investigate expression patterns and kinetics of putative antigens specific for the DETC TCR. In vitro tetramer studies showed stimulatory keratinocyte cell lines express DETC TCR ligands. Ex vivo tetramer staining in wounded epidermal sheets revealed rapid upregulation of antigen on keratinocytes at, but not distal to, the wound site prior to DETC activation followed by a loss of antigen after DETC activation. This study represents the first visualization of DETC antigen expression during wound repair and provides novel information about patterns of antigen expression and early stages of DETC activation during wound repair. Ongoing studies using the DETC TCR tetramer are focused upon identification of the unknown DETC antigen. This work is supported by NIH grants AI064811 to W.L.H, A142267 to L.T, and a NSF GRFP to H.K.K.
microRNA influence on host response to Francisella infection
Authors: Cremer Thomas John , Hunter Melissa G. , Elton Terry S. , Marsh Clay B. , Tridandapani Susheela , Butchar Jonathan P.
Published: June 2021

The gram‐negative bacterium Francisella tularensis has the ability to subvert host immune response and is the causative agent of the disease tularemia. Previous work has identified the roles of PI3K, Akt and SHIP in modulating host resistance to Francisella. However, the mechanisms of F. tularensis host cell subversion are still poorly understood.

microRNAs (miRs) have emerged as an important regulatory system in the modulation of host innate immune response. Since miRs have the potential to regulate key immune functions such as NFkappaB activity and TLR signaling, we examined whether they played a role during Francisella infection. We performed a miR array analysis of human myeloid cells infected with Francisella. This led to the identification of several miRs that were significantly up‐ or down‐regulated by Francisella. We subsequently verified many of these changes using real‐time RT‐PCR in both human and murine cells. Currently we are examining the roles of these miRs by identifying their targets and by modulating miR activity itself during Francisella infection. Interestingly, our data so far indicate that SHIP and PI3K/Akt regulate the expression of several miRs. As specific miR targets are identified within the context of Francisella infection, it is likely that novel therapeutic targets will be found, and that the mechanisms of Francisella host cell subversion will be further elucidated.
Influence of Metal Ions on Immune Reactivity
Authors: Chan Erwin PH , Zellweger Rene , Filgueira Luis
Published: June 2021

Orthopaedic metal implants are routinely used in bone fracture repair and for joint replacement therapies. However, approximately 15% of recipients suffer from inflammatory reactions and aseptic loosening. One possible cause is an immune reactivity towards the metal implants. Metal implants in patients undergo biocorrosion releasing metal ions and wear particles. Metal ions are able to circulate in the body and bind to extracellular and/or intracellular proteins. Any immune reactivity by patients would be initiated by professional antigen presenting cells, dendritic cells (DCs) and effected by CD4+ T‐cell.

For this in vitro study, Titanium (IV) and Vanadium (IV) ions were chosen as they are major components in current metal implants. Using energy filtered transmission electron microscopy, uptake of Titanium (IV) by human DCs showed intracellular accumulation as phosphorus containing titanium complexes at the surface and intracellular membranes, as well as in ribosomal and nuclear chromatin structures. Changes in the DC surface markers after exposure to metal ions measured using flow cytometry. Increase in expression of co‐stimulatory molecules (CD80, CD86 and CD40) was seen in vanadium exposed DCs. Upregulation of cytokines IL4, IL10, IFN‐g and TNF‐a was detected in the supernatants of DCs exposed to titanium (IV). Finally, the ability of metal exposed DCs to interact with lymphocytes was also investigated through flow cytometry. Decrease in T‐lymphocytic CD25 was seen after 5 day culture with Titanium (IV) treated DCs whilst vanadium treated DCs were able to maintain CD25 expression.

The reactivity towards various metal ions varies with individuals. It is suggested that responders towards metals would have a reduced regulatory capability through CD4+CD25+ cells, allowing the proliferation of inflammatory osteo‐immune Th17cells.
The Association of Cargo Receptor Bap31 with MHC I is Regulated by Bap29
Authors: Prooyen Nancy Maire Van , Edidin Michael
Published: June 2021

The proper cell surface presentation of major histocompatibility complex class I (MHC I) molecules loaded with high‐affinity peptide is critical for T cell recognition of pathogens. MHC I is assembled with a peptide in the endoplasmic reticulum (ER). We present evidence of a novel post‐ER quality control mechanism that ensures only high‐affinity peptide‐loaded MHC I (pMHC I) molecules reach the cell surface. The cargo receptor Bap31 aids in the ER export of pMHC I to the ER‐Golgi intermediate compartment (ERGIC). Bap31 then recycles low‐affinity pMHC I molecules back the ER, while high‐affinity pMHC I molecules continue to traffic to the cell surface. We use fluorescence resonance energy transfer (FRET) and quantitative fluorescence imaging in HeLa cells to show clustering between Bap31 and MHC I. We also show that anterograde traffic of both Bap31 and MHC I to the ERGIC is increased upon a short pulse of high‐affinity peptide, which creates a bolus of MHC I molecules ready for ER export. An intermediate increase is shown when cells are fed with a low‐affinity peptide. Overexpression of Bap29 in cells inhibits Bap31 traffic to the ERGIC and decreases MHC I surface expression. Bap29 is a homolog of Bap31 and has been shown to form heterodimers with Bap31. Unlike Bap31, Bap29 is only found to localize in the ER. Whereas, overexpression of Bap31 increases MHC I cell surface expression and stability. Thus, Bap31 is directly involved in MHC I ER export and this function is regulated by Bap29.
ICAM‐1 expression is required for regulatory T cell localization in the lungs of M tuberculosis infected mice
Authors: Windish Hillarie Plessner , Flynn JoAnne L
Published: June 2021

