bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR-26a as a novel potential therapeutic via inhibit CD38 translation and may overcome datatumumab resistance in multiple myeloma(MM)
Authors: Zhao Jianjun , Hu Yi , Liu Huimin , Fang Chuanfeng , Li Chen , Xhyliu Fjorela , Bodo Juraj , Dysert Hayley , Habermehl Gabriel , Russell Benjamin , Li Wenjun , Chappell Marcia , Jiang Xiaofeng , Ondrejka Sarah , Hsi Eric , Maciejewski Jaroslaw P , Yi Qing , Anderson Kenneth C , Munshi Nikhil C , Ao Geyou , Valent Jason , Lin Jianhong 
Published: January 2023

Abstract
Daratumumab is the first CD38 antibody drug for MM patients therapy. CD38 remains at a low level during daratumumab treatment and shows a sustained high quality response. In daratumumab resistant MM cells, CD38 expression was found either totally restored or at even higher levels. Nevertheless, a strategy to pressure the MM cells to maintain low CD-38 expression may have clinical benefit. miR-26a is usually downregulated in cancer and has been show to have potential clinical use. Here, we investigated miR-26a function in MM and tested single-wall carbon nanotube delivery of miR-26a in vitro and in vivo. GSE16558 dataset analysis showed miR-26a was downregulated in patient MM cells compared with plasma cells from healthy donors. miR-26a overexpression inhibited proliferation, repressed migration, and induced apoptosis in MM cell lines. To identify the targets of miR-26a, RPMI8226-V-miR-26-GFP and RPMI8226-V-GFP cells were cultured using Stable isotope labeling by amino acids in cell culture (SILAC) medium followed by mass spectrometry analysis. CD38 protein was found downregulated in MM cells overexpressing miR-26a and subsequently confirmed to be a direct target of miR-26a by reporter assay and immunoblotting. In addition, when overexpressed, miR-26a had a synergistic effect with bortezomib (BTZ) or melphalan (MEL) treatment. To determine whether the inhibition of MM was due to inhibited CD38, we knocked down CD38 in MM cells and duplicated the MM inhibition observed with exogenous expression of miR-26a, whereas restoration of CD38 overcame the inhibition of miR-26a in MM cells. Furthermore, miR-26a inhibited CD38 expression provoked cell apoptosis and inhibited cell proliferation in human MM xenograft mouse models.
Inhibigens, personal neoantigens that drive suppressive T cell responses, abrogate protection of therapeutic anti-tumor vaccines
Authors: DeVault Victoria L , Starobinets Hanna , Adhikari Sanmit , Singh Simran , Rinaldi Stephanie , Classon Brendan , Flechtner Jessica B. , Lam Hubert 
Published: January 2023

Abstract
Therapeutic cancer vaccine efficacy is reliant on tumor-specific neoantigens. Empirical methods to identify relevant neoantigens may overcome poor predictive values of current in silico approaches. The ATLAS™ platform is a personalized bioassay that uses high-throughput screening of autologous APCs and T cells against a patient’s mutanome to identify neoantigens that are characterized as stimulatory or inhibitory (inhibigens) based on changes in T cell cytokine secretion. In a B16F10 murine model, therapeutic vaccination with ATLAS-identified neoantigens resulted in arrested tumor growth with durable immune responses that protected mice from re-challenge. Mice that were vaccinated with an inhibigen and neoantigen combination had significantly abrogated tumor protection relative to controls. IFNγ ELISpot analysis revealed that inhibigen vaccination suppressed all antigen-specific immune responses, suggesting that inhibigens can be immunodominant. Inhibigen vaccinated mice had multiple tumor microenvironment changes including reduced T cell infiltration, altered CD8+/CD4+ T cell ratios and increased inhibitory marker expression relative to controls. These results indicate that the presence of inhibigens in an otherwise protective vaccine can alter the tumor microenvironment and abolish T cell-mediated protection. Epitope mapping of neoantigens and inhibigens and tetramer design for differential gene signature analysis of inhibigen-specific T cells is being performed. These data suggest that identification and exclusion of inhibigens from cancer vaccines is critical to prevent unintended pro-tumor responses.
Momordica charantia and Cisplatin Treatment Increase the Cytotoxic Effects on Acute Leukemia Cells
Authors: Valenzuela Hector F , Teller Taylor 
Published: January 2023

