bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interferon Genes are Influenced by Sex Hormones (17b-estradiol) in SLE
Authors: Singh Ram Pyare , Hahn Bevra H 
Published: January 2023

Abstract
Environmental factors, genetic defects, miRNA dysregulation, and hormonal factors can influence susceptibility to SLE. Estradiol has been shown to increase the expression of interferon genes and pathways and thus could promote susceptibility to the disease in women. Recent evidence suggests the existence of a nexus between inflammatory pathways and 17b-estradiol, resulting in increased interferon stimulated genes (ISGs), autoantibodies and dysregulation of immune cells in SLE. The mechanisms by which 17b-estradiol interacts with IFN and various immune cells in SLE is poorly understood.
Aim is to determine the role of estradiol in the regulation of candidate target genes and miRNAs and mechanisms of regulation of autoantibody production in SLE.
Women may be more susceptible than men to SLE and other autoimmune diseases in part because many healthy women have higher interferon regulated genes. We found that plasma estradiol levels positively correlated with levels of serum/plasma IL-6, and 21/IL-23 in SLE patients. Plasma 17b-estradiol levels are significantly increased in female SLE patients compared to healthy females (p&lt;0.01). Furthermore, we found that estradiol increases proinflammatory cytokines, and level of estradiol positively correlated with expression of miR21, 25, and 186 in SLE patients. Expression of miR21, miR25 and miR186 are positively correlated with SLEDAI score in SLE.
We found that expression of interferon genes is influenced by sex hormones in SLE. Understanding the role of 17b-estradiol in the regulation of pro-inflammatory pathways, ISGs, and microRNAs will further advance our understanding of SLE disease pathology and may identify additional novel therapeutic targets.
Augmentation of the Conversion of 25-hydroxyvitamin D into 1,25-Dihydroxyvitamin D Specifically in Inflamed Intestines for the Treatment of Inflammatory Bowel Disease
Authors: Liu Chenfan , Xu Yi , Cheng Yanmei , Baylink David J. , Abdalla Maisa , Huang Mei , Tang Xiaolei 
Published: January 2023

Abstract
An important pathogenic mechanism of inflammatory bowel disease (IBD) is the penetration of intestinal epithelium barrier by luminal microbes, which does not have a clinical solution. In this respect, previous data have shown that Lgr5+ intestinal stem cells (ISCs) can differentiate into all intestinal epithelial cells and that 1,25(OH)2D, i.e. the active vitamin D metabolite, is essential for the development of Lgr5+ ISCs. However, supplementation of native vitamin D, though effectively raising blood 25(OH)D levels, did not reach the expected outcomes in IBD patients. The data suggest that the conversion of 25(OH)D into 1,25(OH)2D cannot meet the demand in intestines. In addition, our recent findings support that direct systemic delivery of the requied 1,25(OH)2D levels to circumvent the insufficient conversion is impossible because of attending hyercalcemia. Here, we propose to augment such conversion specifically in inflamed intestines using engineered macrophages (MAC-CYP cells) that specifically home into inflamed intestines and overexpress 1alpha-hydroxylase (i.e. the physiological enzyme that converts 25[OH]D into 1,25[OH]2D). We showed that intraperitoneally administered MAC-CYP cells homed specifically into inflamed intestines, significantly suppressed ongoing experimental colitis without causing hypercalcemia, and augmented the migration of Lgr5+ ISCs which differentiated into mature intestinal epithelial cells under physiological and colitis conditions. In vitro, we showed that 1,25(OH)2D enhanced the survival of multipotent Lgr5+ ISCs. In conclusion, our data suggest that specific augmentation of 1alpha-hydroxylase activity in inflamed intestines is a promising therapeutic strategy for IBD.
Endogenous antisense regulates CD39 in Crohn’s disease upon interaction with nucleolin and heterogeneous-nuclear-ribonucleoprotein-A1
Authors: Vuerich Marta , Harshe Rasika , Xie Anyan , Abrahão-Frank Luiza , Gromova Barbora , Zhang Haohai , Mukherjee Samiran , Robles Rene’ J. , Moss Alan C. , Robson Simon C. , Longhi Maria Serena 
Published: January 2023