Mycobacterium tuberculosis (Mtb) is a widespread human pathogen that persists in the lungs of latently infected individuals. Formation of the granuloma, a hallmark lesion of tuberculosis, allows leukocytes to control infection with Mtb. We hypothesized that the adhesion molecule ICAM‐1 plays a role in the granuloma formation and in the cell to cell communication that takes place at the locus of infection While previous studies in ICAM‐1−/− mice have indicated that ICAM‐1 is required for long‐term control over Mtb infection, the mechanism remains unclear. In this study, ICAM‐1−/− mice infected with Mtb survived similarly to wild type controls with equivalent bacterial burden. Although granuloma formation appeared normal in the absence of ICAM‐1, higher overall lymphocytic infiltrate was observed by H&E staining and flow cytometry. Higher T cell numbers was apparently due to inhibited contraction in the absence of ICAM‐1 following primary Mtb infection. T regulatory cells were also significantly reduced in ICAM‐1−/− mice, which could play a role on T cell contraction. In this study we have both investigated the role of T regulatory cells in controlling T lymphocytes. Results suggest that ICAM‐1 expression may help to control lung pathology by supporting the function of T regulatory cells in the lungs. Future studies will attempt to elucidate the mechanism by which ICAM‐1 affects T regulatory cell recruitment to or retention in the lungs.

Funding provided by NIH R01 HL71241
The role of CD137+ T regulatory cells in controlling T1D
Authors: Kachapati Kritika , Wu Yuehong , Mittler Robert , Ridgway William M.
Published: June 2021

CD4+CD25+Foxp3+ Tregs maintain immunologic tolerance and are important in diabetes pathogenesis in non‐obese diabetic (NOD) mice. NOD.B10 Insulin dependent diabetes (Idd) 9.3 congenic mice are protected from diabetes; CD137 is the major Idd9.3 candidate gene. We published that treatment of NOD mice with an agonist anti‐CD137 antibody (3H3) prevented diabetes through expansion of Tregs in vivo. Here we show that depletion of Tregs with anti‐CD25 abolished 3H3 mediated prevention of diabetes, confirming that anti‐CD137 antibody targets Tregs. A subset of Tregs constitutively expresses CD137. We showed that CD137+ Tregs produce significantly higher levels of IL‐10 and CD69 than CD137‐ Tregs, but the levels of TGF‐b1, Foxp3 and CD62L are similar between subsets. NOD.scid recipients of anti‐CD25 treated splenocytes from NOD.Idd9.3 mice develop diabetes, suggesting that Tregs play a role in protection from diabetes in NOD.Idd9.3 mice. We show an age dependent decline in CD137+ Tregs in NOD, but not in NOD.Idd9.3 congenic mice. In concordance with studies that link CD137 with long term survival, we have observed that CD137+ Tregs express higher levels of mRNA for anti‐apoptotic molecule Bcl2, indicating that CD137 co‐stimulation is important for in‐vivo survival of Tregs. CD137 co‐stimulation of Tregs is hence important in balancing pathogenic effectors and preventing Type 1 Diabetes (T1D) in the NOD model.
Anti‐CD20 depletion of B cells inhibits spontaneous autoimmune thyroiditis (SAT)
Authors: Yu Shiguang , Braley‐Mullen Helen
Published: June 2021

All NOD.H‐2h4 wild type (WT) mice given NaI water develop SAT, but B cell‐deficient (B−/−) mice are resistant. B cells presumably function as APC for activation of CD4+ T cells. B −/− mice develop SAT comparable to WT mice after transient depletion of T reg, suggesting T reg are preferentially activated if autoantigen is presented by non‐B cells. Anti‐CD20 or isotype control was given to young (1–2 wk) or adult (7 wk) WT mice; all mice were given NaI water at 8 wk, and SAT was evaluated 8 wk later. WT mice given anti‐CD20 at 1 and 2 wk of age developed minimal SAT, although B cells had repopulated by 6–8 wk of age. Transient depletion of T reg during B cell depletion reversed the effects of anti‐CD20, and all mice developed SAT. SAT was also inhibited in adult mice given anti‐CD20 if B cell depletion in blood was maintained for 8 wk. Transient B cell depletion of adult mice did not inhibit SAT development. Anti‐CD20 depleted most circulating B cells, but only 60–80% of splenic B cells in adults. Most follicular B cells were depleted, but marginal zone B cells were resistant. The results suggest that in the absence of B cells, other APC activate T reg. This may be one mechanism by which B cell depletion inhibits autoimmune disease. The effects of B cell depletion and the underlying mechanisms may differ depending on when anti‐CD20 is administered. (Supported by Arthritis Natl. Res. Fdn). Anti‐CD20 was provided by Drs. M. Kehry and R. Dunn, Biogen, Idec.
Locally Activated Complement Components (LACC) Play Key Role in the Pathogenesis of Arthritis
Authors: Wang Yi , Peng Tao , Liu‐Chen Susan
Published: June 2021