Abstract
Chemotherapy was designed to target specific proteins by either upregulating or downregulating specific cellular pathways to induce apoptosis and stop cell proliferation of cancerous cells. However, a patient’s cancer cells are known to mutate and potentially develop resistance the cytotoxic mechanisms of these chemotherapy drugs. In addition, high dosages of chemotherapy drugs results in harmful side effects to the patients. As a result, researchers have been searching for ways to reduce drug dosages but maintain chemotherapeutic drugs killing efficiency. Bitter Melon (Momordica charantia) extract is considered a potential anti-cancer agent due to its antitumor and anti-inflammatory properties. The objective of this study is to examine the anti-cancer effects of bitter melon extract (BME) and to show an increased cytotoxicity of acute T-cell leukemia (Jurkat) treated with both cisplatin and BME. The results have shown that BME, when introduced at a 1% concentration, decreased the viability of Jurkat cells by an average of 12% (P-value 0.02). A high dosage treatment of Cisplatin (10μM) and a 1.5% concentration of BME decreased cell viability by 75% percent (P ≤ 0.05) when compared to the control group. At a low dose treatment of cisplatin (5μM), a 1.5% concentration of BME decreased the cell viability by 58.2% (P-value = 0.005). Our results indicate that a combination of these two compounds may help reduce to the need to use high dosages of cisplatin.
Uptake and activation profile of murine dendritic cells in response to stimulation with functionalized iron oxide nanoparticles
Authors: Golshan Aneesa , Hui George 
Published: January 2023

Abstract
Subunit vaccines typically have better safety profiles than live attenuated or killed whole-cell vaccines, but are often less immunogenic and less efficacious when deployed alone. Thus, immunological adjuvants are frequently formulated with subunit vaccines to improve efficacy. However, few vaccine adjuvants are FDA-approved; and for many adjuvants their mechanisms of action are poorly understood. We previously explored the use of iron oxide (IO) nanoparticles (NPs) in subunit vaccine delivery and show that the IO NPs also possess adjuvant-like qualities, eliminating the need for additional adjuvants in the vaccine formulation. This study further dissects the mode of action of IO NPs as immunological adjuvants by examining the relationship of particle size and uptake on the activation profile of murine bone marrow derived dendritic cells (BMDCs) in response to in vitro stimulation with functionalized IO NPs. Using IO NPs of sizes ranging 5 – 30 nm, we showed by flow cytometry immunophenotyping that only IOs of 20nm and 30nm could induce an activated BMDC subset. The level of NP uptake by BMDCs, as measured by Prussian Blue staining, also varied with particle size, with IO of 5nm being the most efficiently internalized. Intriguingly, the levels of BMDC activation did not correlate with the level of IO NP uptake. We hypothesize only IO NPs taken up via selective endocytic pathways will activate BMDCs. The production of cytokine/chemokines by these BMDCs as further characterizations of the adjuvant-like profiles of IO NPs in relation to particle size and cellular uptake is currently being examined. These studies begin to dissect the mode of action of IO NPs as a self-adjuvanted vaccine delivery system on the innate-adaptive immune interface.
Promotion of cross-presenting DC expansion in humanized mice and antigen-specific immunity in murine models of vaccination and cancer by Albumin-Flt3L
Authors: Lam Brandon Krishna , Lin John , Kung Yu Jui , Tan Marietta , Yang Andrew , Wu T.C. , Hung Chien-Fu 
Published: January 2023