Abstract
The ectoenzyme CD39 hydrolyzes ATP to generate immunosuppressive adenosine. We have shown that CD39 levels and activity are reduced in Treg and Th17-cells from Crohn’s patients. This impairment is linked to heightened levels of endogenous antisense (AS) present at the 3′ end of the human CD39 gene and regulating CD39 at mRNA and protein level.
Here we note that CD39-specific AS is predominantly located in the nucleus of peripheral blood-derived Treg and Th17-cells of healthy subjects (HS) and Crohn’s disease patients. RNA pulldown assay followed by mass spectrometry shows that AS regulates CD39 upon interaction with nucleolin (NUCL) and heterogenous-nuclear-ribonucleoprotein-A1 (HNRNPA1). Silencing of NUCL and/or HNRNPA1 results in higher CD39 levels in both Treg and Th17-cells. Blockade of antisense in vitro using FANA oligonucleotides decreases AS while boosting CD39 in HS and Crohn’s Treg and Th17-cells. AS silencing in vivo ameliorates experimental colitis induced by trinitrobenzene-sulfonic-acid in NOD/scid/gamma mice reconstituted with antisense+ human CD4-cells and concomitantly administered FANA oligonucleotides. Compared to untreated controls, FANA-treated mice show decreased disease activity index, higher colon length, lower histology score and, phenotypically, increased proportions of circulating CD39+CD4+-cells and decreased frequencies of peripheral blood and splenic CD4+IL-17+-cells.
In conclusion, CD39-specific AS dampens CD39 levels in Crohn’s Treg and Th17-cells by interacting with NUCL and HNRNPA1. Inhibition of AS controls disease activity in experimental colitis suggesting that AS blockade might serve as a novel therapeutic tool to restore CD39 and curb inflammation in Crohn’s disease.
Mesenchymal stem cells derived exosomes promote the expansion of Bregs and alleviate the collagen-induced arthritis
Authors: Tian Jie , Zhu Qiugang , Rui Ke , Lu Liwei , Wang Shengjun 
Published: January 2023

Abstract
Olfactory ecto-mesenchymal stem cells (OE-MSCs) are a population of cells which has been recognized as a novel resident stem cell type in the olfactory lamina propria. OE-MSCs have been shown to exert their immunosuppressive capacity by modulating T cell responses. However, it remains unclear whether OE-MSCs possess any immunoregulatory functions on regulatory B cells (Bregs). Exosomes are secreted nanosized membrane vesicles that are increasingly implicated as an important communication tool among various cell types. In this study, exosomes derived from olfactory ecto-mesenchymal stem cells (OE-MSCs-Exo) effectively enhanced the proportions of CD19+IL-10+ Bregs in the spleen and draining lymph nodes, thus suppressing the development of collagen-induced arthritis (CIA). In culture, OE-MSCs-Exo could significantly promote the differentiation and expansion of CD19+IL-10+ Bregs, and the further investigation demonstrated that the expansion of Bregs was orchestrated by Ebi3 secreted by exosomes. Taken together, OE-MSCs-Exo have the potential to alleviate the severity of CIA through inducing Bregs, indicating OE-MSCs-Exo may represent a new therapeutic strategy for the treatment of rheumatoid arthritis.
Peptide fragments of cystatin protein from filarial parasite has potent anti-inflammatory effect on DSS-induced colitis in mouse
Authors: Khatri Vishal , Chauhan Nikhil , Prasanna Kumar S B , Kalyanasundaram Ramaswamy 
Published: January 2023

Abstract
The therapeutic potential of filarial parasite derived recombinant cystatin was reported previously by our group in the mouse model of colitis. We showed that cystatin-treatment elevated IL-10+FoxP3+Tregs, IgM+B1a cells and AAMs in the colon and peritoneal cavity. In this study, we attempted to identify the therapeutically active peptide(s) of cystatin. Total length of cystatin is 157 aa. We first synthesized three 40-mer peptides of cystatin. 25μg of peptide 1, 2 or 3 was injected i.p. into groups of 10 mice each on days 3–6 following DSS-administration. Control mice received DMSO only. Mice that received whole cystatin protein remained as positive control. Following treatment, clinical and pathological disease parameters were determined. Our results show that treatment with peptide 1 and 2 significantly ameliorated the inflammatory responses in the colitis mice and significantly reversed the gross and histopathological changes in the colon. However, peptide 3 had no effect in alleviating the colitis symptoms. Analysis of the colon tissue showed that the myeloperoxidase activity was significantly (p&lt;0.005) decreased following peptide 1 and 2 treatment. The frequencies of F4/80+TLR-4+CD11c+ peritoneal macrophages were significantly decreased in colitis mice. There was also reduced infiltration of LY6G+ cells and MPO+ cells and increased FoxP3+Tregs counts in the colon tissue of these animals compared to the controls. These attenuative effects of both peptide 1 and 2 in colitis was comparable to the whole cystatin protein treatment. These studies thus demonstrate that peptide 1 and peptide 2 of the parasite cystatin can be potentially developed as a peptide therapy for colitis. Study supported by Blazer Foundation of Rockford.
Effect of Curcumin on pro-inflammatory cytokines in primary Sjögren’s Syndrome
Authors: Jayakanthan Kabeerdoss , Sandhya Pulukkol , Mohan Hindhumathi , Danda Debashish 
Published: January 2023