This study was to determine if LACC play a key role in collagen‐induced arthritis. Inhibition of LACC was achieved by intra‐articular (i.a.) injection of an anti‐C5 mAb, BB5.1, into already inflamed limbs (AIL). BB5.1 prevents the generation of C5a and C5b‐9. We selected an i.a. dosing that has no detectable effect on systemic complement activity (SCA) when given i.p. The therapeutic effect was evaluated by measuring the thickness of AIL and the number of newly recruited inflamed limbs (NRIL) during a 12d observation. Our results showed that i.a. injection of BB5.1 to AIL achieved significant therapeutic effect and reduced thickness of AIL from 5.08 ± 0.18 mm in controls to 4.62 ± 0.19 mm in an i.a. BB5.1 cohort. The same dose of BB5.1 by i.p. injection had no detectable impact on SCA, and resulted in no effect on AIL. Remarkably, i.a. C5 inhibition was sufficient to completely block the disease progression with no NRIL during the 12d period while animals in other cohorts all had a significant number of NRIL, ranging from a 300x increase in a cohort with i.a. injection of control mAb to a 240x increase in a cohort with i.p. injection of the same doses of BB5.1. Our data indicated that LACC are potent pro‐inflammatory mediators and play a key role in amplifying the downstream inflammatory process. Targeting C5a and C5b locally blocked the inflammatory amplification loop and achieved significant therapeutic effects without blocking SCA.
A Novel Therapy for Autoimmune Arthritis Using CD40 Gene‐Silenced Dendritic Cells
Authors: Zheng Xiufen , Suzuki Motahiko , Zhang Xusheng , Sun Hongtao , Kubo Norihiko , Beduhn Marianne , Inman Robert D , Garcia Bertha , Min Wei‐Ping
Published: June 2021

CD40 plays a critical role in dendritic cell (DC)‐mediated immune modulation. We have previously achieved immune modulation through RNA interference (RNAi), implying the therapeutic potential of RNAi‐modified DC as antigen‐specific tolerogenic therapies. To date, an RNAi‐based treatment for autoimmune arthritis is not reported. We hypothesized that treatment with CD40‐silenced DC may develop antigen‐specific tolerance and may be beneficial to the prevention and intervention of autoimmune arthritis. To test this, we generated DC and knocked down CD40 using small interfering RNA (CD40‐siRNA). CD 40 silenced DC displayed inhibitory capacity of T cell response in MLR. Immunization with type II collagen (CII)‐pulsed and CD40 gene‐silenced DC (CII‐pulsed/gene‐silenced DC) resulted in antigen‐specific nonresponsiveness in T cell responses. Vaccination with CII‐pulsed/gene‐silenced DC prevented collagen‐induced arthritis (CIA) disease development in a murine rheumatoid arthritis model. Furthermore, administration of CII‐pulsed/gene‐silenced DC at pre‐clinic stage was sufficient to inhibit progression of CIA. The therapeutic effects were further evidenced by decreased clinical scores, inhibited inflammatory infiltrates, and suppressed T cell and B cell responses to CII. In conclusion, this study is the first demonstration of immunotherapy using CD40 silenced DCs for autoimmune arthritis.
Cyclosporin A inhibits the production of IL‐17 by memory Th17 cells from healthy individuals and patients with RA
Authors: Wu Changyou , Zhang Cai , Yang Binyan
Published: June 2021

Recent evidence from several studies indicated that IL‐17‐producing Th17 cells can represent the key effector cells in the induction and development of autoimmune disorders. Cyclosporin A (CsA) is a commonly used immunosuppressive agent to treat a wide range of autoimmune disorders including RA. Here, we demonstrate that PBMCs and purified CD4+ T cells from healthy individuals and patients with RA could be induced to produce a large amount of IL‐17 after stimulation with anti‐CD3 plus anti‐CD28 mAbs. Phenotypic analysis indicated that the majority of IL‐17‐producing cells were Th17 cells with memory phenotype. The addition of CsA into cell cultures significantly inhibited the production of IL‐17 by Th17 cells at protein and at mRNA levels. Compared to the PBMCs from normal individuals, PBMCs from the patients with RA produced higher levels of IL‐17 that was also significantly inhibited both at protein and at mRNA levels by CsA. The mechanism might be the effect of CsA on the activation of T cells because the expression of CD69 and CD25 molecules on T cells was markedly reduced in the presence of CsA. Taken together, these results demonstrated that CsA suppressed the production of IL‐17 and inhibited the differentiation of Th17 cells from both healthy individuals and patients with RA.
Metformin, a diabetic drug attenuated autoimmune inflammatory disease of CNS in animal models of multiple sclerosis
Authors: Nath Narender , Khan Mushfiquddin , Singh Avtar K , Singh Inderjit , Giri Shailendra
Published: June 2021

