bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of age, sex, and location on the diversity of the murine gut microbiome and/or expression of pro-inflammatory cytokines
Authors: Webster Sarah E , Vos Duncan , Rothstein Thomas L , Holodick Nichol E 
Published: January 2023

Abstract
The microbiome and immune system have a unique interplay, which influences homeostasis within the organism. Both the microbiome and immune system play important roles in health and in diseases of the aged. Various groups have demonstrated divergent changes in gut microbiota during aging, but these studies have largely ignored the compounding factor of biological sex in this aging, and little is known about the effect of institutional environment on the composition of gut microbiota in normal healthy mice. To better understand the roles of sex, aging, and environment in influencing the gut microbiome, we obtained normal healthy BALB/cByJ mice from a single source and aged male and female mice in two different geographical locations. A 16s rRNA microbiome analysis indicated that both age and sex play a role in microbiome composition; additionally, location plays a role in the diversity present as well. Interestingly, these microbiome changes occurred with changes in serum expression of several different pro-inflammatory cytokines including IL-10 and IL-6, which were also both differentially regulated in context to sex and aging. B-1a cells are known to produce mucosal IgA as well as IL-10 and IL-6, which play roles in regulating the microbiome. Furthermore, we found both IL-10 and IL-6 play a role in the constitutive expression of pSTAT-3 in B-1a cells. Together these results demonstrate sex and age shape the gut microbiome as well as systemic cytokine expression, which can influence, and be influenced by B-1a cells. In addition, location of housing can also influence the microbiome despite common animal sourcing. These results emphasize the importance of sex, age, and housing location in the mechanism of development of the gut microbiome.
Supported by NIAID of the NIH (R01AI154539)
I3C-MEDIATED PROTECTION AGAINST COLITIS DEPENDENT ON AHR EXPRESSION ON VIL1-EXPRESSING COLONIC EPITHELIAL CELLS
Authors: Saxena Archana , Mitchell Chandani , Wilson Keisha , Rutkovsky Alex , Wisniewski P J , Dopkins Nicholas , Nagarkatti Mitzi , Nagarkatti Prakash , Busbee Brandon 
Published: January 2023

Abstract
Many current treatments for ulcerative colitis (UC) often causes side effects warranting safe therapeutic strategies to control the pathogenesis of colitis. Current study was aimed to ascertain the possible role of aryl hydrocarbon receptor (AhR) in vil1-expressing colonic epithelial cells (CECs) during I3C-mediated protection against colitis. We investigated how intestinal regulatory mediators were altered in the absence or presence of AhR in CECs during I3C treatment under colitis or colitis-like conditions. We generated conditional AhR knockout mice in vil1-expressing CECs using the cre-flox system and induced colitis using the dextran sodium sulfate (DSS) model. Results showed that the mice with AhR deficiency in CECs (AV mice) lost the protective effects of I3C treatment during colitis and had a higher disease score with increased inflammation in the colon compared to the controls. Also, after treatment with I3C during DSS-induced colitis, AV mice were not able to prevent colitis-associated gut microbial dysbiosis even though flow cytometry analysis revealed AV mice were still capable of increasing IL-22 production by ILC3s in the colon. IL-22-ILC3 immune cell response was not the only major mechanism involved in I3C-mediated protection against colitis and regulation of the gut microbiome. Transcriptome analysis of RNA isolated from enriched CECs of experimental mice showed significant altered expression of several microRNAs, mucins (muc3 and muc13), and tight junction proteins in AV mice compared to controls. PCR gene expression data and direct effects of I3C on CECs using colonic organoids validated these results. In summary, AhR expression in CECs play a critical role in I3C-mediated prevention of colitis.
Ingestion of subtoxic doses of cadmium induces persistent dysbiosis and enhances susceptibility to DSS-induced colitis long after exposure
Authors: Kim Eunsoo , Cormet-Boyaka Estelle , Boyaka Prosper N 
Published: January 2023