Abstract

Introduction
Curcumin reduces disease severity and ameliorates lupus-like/ Sjögren’s Syndrome-like disease in mice model. The immunological basis of these effects is unknown. This study examined the effect of curcumin on pro-inflammatory cytokines secreted by salivary gland in patients with primary Sjögren’s syndrome (pSS).

Methods
Minor salivary gland (MSG) tissue was collected from patients undergoing biopsy for suspected pSS. The tissues were treated with phytohemagglutinin (PHA) alone as well as PHA with curcumin (30μM) and cultured in RPMI 1640 medium for 48 hours at 37°C in CO2 incubator. After the incubation period, culture supernatant and tissue were stored in the freezer (−80 °C). IL-6 levels were measured in supernatant by ELISA kits. Expression of pro-inflammatory cytokines, IL-6, IL-8, TNF-α, IL-1β, IL-4, IL10, IL-17 IL-21, and IFN-γ was done by qPCR. Differences between groups were tested by Student’s t-test.

Results
Forty seven patients were recruited. Eight patients satisfied ACR/EULAR criteria for pSS. Seven patients with absent glandular inflammation and negative serologies constituted sicca controls. In pSS group, but not in controls, median IL-6 levels in supernatant was less in curcumin treated as compared to PHA alone [5.5 (0.7 – 1.3) vs 18.3 (12–32) ng/ml;p=0.04]. mRNA expression levels of IL-6 and IL-1β were lower in curcumin treated groups as compared to PHA alone in both cases and controls (p= 0.0009 & p=0.04 respectively). There was no difference in other cytokine levels between the treatment groups.

Conclusion
Curcumin reduces secretion of IL-6 levels in salivary gland tissue of patients with pSS. Curcumin suppressed PHA induced mRNA expression levels of IL-6 and IL-1β in MSG tissue of pSS and controls.
Improving Hematopoietic Stem Cell transplantation with Flonase for potential use in treating a novel mouse model of Idiopathic Thrombocytopenic Purpura
Authors: Varady Erika , Inlay Matthew 
Published: January 2023

Abstract
Idiopathic Thrombocytopenic Purpura (ITP) is a rare autoimmune disease which causes the destruction of platelets. Patients who suffer from ITP can have excessive bleeding due to a lack of platelet coagulation. Current therapies for ITP include steroid, and intravenous immunoglobulin treatment, however they do not guarantee lasting remission. Spleen removal is the only therapy that can lead to lasting remission but is very invasive and damaging to the patients. The purpose of this study is to find a more effective and permanent therapy to treat ITP, such as through bone marrow transplantation (BMT), in a novel mouse model of ITP. BMT can be a risky procedure, so we sought to first improve it by upregulating the important chemotactic receptor, CXCR4, on the surface of hematopoietic stem cells (HSCs). We can increase surface CXCR4 on HSCs by treatment with the glucocorticoid drug fluticasone propionate (Flonase), which increases migration towards the chemokine SDF-1. Our data indicate that after Flonase treatment, HSCs significantly increase bone marrow engraftment in mouse competitive transplantations. Second, we have created an inducible ITP mouse model using CRISPR technology to test BMT as a possible therapy for ITP. Our mouse model expresses foreign antigens ovalbumin and hen egg lysozyme on platelets to elicit an immune response and platelet destruction. A novel ITP mouse model can be useful for testing potentially more permanent therapies for ITP.
Anaplastic lymphoma kinase fusions as a target for TCR-directed cellular therapies
Authors: Heather James M , Spindler Matthew J , Cobbold Mark , Gainor Justin F , Johnson David S , Hata Aaron N 
Published: January 2023