Metformin is the most widely prescribed oral anti‐diabetic and hypoglycemic drug. Here we examined the efficacy of metformin in relapsing/remitting (SJL) and chronic (C57BL/6) models of EAE. Administration of metformin restricted the infiltration of mononuclear cells in central nervous system (CNS), thereby; downregulated the expression of proinflammatory cytokines (IFN‐gamma, TNF‐alpha, IL‐6, IL‐17 and iNOS), CAMs, MMP9 and chemokine (Rantes) in CNS of treated animals. Metformin treatment restored the lipids alterations (total phospholipids and in free fatty acid) in CNS during EAE suggest a possible involvement of AMP‐activated protein kinase (AMPK) which acts as cellular energy sensor in cells. Activation of AMPK with metformin was observed in macrophages and inhibits phospholipids and neutral lipid biosynthesis. Further it down regulated the expression of pro‐inflammatory mediators (iNOS and Cox2) induced with LPS/IFN‐gamma. It also downregulated recall responses, Th1 as well as Th17 cytokines and induced IL‐10 production in total spleen cells of treated and untreated EAE animals. Together, these findings reveal that metformin may have possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases. Grants: RG 3810‐A‐1, PP1283 from National Multiple Sclerosis Society (SG) and NS‐22576, NS‐34741, NS‐37766 and NS‐40810 from NIH (IS).
Interferon (IFN) beta ‐1a induces IL‐27 and IL‐12, and down‐regulates IL‐23 and IL‐1beta in dendritic cells (DCs), establishing inhibitory conditions for Th‐17 cell differentiation: Implications for treatment of multiple sclerosis (MS)
Authors: Ramgolam Vinod , Speer Danielle , Markovic‐Plese Silva
Published: June 2021

Background: Th‐17 cells have been implicated in the pathogenesis of MS. DC‐derived cytokines IL‐6, IL‐1 beta and IL‐23 promote, whereas IL‐27 and IL‐12 suppress Th‐17 cells differentiation. Objective: To investigate the effect of IFN beta‐1a, a standard therapy for MS, on DC‐derived cytokines and signaling events that regulate Th‐17 cells differentiation. Materials/Method: Monocyte‐derived mature DCs from 13 donors were cultured in the absence or presence of IFN beta‐1a (1000 IU/ml) and analyzed for cytokine gene expression by quantitative RT‐PCR and for signal transduction by Western blots. Results: IFN beta‐1a increased the expression of IL‐27 (191.5‐fold, p=0.002), IL‐12p35 (6.7‐fold, p=0.008) and decreased IL‐23 (−3.7 fold, p=0.002), and IL‐1 beta (−2.7‐fold, p=0.004) in DCs derived from 10 healthy donors. The results were confirmed in 3 MS patients. IFN beta‐1a induced phosphorylation of STAT‐1, a transcription factor for IL‐27. The role of STAT1 as a transcription factor for IL‐27 was confirmed in the experiments where STAT‐1 gene silencing reduced IL‐27 transcription by 30% in IFN beta‐1a‐treated DCs. IFN beta‐1a induced the expression of SOCS3, which may mediate inhibition of IL‐23 and IL‐1b expression. Conclusion: IFN beta‐1 induces IL‐27 expression via STAT‐1 activation and inhibits IL‐23 and IL‐1beta, possibly through the induction of SOCS3, promoting the suppression of Th‐17 cell differentiation in MS.

The study was supported by EMD Serono.
Aptameric green fluorescent protein (A‐GFP) selected from ribosome display (RD) library on solid phase IgE prevents human IgE binding to human FceRIa
Authors: Chen Swey‐Shen , Yang Yong‐Min
Published: June 2021

Ribosome display is a complete in vitro system that permits selection of gene based on the physical association of its encoded message cognately to the protein it henceforth translates. The resulting ternary complexes of aptameric protein‐mRNA‐ribosome (ARM) specific for the ligand are immobilized on the designated solid phase ligand. Herein, green fluorescent protein (GFP) is fused to Cκ stuffer region as scaffold with 5′ T7 and Kozak/ATG sequences for transcription/translation‐coupled reactions. In non‐library modality, the presence of as low as 10 femtogram DNA rd4 construct of 1.2 kb, i.e., approximately 7,500 molecules, are sufficient for recursive rounds of selection by MAb anti‐GFP coated on solid phase. Next, ribosome display library constructed within site 6 and site 8/9 of GFP was employed for selecting aptameric protein that binds to human IgE on solid phase. An input 10 μg of 10‐mer aptameric GFP library for the respective dual site entails 7.5×1012 physical molecules (1.2 kb), expressed within a potential diversity of 1.0×1026 of possible peptide aptamers. Recombinant aptameric GFP was shown to bind to human IgE PS, BED, JW8, but not human IgG, lysozyme, BSA. Aptameric GFP also competes with the soluble receptor for binding human IgE on solid phase. Fragments of 25 to 100 bp from six IgE‐binding aptameric DNA by DNaseI were then shuffled, reassembled via internal homology by PCR. The molecularly evolved species exhibited improved binding to IgE. Thus, RD is an adequate technology platform for selecting aptameric GFP that specifically inhibits IgE binding to FcεRIα.
Inactivation of Notch signaling leads to a defective dendritic cell differentiation in cancer
Authors: Cheng Pingyan , Nefedova Yulia , Gabrilovich Dmitry I.
Published: June 2021