Abstract
Health officials often focus on intoxication by high doses of heavy metal pollutants. However, most people will more likely be exposed to subtoxic doses via contaminated water or food. We addressed the effects exposure to subtoxic doses of heavy metal pollutants could have on the gut immune homeostasis. We report that chronic ingestion of environmentally relevant subtoxic doses of cadmium does not impair the barrier function of the intestine in mice. On the other hand, chronic exposure to subtoxic doses of this heavy metal stimulates the growth of intestinal epithelial cells including Paneth cells, and increases the production of antimicrobial peptides by Paneth cells. We also found that subtoxic doses of cadmium induce a dysbiosis of the gut microbiota that persist months after the end of the exposure. Importantly, 12–14 months after exposure to cadmium, the cadmium-exposed mice weighed more and had more fat content than age-matched controls mice suggesting that they have developed a state of chronic inflammation. Cadmium is also known to accumulate in soft tissues with a half-life of 10–20 years. Thus, to investigate the long-term effect of exposure to subtoxic doses of cadmium, control and post-menopausal mice (&gt; 15 months old) previously exposed to cadmium were treated with dextran sodium sulfate (DSS) in drinking water. Post-menopausal mice previously exposed to cadmium developed more severe signs of DSS-induced colitis including weight loss, shortened large intestine. Furthermore, they exhibited enhanced Th17 responses in mucosal tissues. Our results provide new insights into the impact of chronic exposure to subtoxic doses of cadmium, and possibly other heavy metals on gut homeostasis and colitis or colon cancer.
Supported by Ohio State University NIH
A Prospectively Created Living Organoid Biobank of Crohn’s Disease Patients Enables Integrative Therapeutics
Authors: Katkar Gajanan Dattatray , Tindle Courtney , Fonseca Ayden , Taheri Sahar , Lee Jasper , Sayed Ibrahim M , Ibeawuchi Stella-Rita , Rama Pranadinata , Fuller Mackenzie , Stec Dominik , Anandachar Mahitha Shree , Goheen-Holland Vanae , Ear Jason , Boland Brigid , Sandborn William , Sahoo Debashis , Das Soumita , Ghosh Pradipta 
Published: January 2023

Abstract
Adult stem cells from various organs can be propagated as epithelial organoids that not only retain their tissue identity, but also their genetic and epigenetic disease-driving traits. We report the establishment of Crohn’s Disease (CD) patient-derived organoid cultures (PDOs) using biopsied tissues from colons of 50 consecutive subjects representing all clinical subtypes (Montreal Classification B1–B3 and perianal disease). Organoids were also generated from healthy subjects. The spectrum of phenotypic and genotypic changes within the “living biobank” agrees well with many observations reported in CD tissues. Gene expression analyses show that despite the heterogeneity of clinical subtypes, there are two major molecular subtypes, each with unique phenotypic features: immune-deficient infectious-CD [IDICD] and senescence-induced fibrostenotic-CD [SIFCD]. CD-PDOs are amenable to high-throughput drug screens allowing for the detection of phenotype reversal. As examples, defective barrier integrity in B1-PDOs was restored with pre-/pro-biotics, impaired microbial clearance in IDICD was reversed using agonists for nuclear receptors, and SIFCD was rectified using senolytics and - morphics. Phenotyped-genotyped CD-PDOs may fill the gap between basic biology and patient trials by enabling pre-clinical Phase ‘0’ human trials for personalized and integrative therapeutics.
A Multi-armed Approach for Identifying Circulating Bacterial Proteins in Melioidosis.
Authors: Hau Derrick , Pflughoeft Kathryn J , Green Heather R , Hannah Emily E , Thorkildson Peter N , Pandit Sujata G , Demers Haley , Magee D Mitchell , Song Lusheng , LaBaer Joshua , Woosley Rebekah , Quilici David R , Mayo Mark , Currie Bart J , Sahl Jason W , Keim Paul S , AuCoin David P 
Published: January 2023