Abstract
The ability to engender CD8+ T cell antitumor immunity is indispensable to the success of essentially all cancer treatment strategies. Because tumor (TM) cells do not efficiently process and present immunostimulatory epitopes to CD8+ T cells, cross-presenting dendritic cells (cDC1s) are often required to elicit potent cytotoxic T cell responses. Flt3L is a cytokine known for its ability to expand cDC1s, but is limited therapeutically due to short half-life and global distribution in vivo. To overcome this, we have generated a novel fusion protein of Albumin and Flt3L (Alb-Flt3L), as albumin has a long half-life and selective trafficking to the lymph node (LN) and TM. We demonstrate that Alb-Flt3L potently expands cDC1s in a Batf3-dependent fashion, exhibits long half-life, and accumulates in the LN and TM. Since the phenotype of human and mouse DCs differ, CD34+ stem cell humanized NSG mice were used to assess the immunomodulatory ability of Alb-Flt3L on human DCs. 20-color cytometry and single cell RNA-seq reveals that Alb-Flt3L potently expands human DCs while enhancing a pro-inflammatory transcriptional profile. To gauge the adjuvant ability of Alb-Flt3L, vaccination models using either OVA or HPV16 E7 proteins were performed and revealed that Alb-Flt3L potently enhances antigen-specific T and B cell responses. Finally, in multiple murine models of cancer, Alb-Flt3L + standard-of-care chemoradiation is able to promote tumor control and neoantigen-specific cytotoxic T cells by tetramer staining. The breadth and depth of the TCR repertoire was also investigated using TCRβ chain sequencing. In conclusion, Alb-Flt3L serves as a simple, yet potent strategy to induce DC expansion, antigen-specific immunity and tumor control.
Anti-tumor efficacy and immune responses induced by a novel therapeutic HPV-specific gorilla adenovirus off-the-shelf immunotherapeutic (PRGN-2009)
Authors: Pellom Samuel Troy , Rumfield Claire Smalley , Morillon Yves Maurice , Roller Nicholas , Brough Douglas , Sabzevari Helen , Greiner Jack , Schlom Jeffrey , Jochems Caroline 
Published: January 2023

Abstract
There are about 44,000 cases of Human Papilloma Virus (HPV) associated cancer each year in the US, most commonly caused by HPV 16 and 18. Prophylactic vaccines have been successful at preventing healthy patients from acquiring HPV infections via the induction of HPV specific antibodies. To treat established HPV-associated malignancies, however, the continued development of new therapies is necessary. One promising new modality is HPV immunotherapeutics, which target the HPV 16 and 18 oncoproteins E6 and E7 with the goal to activate antigen specific cytotoxic T cells. Here, we evaluated PRGN-2009, a novel gorilla adenovirus GAd HPV off-the-shelf immunotherapeutic containing multiple CTL agonist epitopes of E6 and E7 to enhance the immune responses. Three weekly administrations with PRGN-2009 in the TC-1 mouse model led to decreases in tumor volume and weight, and significant increases in HPV16 E6-specific splenocytes evaluated by IFNg ELISPOT. PRGN-2009 also increased the tumor-infiltrating CD8 and CD4 T cells, as well as multi-functional (IFNg+, GzmB+) CD8 T cells in the tumor microenvironment (TME). Additionally, PRGN-2009 was tested in SiHa, a human HPV16+ cervical tumor, in the NSG β2m−/− PBMC humanized mouse model. Weekly PRGN-2009 administrations led to a reduction in tumor and a trending increase in CD8 and CD4 T cells in the tumor; IHC confirmed the increase of CD8 T cells into the TME. These studies provide the first evaluation of the GAd HPV off-the-shelf immunotherapeutic PRGN-2009 and its therapeutic impact against HPV-associated cancers.
Activation Induced Cytidine Deaminase and the Evolution of Antigen Receptor Immunogenetics
Authors: Criscitiello Michael F 
Published: January 2023

Abstract
All jawed vertebrates share fundamental components of the adaptive immune system. Cartilaginous fish are the most divergent jawed vertebrate group relative to mammals and use a major histocompatibility complex, B cells, and T cells. RAG mediates the rearrangement of gene segments to create both B and T cell receptors. B cell receptors further undergo diversification after antigen exposure when activated B cells extensively alter their rearranged genes to enhance affinity to antigen. This receptor modification is mediated by the enzyme activation-induced cytidine deaminase (AID). Remarkably, AID also catalyzes receptor modifications in alpha chain of TCR within shark thymus. Thus, the ancestor to modern vertebrates may have used an AID-like enzyme for lymphocyte receptor development, a mechanism lost in later vertebrates because of its potential for breaking down self-tolerance in mature lymphocytes. At the other end of the vertebrate tree, the repertoire of Bos taurus antibodies is characterized by a subset of heavy chains with variable domains VH encoding ultralong complementarity determining region CDR3. These ultralong CDR3 range from forty to over seventy amino acids in length and form a unique beta-ribbon “stalk” and disulfide bonded “knob”. Deep sequence analysis of the B. taurus heavy chain repertoire unveiled ultralong CDR3s were products of rearrangement between the longest VH and DH segments, IGHV1-1 and DH8. Both germline and somatic genetic factors and processes appear to be involved in diversification of this structurally unusual bovine ultralong CDR3 repertoire. These unheralded uses of AID will be discussed in the broader context of immunogenetics evolution.
Interaction between biological sex and early life adversity on gastrointestinal (GI) immune development
Authors: Fardisi Mahsa , Thelen Kyan , Rajput Mrigendra , Moeser Adam J 
Published: January 2023