Notch receptors/transcription regulators play an important role in the fate decision for hematopoietic progenitor cells (HPC). Previously we and others have demonstrated that Notch signaling may play a critical role in the development of dendritic cells (DC). Here we report that Notch signaling is involved in the abnormal differentiation of DC during tumor progression. We have found that Notch signaling (evaluated by the activity of CBF1 transcription factor and the expression of down stream targets Hes1 and Hes5) was dramatically reduced in HPC isolated from tumor‐bearing mice. The downregulation of Notch signaling in HPC caused defective differentiation of DC. Treatment of HPC or tumor‐bearing mice with Stat3 inhibitor JSI‐124 significantly increased Hes1 expression in HPC and DC differentiation. Using macrophages from Stat3−/− mice and induced activation of Stat3 in HPC by IL‐6 we have confirmed that Stat3 negatively regulated Notch signaling. Thus, our data suggest that tumor associated factors inactivate Notch signaling in HPC, leading to abnormal DC differentiation through Stat3 upregulation.
Using gamma‐cytokine complexes to improve antigen specific CD8 T cell responses in tumor‐bearing mice
Authors: Verdeil Gregory , Marquardt Kristi L , Biggs Judith A , Surh Charles D , Sherman Linda A
Published: June 2021

In the absence of inflammatory signals, the exposure of T cells to tumor antigen in the periphery results in tolerance. Remaining tumor specific T cells are usually of low avidity or anergic. Immunotherapy aims at reversing this tolerance to induce an efficient T cell response. STAT5 Cytokines of the interleukin‐2 family signal through STAT5 and are candidates to increase T cell anti‐tumor response. The effects of these cytokines are greatly increased when the cytokine is complexed with a specific antibody.

We have studied the potential of cytokine complexes to serve as adjuvants for CD8 cells activation in a murine model, RIP‐Tag2‐HA, in which pancreatic insulomas expressing the influenza hemagglutinin (HA) as a surrogate antigen develop spontaneously. HA specific CD8 cells become effector after 3 days of treatment with IL‐2 complexes and antigen in vivo. This differentiation leads to the elimination of endogenous tumors by high avidity HA specific CD8 cells. Survival of CD8 cells is increased by using the TLR ligands polyIC or by extending the length of treatment with IL‐2 complexes. Under such conditions, even low avidity HA specific CD8 cells eliminate the tumors. We further show that cytokine complexes also increase survival of adoptively transferred, ex‐vivo activated HA specific CD8 cells. These results indicate that IL‐2 complexes are strong adjuvants that greatly enhance tumor vaccines or immunotherapy.
Sperm protein 17 is expressed in primary and metastatic breast cancer
Authors: Chiriva‐Internati Maurizio , Ferrari Raffaele , Yu Yuefei , D’Cunha Nicholas , Grizzi Fabio , Cobos Everardo , Jenkins Marjorie R
Published: June 2021

Objective. Breast carcinoma (BC) is a major health concern for millions of women. The cancer testis antigen (CTA) Sperm protein 17 (Sp17), has been identified in multiple myeloma and ovarian cancer. This study evaluated Sp17 expression in both normal breast tissue and primary invasive ductal BC.

Methods. We analyzed Sp17 expression in 7 normal breast tissues, 22 primary BCs by immunohistochemistry (IHC) and three human cell by Western Blotting (WB).

Summary of Results. No immunoreactivity was recognized in normal breast tissues while BCs showed strong cytoplasmic immunoreactivity with 15/22 positive cases (70%) for Sp17 protein.

Conclusions. The data demonstrate the expression of Sp17 in breast cancer. Further studies will elucidate the role of Sp17 in BC, and its potential use as a BC immunotherapeutic target antigen.
Effect of L‐carnitine supplementation on low birth weight Korean infants
Authors: Seong So‐Hui , Cho Soo‐Chul , Cha Youn‐Soo
Published: June 2021

In the present study, low birth weight infants(LBWI) were studied in order to assess any specific changes in serum lipids profile or carnitine concentration as a consequence of carnitine supplementation. LBWI were 25 newborns with body weights under 2,500g, the 25 LBWI were divided into 2 groups: L‐carnitine supplemented (received L‐carnitine 10mg/kg/day, LCS) or L‐carnitine non‐supplemented (LCNS) group. The study and control groups, each consisting of 25 infants, did not differ significantly in gestation age, Apgar index, birth weight, height, head circumference or chest circumference. The addition of carnitine as a nutritional supplement did not clearly enhance growth in our group of Korean premature infants. But, lipid profile and serum carnitine level were significantly improved after carnitine supplementation. Therefore, our findings suggest that continuous carnitine supplementation is required for catch up growth of premature infants in Korea.
The influence of various types of physical activity on changes in body fat and weight during the postpartum period
Authors: Deierlein Andrea , Siega‐Riz Anna‐Maria , Evenson Kelly
Published: June 2021

Few studies have examined physical activity patterns during the postpartum (pp) period and the contributions of different types of activity to changes in body weight and fat during this time. We analyzed data from 499 women with singleton pregnancies who participated in the Postpartum PIN Study to examine the association between physical activity and weight and body fat changes between 3 and 12 months pp. Body fat % from BIA, weight, and height were measured by study investigators. Total physical activity, as well as recreational, work, and childcare activity, during the previous 7 days was self‐reported and converted into units of MET hrs/wk. Women had average increases of 1.25 (SD 38.30), 6.80 (SD 23.0), and 1.30 (SD 21.93) MET hrs/wk of total, work, and childcare activity, respectively, and an average decrease of 7.74 (SD 14.76) MET hrs/wk of recreational activity. The mean change in body weight and % fat was −1.74 kg (SD 4.21) and −1.60% (SD 3.25), respectively. Linear regression was used to estimate the associations between changes in recreational, work, childcare, and total activity (MET hrs/wk) at 3 and 12 months pp with changes in weight and % body fat during the same period, adjusted for covariates. An increase in MET hrs/wk of work activity between 3 and 12 months pp was associated with significant decreases in body weight and % fat by 12 months pp. Significant associations were not found for the other activity domains.
Precision and validity of self‐reported anthropometry in Guatemalan adolescents
Authors: Campos J Raquel , Aquino Brenda , Solomons Noel W.
Published: June 2021

Background:

The validity self‐reported height (Ht) and weight (Wt) in adolescence has often been reported, but rarely validated. Its reproducibility is unknown.