Abstract
Chromosomal rearrangement derived gene fusions with the catalytic domain of anaplastic lymphoma kinase (ALK) drive oncogenesis in several cancers, including in ~5% of non-small-cell lung cancers (NSCLCs). While ALK tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of these patients the majority will develop resistance; novel treatments are required. We hypothesize that the ALK kinase domain may be a suitable target for directed immunotherapy. Full length ALK is normally expressed during fetal development but becomes highly restricted in adults, and anti-ALK immune responses are readily detected in other ALK-fusion+ cancers, correlating with good prognosis.
Using peptide pool expansions and T cell activation assays, we have detected numerous anti-ALK T cell responses from normal donors and ALK+ NSCLC patients. These donors express a variety of HLA alleles, and some donors display reactivity to multiple pools spanning the kinase domain, suggestive of common T cell responses to multiple ALK epitopes.
Leveraging a high-throughput microfluidic technique to clone and functionally express natively-paired T cell receptor (TCR) genes from these ALK-reactive T cell populations, we are screening for both the exact antigenic peptides and the HLA restrictions of these epitopes. TCRs thus isolated will then be tested against a panel of ALK+/− patient derived and cancer cell lines using in vitro and in vivo models, to assess potential utility in cytotoxic TCR-directed immunotherapies. These patient derived models include those with acquired TKI resistance: by comparing these mutational hotspots with putative epitope sites we expect to find TCRs capable of killing ALK+ cancer cells irrespective of prior treatment.
Unbiased analysis of all possible neoepitopes of MC38-FABF tumor reveals a new universe of cancer neoepitopes with unexpected properties
Authors: George Mariam M , Brennick Cory A , Moussa Marmar M , Hagymasi Adam T , Seesi Sahar Al , Shcheglova Tatiana V , Englander Ryan P , Keller Grant L.J , Balsbaugh Jeremy L , Baker Brian M , Mandoiu Ion I. , Srivastava Pramod K 
Published: January 2023

Abstract
Cancer neoepitopes are the only truly tumor-specific antigens and therefore, the most suitable as cancer vaccines. Current methods to predict neoepitopes, based on studies of viral epitopes, emphasize high affinity MHC-peptide interactions. Increasing evidence in human and murine models indicates that the present neoepitope prediction methods are mostly inaccurate in predicting true MHC I-restricted cancer neoepitopes. Here, in a completely unbiased approach, all possible neoepitopes in a mouse tumor model were tested for their ability to mediate tumor rejection and also CD8+ T cell responses. These studies show that the true tumor rejecting neoepitopes have different properties from those of viral epitopes. Further, CD8+ T cell responses elicited by these neoepitopes possess a more plastic chromatin phenotype with stem-like properties that is known to be associated with anti-viral and anti-tumor immune responses. Such cancer neoepitopes can be exploited for generation of personalized cancer vaccines.
Establishment and Preclinical Therapy of Patient-derived Hepatocellular Carcinoma Xenograft Model
Authors: wu yuwei , Tian Zhigang , Sun Rui 
Published: January 2023

Abstract
Hepatocellular carcinoma (HCC) is a world-wide health problem. Poor and delayed diagnoses as well as high recurrence rate resulting in high mortality rate. In this study, we established a patient-derived xenograft (PDX) model from HCC patients, and continuously maintained with subcutaneous passage more than 20 times. This HCC PDX tumor exhibited the same histological characteristics with the HCC patient and could be used to verify therapeutic effect of liver cancer. We further evaluated this PDX model by experimental chemotherapy, demonstrating that this HCC PDX model was sensitive to sorafenib treatment. Further, the potential of natural killer cell-based immunotherapy for HCC was tested using this model. We found that NK92 cells effectively suppressed the tumor growth in vivo and prolonged the survival time of HCC-bearing PDX mice. This study indicates that HCC PDX model is a good platform to testify the efficacy of preclinical chemotherapy and immunotherapy.
Unraveling tumor-specific iNKT cell plasticity
Authors: Cortesi Filippo , Konczalla Leonie , Sturmheit Tabea M , Siracusa Francesco , Gagliani Nicola 
Published: January 2023

Abstract
Despite the overall success of T-cell based immunotherapies, the number of patients that benefit is still lower than expected. Invariant Natural Killer T cells (iNKTs) offer an alternative and appealing therapeutic platform owing to their intrinsic features and independence from MHC restriction. In two mouse models, mirroring prostate or colon cancer, iNKTs play strikingly opposite roles, either promoting a TH1-skewed anti-tumor response, or fostering tumor progression with TR1-oriented status. The tepid results of iNKT cell-based therapies could reflect a thus far unappreciated plastic conversion of inflammatory iNKTs into regulatory NKT10 within the tumor’s microenvironment.
This study aims to elucidate the occurrence and the dynamics of the inflammatory-to-regulatory iNKT cell plasticity in solid tumors, to clarify the environmental cues triggering their conversion and the molecular mechanisms that govern it. By employing innovative multi-cytokine reporter and fate mapping mice, we reliably detected iNKTs actively switching from producing IFNγ (exNKT1) to producing IL10, in the context of colon polyposis. Further analyses aim to unravel the molecular mechanisms of iNKT cell plasticity and to investigate the contribution of the tumor-specific microbial component.
The currently incomplete understanding of iNKT cell plasticity is dampening the appropriate use of these powerful cells in therapeutic settings. As such, clinical protocols employing iNKTs for treating cancer have so far achieved only modest results. By addressing the molecular mechanisms underlying NKT10 conversion, we are likely to find pathways that can be targeted to fully unleash the anti-tumor power of these innate-like T cells in immunotherapy.
A New Cellular Cancer Immunotherapy Platform Technology Using Autologous Human Adipose-Derived Mast Cells
Authors: Fereydouni Mohammad , Motaghed Mona , Ahani Elnaz , Moorman Whitney , Lee Sung Hyun , Kafri Tal , Kepley Christopher L. 
Published: January 2023