Abstract
The detection of pathogen-associated macromolecules in clinical samples is a powerful alternative to more traditional gold standards of diagnosing infectious diseases. Burkholderia pseudomallei, the causative agents of melioidosis, is a facultative, intracellular bacteria categorized as a Tier 1 Select Agent by the United States Federal Government for its capacity for large-scale dissemination, elevated rates of mortality and morbidity, and minimal medical countermeasures in place. B. pseudomallei is prevalent in tropical regions and is intrinsically resistant to many first-line antibiotics. The current gold standard for diagnosing melioidosis is blood culture, however this method is inadequate and timely. The multifaceted display of clinical presentations of melioidosis further emphasize the need for specific, yet rapid diagnostics. To further characterize viable bacterial targets present during an infection, a multi-armed approach was used to analyze clinical melioidosis samples through direct and indirect platforms. First, the In vivo Microbial Antigen Discovery (InMAD) platform utilized syngeneic CD1 mice to indirectly detected bacterial proteins in clinical samples in conjunction with a high-density nucleic acid protein array (HD-NAPPA). Secondly, patient serology was evaluated on the HD-NAPPA to determine generated antibody response in the host as these proteins may be shed targets from these intracellular pathogens. Third, protein profiling by liquid chromatography with tandem mass spectrometry (LC-MS/MS) would depict proteins in an unbiased proteomic methodology. Converging data from each approach resulted in multiple targets of interest to be evaluated as biomarkers of melioidosis.
NSAIDs-induced oxidative stress sensitizes tumor cells to T cell cytotoxicity through the TRAIL-DR5 axis
Authors: Aboelella Nada S , Zhou Gang 
Published: January 2023

Abstract
Adoptive T cell therapy (ACT) has shown promising therapeutic outcomes in patients with hematological malignancies. However, the success of ACT is limited to a small fraction of treated patients. Hence, developing new strategies to enhance the potency of ACT are urgently needed for better therapeutic outcomes. Our previous study demonstrated that inducing oxidative stress in tumor cells is critically involved in tumor rejection by ACT. In the current study, we report that indomethacin, a prototypical non-steroidal anti-inflammatory drug (NSAID), can intensify ROS in tumor cells and sensitize them to ACT. Mechanistically, our data indicate that indomethacin treatment leads to enhanced expression of death receptor 5 (DR5) in tumor cells, rendering them more susceptible to TNF-related apoptosis-inducing ligand (TRAIL)-induced cell death. We found that tumor-specific T cells upregulated TRAIL expression upon adoptive transfer. Using genetic-based approaches, we showed that DR5-deficient tumor cells were unresponsive to the beneficial effect of indomethacin, while overexpressing TRAIL in donor T cells led to further improvement in mouse survival. Collectively, our study demonstrates that the pro-oxidative feature of selected NSAIDs can be exploited to augment the efficacy of T cell therapy. Our findings provide a strong rationale for targeting tumor redox to achieve more effective tumor destruction through the combination of pro-oxidants and ACT.
Combination therapy for treating drug-resistant multiple myeloma
Authors: Kim Byung-Gyu , Choi Sung Hee , Luo George , Kim Seong-Jin , Malek Ehsan , Driscoll James , Letterio John 
Published: January 2023

Abstract
Proteasome inhibitors (PIs) have remarkably improved the survival of multiple myeloma (MM) patients but dose-limiting toxicities and the development of drug resistance limit their long-term utility. Elevated TGF-β levels in MM patient sera correlate with chemoresistance, disease progression, metastasis and poor prognosis. Therefore, we evaluated the anti-MM therapeutic potential of a TGF-β type I receptor kinase inhibitor, Vactosertib. In vitro treatment of Vactosertib synergistically inhibited the growth of PI-resistant MM cells in combination with the ixazomib by suppressing TGF-β activation of Smad2/3 and expression of PSMB5, which encodes the proteasome 5 catalytic subunit targeted by PIs. Oral administration of Vactosertib as a single agent inhibited MM progression and induced a decrease in mortality and an increase in body weight of the mice bearing MM. Vactosertib alone also attenuated TGF-β activation of Smad2/3, reduced the expansion of CD11b+ Gr-1+ myeloid derived suppressor cells (MDSCs) in bone marrow tumor microenvironment, and diminished the population of Foxp3+ regulatory T cells (Treg) in the spleen. Combination therapy of Vactosertib plus ixazomib was exhibited a synergistic anti-tumor effect when compared to either Vactosertib or ixazomib alone by greatly prolonged survival and significant a reduction in both MDSCs and Tregs. Taken together, our data provide the rationale for clinical evaluation of Vactosertib in MM and demonstrate proof-of-concept that combination of Vactosertib and PIs may overcome chemoresistance and enhance durable patient responses.
Supported by 1R03CA259901-01A1
Lactobacillus rhamnosus GG re-shapes gut microbiota and triggers STING-type I IFN-dependent antitumor immunity
Authors: Wang Liangliang , Liang Hua Laura , Weichselbaum Ralph 
Published: January 2023