Objectives:

To determine the precision and validity of self‐reported Ht and Wt in adolescents from 11 to 14 y of age.

Methods:

Nutritional questionnaires, including self‐reported Ht and Wt, were performed in low‐income urban Guatemalan schools at 2‐wk intervals in 100 subjects each, in 4 age‐groups (11,12,13,14 y), equally divided by sexes (F,M). Direct Ht and Wt measurements were made after the 2nd interview. BMIs were derived as kg/m2. Similarities in group‐medians and strength of individual associations were calculated.

Results:

Not all participants self‐reported a Ht and a Wt value on both or either occasion; 30% reported both values both times. For 118 subjects reporting the Ht twice, Spearman correlation was r=0.90 and the medians differed by 2.5 cm F and 0.5 cm M. For Wt repetition in the same subjects, r=0.93 and the medians differed by 1.1 lbs F and 0.0 lbs M. With respect to true BMI and the derived value from self‐reported on the same day, r=0.65.

Conclusion:

Self‐reported anthropometry may provide valuable estimates at the group level, but is not adequate for individual assessment in this age group.
The use of an acrylic board to separate regions of interest during dual energy x‐ray absorptiometry scanning in extremely obese women
Authors: Earthman Carrie P , Valentine Bret J , Sibley Shalamar D , Beckman Tiffany R , Kellogg Todd A , Ikramuddin Sayeed , Dobratz Jennifer R
Published: June 2021

Dual energy X‐ray absorptiometry (DXA) is a noninvasive and clinically accessible tool for measuring body composition; however, there are methodological limitations for application in extreme obesity. Size and weight in excess of instrument capacity, and tissue overlay are important issues. The study objective was to evaluate the use of an acrylic board for the resolution of breast overlay in women undergoing half‐body DXA scans. This was a cross‐sectional study of extremely obese women (n=18; BMI: 46.8±7.6 kg/m2; age: 47.9±10.1 y). Three techniques (no support; gauze taping; and a ½ × 14 × 12 inch acrylic board) were evaluated for separating regional areas of interest, in sequential scans. For estimates of truncal right‐sided fat mass (FM), there was no difference between no support and taping (P = 0.903). The acrylic board yielded significantly lower truncal FM results compared to no support (−1123±1704g; P=0.010) and to taping (−1051±1711g; P=0.022). Use of an acrylic board provided the best regional separation. Precision between scans was good, with coefficients of variation of 2.8%, 2.3%, and 4.4% for right leg FM, lean mass (LM), and bone mineral content (BMC), respectively. There were no differences in the right leg FM, LM, or BMC values across the 3 scans by ANOVA. An acrylic board placed under the armpit can be utilized to resolve the problem of breast overlay in extremely obese women undergoing DXA scans.
Evidence for the involvement of early insulin resistance in the development of cachexia in mice bearing colon‐26 tumors
Authors: Asp Michelle L. , Tian Min , Wendel Angela A. , Belury Martha A.
Published: June 2021

Cachexia occurs in ~30% of cancer patients, resulting in severe muscle and adipose atrophy, and poor prognosis. As resistance to insulin has been associated with cachexia, we sought to determine if this occurs prior to weight loss and whether sensitization to insulin attenuates cachexia in CD2F1 mice bearing colon‐26 (C26) tumors. Insulin sensitivity, measured by insulin tolerance test area under the curve, worsened in mice with tumors (T) compared to those without tumors (NT) ≥ 2 days before body weight differences were detected. Decreased quadriceps Akt activation corroborated these findings. Treatment of T mice with the insulin sensitizer rosiglitazone (ROSI, 20mg/kg/d) improved insulin resistance, evidenced by a larger blood glucose response to insulin 60 minutes after insulin administration compared to T mice without ROSI. Treatment with ROSI also prevented tumor‐induced depletion of adiponectin, an insulin‐sensitizing adipokine, and resulted in higher body weight at the end of the study. In conclusion insulin resistance occurred before weight loss, and sensitization to insulin by ROSI prevented weight loss in tumor‐induced cachexia. These data suggest a role for early insulin resistance in the pathology of cancer cachexia and sensitization to insulin in decreased severity of this disorder. Supported by Cognis Corporation and Ohio Agricultural Research and Development Center.
Carcass energy content and adiposity in response to diet energy levels and moderate exercise in diet‐induced obese and non‐obese rats
Authors: Vander Tuig Jerry G. , Chi Myung S. , Taylor Veronica , Galbreath Karen
Published: June 2021