Abstract

Background
Autologous immune cell-based therapies to re-activate the immune system have been developed to treat patients with cancer. For example, chimeric antigen receptor T cell (CAR T) therapy is an FDA approved strategy that uses autologous T cells as a cancer treatment. Mast cells (MC) are important immune sentinels and widely recognized for their role as mediators of Type I hypersensitivity. However, they also secrete anti-cancer mediators such as tumor necrosis factor alpha (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF) which are being investigated in clinical trials for cancer treatment.

Methods
We generated adipose-derived mast cells (ADMC) and sensitized with anti-CD20 IgE antibodies and challenged with B-lymphoma cells. In addition, immunocompromised mice were examined for the maximal tolerated dose using ADMC. The ability of the ADMC to be transduced with lentiviral vectors carrying green fluorescence protein was examined.

Results
It is shown that CD20 IgE-sensitized ADMC bind to and are activated by CD20 positive B-lymphoma cells. The ADMC injected into mice do not display signs of anaphylaxis by the systemic injection of up to 1 × 106 ADMC/mouse. It is also shown for the first time that ADMC and their adipose-derived stem cell precursors can be transduced with a lentiviral vector carrying green fluorescence protein without affecting function.

Conclusion
This discovery indicates the ADMC could be transduced with other tumor killing molecules to create a “super killing” cell with potent and diverse anti-tumor activity. Using tumor targeting IgE’s, autologous ADMC could be used as a “Trojan Horse” to deliver these anti-tumor mediators to tumors and serve as a new cancer immunotherapy platform.
The importance of CD4+ Tumor-Infiltrating Lymphocytes (TIL) in Adoptive Cell Transfer
Authors: Hall MacLean , Joerger Autumn , Scott Ellen , Schachner Ben , Weber Amy M. , Nagle Luz , Blauvelt Jamie , Smeltzer Shayna , Morse Jennifer , Kidd M. Scott , Wiener Doris , Richards Allison , Rich Carolyn Jeani , Kodumudi Krithika , Beatty Matthew S. , Sarnaik Amod A. , Pilon-Thomas Shari 
Published: January 2023

Abstract
Immunotherapy, including adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TIL) predominantly targets improvement in MHC Class I-mediated anti-tumor immune responses. The primary objective of this study is to better understand the role of CD4+ TIL in ACT as a complementary avenue for therapeutic efficacy. Briefly, CD4+ TIL were isolated by negative selection from metastatic melanoma patients who received TIL therapy at Moffitt Cancer Center on IRB approved protocols. Individual T cell clones were tracked by TCRbeta sequencing to quantify clonal persistence in patients. CD4+ TIL clones were found to be decidedly persistent in a candidate patient who achieved a complete response (CR) after infusion of 88% CD4+ T cells. CD4+ TIL from additional patients were stimulated with anti-CD3/CD28 in vitro and those who were clinical responders demonstrated a pleiotropic cytokine profile marked by an elevated ratio of Th1:Th2 cytokines (p=0.07, n=13). When cultured with APCs loaded with autologous tumor (AT), CD4+ TIL produced high levels of IFN-gamma in an MHC Class II-dependent manner. Induction of MHC Class II on melanoma cell lines and AT determined that CD4+ TIL secreted IFNg and TNFa directly in response to AT. ACT of tumor-reactive CD4+ TIL in immunodeficient (NSG) mice provided significant control of AT growth when compared to non-reactive CD4+ TIL. Preliminary data in syngeneic mouse models also suggests that antigen-specific CD4+ T cells aid in initial tumor rejection, memory formation and epitope spreading, resulting in an overall increased therapeutic efficacy during ACT. This data supports the conclusion that CD4+ TIL are tumor-reactive and instrumental to an effective anti-tumor immune response in cancer patients.