Abstract
Lactobacillus rhamnosus GG (LGG) is one of the most well characterized and widely used probiotics. The beneficial roles of LGG in modulating immune response and inflammatory state during cancer development have been well demonstrated. However the true therapeutic importance of its role in current radiotherapies and immunotherapies is still unclear. Using murine models of colorectal cancer and melanoma, we demonstrate that oral administration of live LGG augmented the antitumor activity of antiPD-1 immunotherapy and/or radiotherapy in either germ-free mice or specific pathogen-free mice. Whole genome shotgun metagenome sequencing analyses revealed that the combination treatment shifted the gut microbial community towards enrichment in Bacteroidetes, Actinobacteria, Proteobacteria, and Cyanobacteria. Notably, among the enriched species, Lactobacillus murinus and Bacteroides uniformis are known to increase DC activation and CD8+ T cell tumor recruitment. Immunologically, the synergistic antitumor effect of LGG and anti-PD1 relied on the increased tumor-infiltrating dendritic cells (DCs) and cytotoxic CD8+ T cells. Mechanistically, treatment with live LGG triggered cGAS/STING-dependent type I interferon (IFN) production in DCs, which resulted in enhanced cross-priming of tumor-specific CD8+ T cells. In DCs, LGG induced IFN-β production depended on cGAS/STING/TBK1/IRF7 axis, as further evidenced by the transcriptome sequencing. Overall, our results demonstrate that oral administration of LGG mediates antitumor immunity through activating DCs in a cGAS/STING-type I IFN-dependent manner. The study provides an alternative and effective strategy to advance cancer immunotherapies and radiotherapies.
High glucose drinks improve the anti-tumor efficacy of brain tumor immunity by gut microbiome modulation
Authors: Kim Jaeho , Lee Heung Kyu 
Published: January 2023

Abstract
Over the past decades, consumption of high sugar drinks has been linked to diverse diseases such as obesity, high blood pressure and diabetes. It has been found that most of these high sugar drinks have negative effect on the host including progression of colorectal malignancies. However, there were little literatures about the effect of intake of these high sugar drinks on distant tumors such as glioblastoma (GBM). We observed the GBM survival rate by supplying 20% glucose water in the GL261 mouse syngeneic GBM model and found consumption of high glucose water increased the survival outcomes. Administration of such high glucose water enhances the anti-tumor efficacy of CD8+ T cells in GBM tumor microenvironment. This change induced a synergistic effect with anti PD-1 immune checkpoint inhibitor in GBM mouse syngeneic model. We found that the gut microbiota induced the anti-tumor effect of high glucose water with negative result of germ-free mice experiment. Through 16S rRNA sequencing analysis of fecal samples of mice, administration of high glucose water induced more abundance of Desulfovibrio genus and proved that this strain played a decisive role in improving the survival rate of the GBM mouse model. As a result, we identified that the intake of high sugar drinks could affect the survival rate of GBM through changes in gut microbiome.
Role of RIG-I in tumor endothelium.
Authors: Baris Adrian , Anand Sudarshan , Khou Sokchea 
Published: January 2023

Abstract
The immune microenvironment plays a critical role in the efficacy of cancer treatment. The manipulation of cytosolic nucleic acid sensors has become a strategy to boost the immune response in cancer therapy, but it is critical to understand how these nucleic acid sensors work in the tumor microenvironment. One aspect of the immune microenvironment is the nucleic acid sensor, which recognizes pathogenic nucleic acids and activates an immune response. Retinoic acid-inducible gene I (RIG-I) is an RNA sensor that responds to dsRNA by activating a type I interferon response. It has been found that RIG-I activation can induce an anti-tumor immune response, but its role in the tumor microenvironment is unknown. Prior studies show regulation of the innate immune response in endothelium can increase the anti-tumor response. Understanding the role of RIG-I in endothelial cells, and how this can be used to potentially reprogram the tumor microenvironment, is critical for developing more effective cancer treatments. In addition, my research on the effects of RIG-I in endothelium has wide-reaching implications beyond cancer treatment. I hypothesize RIG-I activation in endothelial cells will produce an anti-tumor immune response. My findings show that endothelial RIG-I activates a robust type I interferon response and inhibits EC function including, inducing apoptosis and inhibiting migration, which is indicative that RIG-I plays a role in the endothelial immune response. RIG-I also plays a role in the expression of the several angiogenic regulators in a tissue-specific manner. This research will provide critical knowledge about the role of RIG-I in tumor angiogenesis, and provide novel treatment avenues for solid tumors.
Supported by grants from NIH (T32) and Knight (CVP-002)
Investigating the role of interleukin-4 in anti-opioid vaccine efficacy
Authors: Crouse Bethany , Hicks Dustin , Pravetoni Marco 
Published: January 2023