Various animal models are used to study development of obesity. Diet‐induced obesity (DIO) in animals fed high‐energy diets is comparable to development of human obesity. This study examined effect of exercise and diet energy levels on carcass energy and fat depots in DIO rats. Six‐week‐old male Sprague‐Dawley rats (185 ± 2 g, mean ± sem) had unlimited access to high‐fat diet (38% kcals from fat) for 12 weeks. Rats from greatest and least weight gain quartiles (445 ± 5 and 334 ± 4 g) were assigned to DIO and non‐obese, diet‐resistant (DR) groups, respectively. For 10 weeks, DIO and DR rats had unlimited access to high‐fat (38% of kcals) or low‐fat (12% of kcals) diet and were exercised or kept sedentary in a 2 × 2 × 2 design (obesity × diet × exercise). Exercise consisted of treadmill running with weekly increases in speed and duration to values of 15 m/min and 1 hr/day for the final 2 weeks. Exercise reduced (p<0.05) weight gain and total carcass energy (22% and 24%) but did not affect energy intake of DR rats fed low‐fat and high‐fat diets. In DIO rats, exercise and low‐fat diet reduced weight gain and energy intake (12%) but did not affect (p>0.05) carcass energy. Exercise reduced epididymal fat weight by 42% and 31% in DR (both diets) and by 25% in DIO rats fed low‐fat diet only. Moderate exercise more effectively reduced carcass energy and fat in DR rats than in DIO rats, primarily when DIO rats were fed high‐fat diet. Supported by USDA/CSREES.
Tofu intake and diabetes incidence in Japanese‐American men
Authors: Chapman‐Novakofski Karen , Yano Katsuhiko , He Qimei , Chen Randi , Willcox Bradley J
Published: June 2021

The Honolulu Heart Program is a long‐term study of cardiovascular disease (CVD) among Japanese American men who were living on Oahu in 1965–68 (T1), when 8006 participated; in 1971–75 (T2), 5877 participated; in 1991–93 (T3), 3741 participated. The objective of this analysis was to evaluate whether soy intake was related to the incidence of Type 2 diabetes mellitus [DM]. All those with a diagnosis of cancer, CVD, stroke, or DM at T1 were eliminated. DM = being told by a physician that you have diabetes, taking an oral agent or insulin, and/or having a blood glucose level > 126 mg/dl or an oral glucose tolerance test > 200. Tofu intake was dichotomized as high [> twice/week] and low (<twice/wk). More had low tofu than high tofu at both T1 [low=2331, high= 523] and T2 [low=1200; high= 503]. Although high intake [n] is similar at T1 and T2, comparisons across time show few with consistent high intake: low/low=1622; low‐high=295; high‐low=248; high‐high=164. There was no significant effect of tofu intake change overall on DM incidence (p=.364). However, tofu intake T2 [Chi square 6.68; p=.0098, CI 1.067, 1.599] and BMI [Chi square 50.4, p=.0001; CI 1.098, 1.179] was associated with DM incidence. The pattern of low‐high tofu intake was associated with DM, whereas low‐low and high‐high was not. This may suggest an effect of increased food or calorie intake rather than tofu per se. Supported by the Illinois Soybean Association, Pacific Health Research Institute, by contract NHLBI‐N01‐HC‐05102, contract NIA‐N01‐AG‐4‐2149 and grants 5 U01 AG019349‐05, R01 AG027060‐01.
Dietary intakes of nutritionally nonessential amino acids among homebound older adults
Authors: Datta Sujay , Sharkey Joseph R. , Carroll Raymond J. , Wu Guoyao
Published: June 2021

Nutritionally nonessential amino acids (NEAA) can be synthesized in humans and serve vital functions in whole‐body homeostasis. The synthesis of amino acids depends on many factors, including age, physiological conditions, availabilities of precursors, disease, and medication. Intakes of NEAA are likely affected by dietary habits (e.g., frequency of meals and food preference), which in turn may be affected by a variety of socioeconomic factors. At present, little is known about optimal requirements of NEAA or reference intakes by humans, including elderly subjects. Using three random 24‐h dietary recalls, we examined dietary intakes of NEAA by 323 homebound older adults who received home‐delivered meals. Data were collected on an assortment of variables, including dietary contents of protein and fat, age, race, sex, marital status, education level, income level and BMI. Statistical techniques, such as regression and analysis of variance, were used to detect the significance of each of these factors and their possible interactions on dietary intakes of NEAA. Results indicate that: 1) those who ate daily breakfast had higher (P<0.05) levels of NEAA than those who did not; 2) income level and gender (when considered separately) affected (P<0.05) NEAA intakes. These findings reveal hitherto‐unknown factors about NEAA intakes by home‐bound elderly subjects. Supported by NIH R25 CA90301.
Climate change impacts on dietary nutrient status of Inuit in Nunavut, Canada
Authors: Nancarrow Tanya L. , Chan Hing Man , Ing Amy , Kuhnlein Harriet V.
Published: June 2021

Introduction: Traditional food (TF) is locally derived food harvested from the environment, which gives vital sustenance to an Arctic Indigenous People, the Inuit. TF contributes significantly to daily required nutrients. The Arctic is experiencing rapid climate change which is affecting access and availability of TF and potentially nutrient intake for Inuit. Objective: To characterizes the nutritional implications of climate change related to the TF system of Inuit in Nunavut, Canada. Methods: Two‐day focus groups and a frequency survey of 12 TF species were carried out in two Nunavut communities to record climate change observations and TF intake (g/day). Intake of 22 nutrients was compared to respective Dietary Reference Intakes. Results: Communities found climate change was affecting the TF harvest in both positive and negative ways. TF provided 100% of the Estimated Average Intakes for protein, vitamins A and B6, riboflavin, P, Fe, Cu, Zn and Se, and of the Adequate Intake for omega 3 fatty acids. Overall median daily intake of TF was 367 g/day and top species/parts were known wildlife foods. Conclusions: If climate change leads to increased TF harvest, nutrient intake has the potential to increase. Climate changes that may reduce access to TF may have serious consequences on dietary nutrient status of Inuit if no countermeasures are taken. Research Supported by: ArcticNet, Canada.
Consumption of pistachios significantly reduces IL‐1 expression in isolated human mononuclear cells
Authors: Gebauer Sarah K , Zhang Jun , Heuvel John P Vanden , Kris‐Etherton Penny M
Published: June 2021