Abstract
Early postnatal life represents a critical window of GI immune development when lifelong immune function is shaped. Yet, little is known on how early life events impact long-term immune development in animals and people. Based on our previous research, we investigated how biological sex and early weaning (EW) stress interact to shape long-term GI immune development in the pig. Female (F), male intact (MI) and male castrated (MC) piglets (Yorkshire-cross) were weaned at 17 d (EW) or at 26 d of age (Later weaning; LW). At 77 d of age, tissue samples were harvested for RNA-seq, qPCR, and immunoassays. Serum cytokine and ileal mucosal IgG responses were measured following oral and intramuscular vaccination for Lawsonia intracellularis (LI) and PCV2, respectively. Compared with LW pigs, EW MC and MI pigs had reduced body weight gain (P&lt;0.05). The impact of biological sex and EW were observed in vaccine responses. Serum from F showed higher PCV2-specific IgG titers and LI-antibody levels compared with MC and MI pigs. EW F had higher IgG titers in response to vaccination compared with LW F. In contrast, EW MC had suppressed antibody titers compared with LW MC. Pathway analysis of RNA-seq data from ileal mucosa revealed enrichment of genes associated with increased in immune-related pathways (e.g. inflammation) in EW F. In contrast, EW MC exhibited enrichment for genes associated with a down-regulation of immune response (e.g. immune cell migration). Together, these studies showed that biological sex and EW have a major impact on GI immune development in the pig. An understanding of the role and underlying sex-specific mechanisms driving altered immune development in EW pigs could reveal new targets for enhancing early and long-term immune development.
Innate-like CD8 T cells in the teleost olfactory-CNS axis express NK cell markers and mount rapid polyclonal responses to viral antigens
Authors: Salinas Irene , Das Pankoj Kumar , Magadan Susana 
Published: January 2023

Abstract
T lymphocytes can perform innate immune functions and display tissue specificity. Wheres innate T cells have been extensively studied in mammals, little is known about their presence and function in other vertebrates. Previous work in our laboratory identified a subset of TCRalpha beta T cells that rapidly infiltrate the olfactory organ of rainbow trout upon nasal vaccination. This rapid response suggested that these lymphocytes play important functions in mucosal innate immune responses. Here we report that CD8 T cells rapidly infiltrate the olfactory organ of rainbow trout not only in response to nasal viral immunization but also in response to other nasal microbial immunizations including killed and live bacteria. Nasal delivery of PAMPS such as LPS or poly I:C did not elicit these responses. Further phenotyping of these cells using qPCR and FISH staining indicate that these innate lymphocytes are NK T cells since they express the teleost NK cell markers NCCRP1 and NITR2. Repertoire analyses of infiltrating CD8 T cells showed a public but polyclonal response with 14 amino acid long CDR3 in response to the virus. Our findings represent the first characterization of NK T cells in early vertebrates and underscore the importance of NK T cells at defending the mucosal barriers of vertebrate animals.
The Association between Colostral density and immunoglubulin concentrations of Dairy Cattle
Authors: Ha Seungmin , Lee Sangjin , Park Yeiju , Hur Taiyoung , Son Junkyu , Kim Euntae , Kim Donghyeon , Lee Jihwan , Sung Hyunhoon , Kim Myounghoo 
Published: January 2023