Abstract
Vaccination against opioids is a novel therapeutic strategy to combat opioid use disorder (OUD) which can be used alone or in combination with currently available pharmacotherapies. Vaccination with opioid-carrier conjugates stimulates the production of opioid-specific antibodies that sequester the target drug in the serum and prevent distribution into the brain, attenuating the opioid’s pharmacological effects including analgesia, respiratory depression, and it’s reinforcing effects. An anti-oxycodone vaccine has shown promising preclinical efficacy, selectivity, and safety, and is now being tested in a Phase I clinical trial. Clinical trials for conjugate vaccines against cocaine and nicotine have shown that clinical efficacy is met in vaccinated subjects displaying high concentration of high affinity IgG titers. To increase anti-opioid vaccine clinical efficacy, we sought to elucidate their underlying immunobiology and identify predictive biomarkers of vaccine efficacy. Previously, our lab has found that the depletion of the cytokine interleukin-4 (IL-4) during anti-oxycodone immunization increases antibody titers, enhances class-switching from IgG1 to IgG2a, and leads to improved vaccine efficacy after oxycodone challenge in mice. Here, we investigated the association between increased IgG2a and improved vaccine efficacy by directly testing the role of this subclass during immune response after vaccination and during drug challenge. Furthermore, pre-immunization levels of IL-4 are explored as a predictive biomarker of vaccine efficacy in mice. Results from these studies will inform next generation vaccine design and biomarker identification in human clinical trial participants.
Supported by grants from NIH (R01DA041730, T32DA007097, F31DA054760, HHSN272201800048C, U01DA051658)
Polyanhydride based nanovaccine promotes long term humoral and cellular response to PDAC associated protein MUC4β
Authors: Christiansen John C , Liu Luman , Kshirsagar Prakash , Wafa Emad , Gautam Shailendra , Aithal Abhijit , Gulati Mansi , Kumar Sushil , Solheim Joyce , Batra Surinder , Salem Aliasger , Jain Maneesh , Wannemuehler Michael , Narasimhan Balaji 
Published: January 2023

Abstract
Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) have an unrelentingly poor prognosis, in part because of the lack of neoantigen targets associated with PDAC tumors. However, another approach would be to take advantage of differentially expressed antigens on PDAC tumor cells. It has been demonstrated that mucin 4 (MUC4) is overexpressed on the tumor cells of many PDAC patients and is considered a promising antigenic target for PC immunotherapy. Previous work by our lab has demonstrated that poly-anhydride (PA) nanovaccines based on 20:80 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) and 1,6-bis(p-carboxyphenoxy)hexane (CPH) nanoparticles (NPs) both induced a humoral immune response to the beta subunit of MUC4 (MUC4β) and an anti-tumor response against OVA in an EG-7 tumor model. In these studies, we show that both a PA-based nanovaccine formulation and a PLGA-based nanovaccine induced MUC4β-specific T cell response. Results demonstrated that restimulation of LN and splenic lymphocytes 40 days after initial vaccination induced both CD4+ and CD8+ MUC4β-specific T cells. The MUC4ß-specific T cells could be detected for at least 180 days post-vaccination. Cytokine secretions from the antigen specific T cells included IL-2, INFγ, and TNF-α; in addition, tetramer analysis detected MUC4ß-specific CD8+ T cells using the MUCβ peptide FTPVFYSQL. Collectively, these results demonstrate that a PA nanovaccine can function as an effective vaccine platform for induction of MUC4ß-specific cellular immunity, and lays the ground work for forthcoming studies in MUC4β-expressing tumor model systems.
Supported by the National Institute of Health (U01 CA213862) and the Iowa State University Nanovaccine Institute. B. N. is grateful to the Vlasta Klima Balloun Faculty Chair.