The effects of nuts on CVD risk have been well studied, but little is known about pistachios. A randomized, crossover, controlled feeding study was conducted to compare the effects of 2 doses of pistachios on CVD risk factors in hypercholesterolemic adults (n=22; LDL‐C = 133 ± 4 mg/dl). Subjects were fed 3 isoenergetic diets for 4 wk each after a 2‐wk run‐in diet [35% total fat (TF), 11% SFA, 8% PUFA, 13% MUFA]. Diets included a Step‐I diet without pistachios (25% TF, 8% SFA, 5% PUFA, 9% MUFA), with 1.5 oz/d (1.5 PD, 10% en; 30% TF, 8% SFA, 6% PUFA, 12% MUFA), and 3 oz/d (3 PD, 20% en; 34% TF, 8% SFA, 8% PUFA, 15% MUFA). There was a significant (P < .05) reduction in IL‐1 expression after the 1.5 PD (−36%) and 3 PD (−44%). Those with low serum CRP (<1 mg/L) had a greater decrease in IL‐1 expression (P<.05). After consumption of the 3 PD, IL‐1 expression was directly associated with expression of TNFα (r = .9, P < .0001), CRP (r = .5, P < .05), IL‐6 (r = .7, P < .001) and ICAM (r = .8, P < .0001). Changes in IL‐1 expression were directly associated with plasma PUFA (r = .3, P < .05), specifically 18:3 n‐6 (r = .4, P < .01) and 20:4 n‐6 (r = .4, P < .01), and inversely associated with MUFA (r = −.5, P < 0.001), specifically 18:1 (r = −.6, P < 0.0001). Including pistachios in a heart healthy diet reduces IL‐1 expression, thus beneficially affecting CVD inflammatory risk status.

Funded by CA Pistachio Commission and partially by PSU GCRC (NIH grant M01RR10732)
Energy and Whole Grain Intake over a Nine Month Period Following Weight Loss
Authors: Grieger Jessica Anne , Katcher Heather , Kris‐Etherton Penny M
Published: June 2021

Following short‐term weight loss, we determined whether dietary advice to continue with a hypocaloric diet and consume whole grains ad‐libitum, has any long‐term effect on body weight. Fifty subjects participated in a 12‐week, randomized, parallel‐arm trial investigating whether a hypocaloric diet with whole grains (WG group) enhances weight loss and improves CVD risk factors, compared to a hypocaloric diet with refined grains (RG group). Nineteen subjects from the WG and 20 subjects from the RG group participated in the subsequent nine‐month follow‐up visit. The mean age and BMI was 46.2 years and 34.3 kg/m2, respectively. At nine months, there were no significant changes in body weight, despite the WG group continuing with a hypocaloric diet (1670 ± 82 kcal, P<.05), and the RG group increasing energy intake (1910 ± 159 kcal, P<.05) compared to baseline. The mean (± SEM) whole grain intakes were similar for both groups (WG: 2.5 ± 0.4 vs. RG: 1.3 ± 0.3 serves/day), but were 50% lower in the WG group compared to their intakes at the end of the weight loss period (5.2 ± 0.5 serves/day, P=.001). It appears difficult to maintain a high intake of whole grains over a long‐term period in addition to a hypocaloric diet. Regular dietary counseling may be an important component for behavioral change to maintain a low energy, high whole grain diet, for long‐term weight loss. Funded by General Mills; partial support provided by PSU GCRC (NIH grant M01RR10732)
Estimated intake of total antioxidants from diets and supplements in the U.S.
Authors: Chun Ock K. , Chung Sang‐Jin , Chung Chin‐Eun , Song Won O.
Published: June 2021

The importance of antioxidants in reducing risks of chronic diseases has been well established; however antioxidant intake in free‐living population has not yet been estimated adequately. This study aimed to estimate total antioxidant intakes from diets and supplement sources in US population and its subgroups. We utilized the USDA flavonoid database, dietary supplement data, and food consumption data of 8,809 US adults aged 19+ yrs in NHANES 1999‐2002. Daily total antioxidant intake averaged 208 mg vit C (46% & 54% from diets & supplements, respectively), 20 mg α‐tocopherol (36% & 64%, resp), 223 RAE carotenes (86% & 14%, resp), 122 μg selenium (89% & 11%, resp), and 193 mg flavonoids (98% & 2%, resp). Energy‐adjusted antioxidant intakes were higher in women, older adults, Caucasian, alcohol non‐consumers (only for vit E and carotenes), non‐smokers (only for vit C and carotenes), and subjects with higher income level and higher exercise levels (except for flavonoids) than those in their counterparts (p<0.05). Sociodemographic subgroups in the US population differed in antioxidant intake as in chronic disease prevalence. The implicated relation between antioxidant intake and the prevalence of chronic diseases should be investigated further.