Abstract
The colostrum contains diverse and numerous immunoglobulins. The neonatal calf obtains majority of passive immunity from colostrum, which especially has huge effects on calf health. Historically, the amount of immunoglobulins in colostrum has been predicted through the density of the colostrum, but this correlation has not yet been clearly determined. In this study, we determined the correlation between the density and the immunoglobulin concentration, the difference between Holstein and Jersey cattle, and the impact by parity number. Densities were measured with Cruise densimeter. The concentration of immunoglobulins was assayed by ELISA. The concentration of total immunoglobulin G (IgG) and antibody against foot-and-mouth disease virus (FMDV) tend to increase following the density of the colostrum. However, the level of antibody against rota-corona virus was not positively correlated with the density. Regarding species and parity effects, interestingly, Holstein cows had significantly higher values in total IgG and FMDV antibody than Jersey cows. Multiparous dairy cows produced colostrums with higher concentrations of total IgG, FMDV antibody than primiparous dairy cows.
GLYCOSYLATION SITE OCCUPANCY OF THE HEMAGGLUTININ GLOBULAR HEAD IS IMPLICATED IN THE IMMUNE RESPONSE TO INFLUENZA A VIRUS
Authors: Alymova Irina , Cipollo John , An Yanming , Kamal Ram , Contessa Joseph , Gansebom Shane , York Ian 
Published: January 2023

Abstract

Objective
N-linked glycosylation of the hemagglutinin (HA) affects host immune responses to influenza A virus (IAV). This study determines the significance of N-linked glycosylation site occupancy of the HA globular head in the generation of effective antibody responses to IAV in mice.

Methods
We grew A(H3N2)2013 IAV in the presence of an inhibitor of N-linked glycosylation, NGI-1, which reduces glycosylation in mammalian cells by targeting the oligosaccharyltransferase. Mass spectrometry-based analysis of this virus revealed reduction of glycosylation in six out of twelve HA N-linked glycosylation sites, compared to virus grown without the inhibitor. The globular head of HA was affected by NGI-1 treatment. The ability of NGI-1-treated HA to generate immune responses was assessed by immunization of naïve mice with two 10 μg HA doses followed by measurement of serum antibody titers by hemagglutination inhibition and ELISA tests.

Results
Reduced occupancy of N-linked glycosylation sites IAV HA globular head correlated with a significant reduction in cross-strain antibody responses. Serum antibody titers directed toward recombinant HAs from A(H3N2) IAVs of 2003–2013 were from 2 to 4 times lower in mice immunized with HA from NGI-1-treated virus than in the mice immunized with HA from the fully glycosylated virus. Similarly, titers of the antibodies that are correlated with protection against influenza disease, measured by hemagglutination inhibition assays, were significantly lower in mice immunized with NGI-treated virus than those immunized with fully-glycosylated virus.

Conclusion
Glycosylation site occupancy of the HA globular head affects the immune response to IAV.
Expression of chemokines and cytokines in influenza A and B patients have a significant correlation to the levels of serum miRNAs
Authors: Othumpangat Sreekumar , William Lindsley G , Beezhold Donald H , Kashon Michael L , Burrell Carmen N , Mubareka Samira , Noti John D 
Published: January 2023

Abstract
Several host cytokines display differential expression in blood plasma and serum levels during influenza virus infection. Influenza may induce a T helper 2 polarized immune response leading to the activation of cytotoxic CD8+ T cells followed by expression of interleukins (IL). MiRNAs are remarkably stable and are key regulators of mRNA transcripts for proteins. MiRNAs are involved in the regulation of influenza virus replication in many cell types. During the 2015–16 and 2016–17 influenza season, we collected blood samples from patients infected with influenza to identify the role of serum miRNAs and cytokines. In influenza B patients, 76 miRNAs were differentially expressed compared to healthy subjects (p &lt; 0.05), while 26 exosome miRNAs were differentially expressed in influenza A patients (p &lt; 0.05). Of these miRNAs, 11 were expressed in both influenza A and B patients. The miRNAs that were differentially regulated between influenza A and B patients included miRNA-21, miR-191-5p, miR-324-5p and miR-199a-5p. MiR-21 is reported to target IP-10. Multiplex analysis of chemokines and cytokines showed that expression of IP-10 was highest in both A and B patients. In addition, influenza A patients showed increased expression of IFNα-2, GM-CSF, IL-13, IL-17, IL-1β, IL-6 and TNF-α, while influenza B patients showed only increase in IL-1α. MiR-150-5p expression showed a high correlation with MCP-1. MiR-133a-3p potentially targets both IL-17A and IL-1b and IL-15 potentially is targeted by miR-885 and miR-122, indicating that some cytokines were targeted by more than one miRNA. Our study shows that specific circulating miRNAs may be expressed by infected lung cells and that these miRNAs may be involved in the inflammatory responses to influenza.