bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole-body immunoPET imaging to monitor immune activation status in situ
Authors: Gibson Heather , Hackett Justin , White Jordan , Mandella Josh , Zeglis Brian , Keinanen Outi , Kalluri Jhansi , Barr Stephen , McCarthy Claire , Wiesend Wendy , Viola Nerissa 
Published: January 2023

Abstract
Advances in immune modulation for cancer and inflammation warrant parallel development of imaging technologies to gauge in situ immune activity. We have developed a toolbox of full-length monoclonal antibody (mAb) positron emission tomography (immunoPET) tracers by desferrioxamine conjugation and 89Zr radiolabeling. Tracer uptake is reported as % injected dose/gram (%ID/g) tissue. Because mAbs to cell surface molecules often facilitate depletion, we tested enzymatic removal of the Fc glycan of CD8 mAb 2.43 to disrupt Fc:FcR interaction and prevent depletion. In the CT26 tumor model, CD8 immunoPET showed similar uptake between WT and deglycosylated tracers. However, unlike WT 2.43, the deglycosylated tracer did not deplete peripheral CD8 T cells, supporting this approach. In addition to surface markers, tracers that define cell function may have great utility. Checkpoint blockade therapy (anti-PD-1/anti-CTLA-4) in CT26-bearing mice shows IFNg immunoPET tracer uptake in 5/5 treated (16.5 ± 3.6 %ID/g) and 2/5 untreated (12.1 ± 4.8 %ID/g) tumors, possibly indicating baseline CT26 immunogenicity. To evaluate antigen presenting cell activation, an IL-12-specific tracer was also developed. Mouse mammary tumor TUBO-bearing mice showed enhanced tracer uptake after intratumoral injection of adenovirus encoding GM-CSF (2.6 ± 0.7 %ID/g) versus controls (0.4 ± 0.4 %ID/g). IL-12 PET was also tested for applications outside of cancer by mimicking inflammation with i.m. LPS injection. LPS-treated mice showed localized, elevated uptake at the site of injection (3.7 ± 0.7 %ID/g) versus controls (0.7 ± 0.1 %ID/g). These results support the use of immunoPET imaging for non-invasive monitoring of immune activity in situ. NIH R37 CA220482.
In silico mouse model of infection and immunity
Authors: Jonas Daniel , Kirby Michael , Schenkel Alan 
Published: January 2023

Abstract
An organism’s immune system tries to protect it by identifying the presence of pathogens and attempting to eliminate them. The defense is twofold: innate immune cells mobilize rapidly, while acquired immune cells slowly develop into pathogen-killing specialists. These responses incur collateral tissue damage, which anti-inflammatory mediators seek to control. This system of checks and balances is responsible for host survival. Experimental research has demonstrated how vastly complex these interactions are, indicating a place for theoretical and computational study. In this work we develop a comprehensive differential equation model of the immune system by considering interactions between immune system components in the presence of pathogen or tissue trauma. Through this step-by-step construction we explore the dependence of the anti-inflammatory mediators on pathogen levels, and also how they temper the immune response at the end of infection. We then challenge the “virtual mouse” with typical pathogens of varying virulence and observe the outcomes via model simulation. We find that anti-inflammation can downregulate the activation and proliferation of immune cells or promote apoptosis as cessation mechanisms, suggesting the need for in vivo experiments. Bifurcation theory describes how the outcomes of infection depend on model parameters, from which we conclude that initial insult and pathogen growth rate allow us to predict whether or not the in silico mouse overcomes the disease in a deterministic framework.
Molecular patterns expressed by a human gut commensal strain of Lactobacillus suppress neuroinflammation
Authors: Sanchez John Michael Sison , Doty Daniel Jason , DePaula-Silva Ana Beatriz , Libbey Jane E. , Fujinami Robert S 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that affects 2.5 million people worldwide. Growing evidence suggests that perturbation of the gut microbiota, a dense collection of microorganisms that colonize the gut, plays a functional role in MS. Utilizing experimental autoimmune encephalomyelitis (EAE), the most commonly used murine model of MS, we previously identified a significant negative correlation between the relative abundance of gut Lactobacillus and the severity of EAE, mirroring what is seen in MS patients. We now report that a human gut-derived commensal strain of Lactobacillus paracasei (Lb) can suppress preclinical murine models of MS with both prophylactic and therapeutic administration. Surprisingly, we found that heat-killed Lb was as effective as live Lb in protecting animals against EAE, as measured by disease score and demyelination. Heat-killed Lb-treated animals had reduced numbers of CNS-infiltrating leukocytes and this was associated with a decrease in select chemokines in the serum. The beneficial effect of heat-killed Lb was dependent on host expression of Toll-like receptor 2 (TLR2), which senses major components of the Lb cell wall, as EAE is not suppressed by heat-killed Lb in TLR2-deficient mice. Thus, Lb-associated molecular patterns may be an important signal to prevent aberrant peripheral immune cell infiltration into the CNS and warrant further investigation as a novel therapy for MS patients.
B Cell derived IL-4 promotes IL-10 secreting TIM-1+ regulatory B cell expansion and regulates Th2 T cell responses
Authors: Zheng Leting , Song Zhixing , Mohib Kanishka , Rothstein David M. 
Published: January 2023

Abstract
TIM-1+ B cells are enriched for IL-10+ B regulatory cells (Bregs). However, TIM-1+ B cells are also enriched for IL-4+ B effector 2 cells (Be2). Tolerogenic α-TIM-1 (RMT1-10) prolongs islet allograft survival (GS) by expanding (IL-10+) Bregs. Interestingly, IL-4KO and IL-4Rα-KO mice are deficient in Bregs and are not responsive to αTIM-1. To establish the importance of IL-4R signaling, and the source of IL-4 for Breg induction, we made tamoxifen (TAM) inducible BALB/c hCD20Cre.ERT2+/− X IL-4Rαfl/fl (B-IL-4RαKO) and hCD20Cre.ERT2+/− X IL-4/13fl/fl mice (B-IL-4KO) to respectively delete IL-4Rα or IL-4/IL-13 in B cells. After TAM, αTIM-1 treatment of alloimmunized B-IL-4RαKO mice had ↓ TIM-1+ B cells (50%), Be2 (50%) and Bregs (40%) vs. IL-4Rαfl/fl littermate controls and a concomittant 33%↑ in IFNγ+ and 33% ↓ in IL-10+ CD4 T cells, and a 20%↑ in IFNγ+ CD8 T cells vs. controls. Finally, α–TIM-1 led to &gt;100d GS in 75% of control mice, but failed to improve GS in B-IL-4RαKO mice (MST 20d, p=0.03). Similarly, TAM treated B-IL-4KO mice had a 3x ↓ in Be2 and Bregs vs. IL-4fl/fl controls, and a 6x drop in IL-4+ CD4 T cells. Importantly, B-IL-4KO mice rejected islets more rapidly (MST 20d) than controls (MST 31d, p=0.04), and α–TIM-1 failed to improve B-IL-4KO GS (MST 17d) vs. controls (MST &gt;100d). In contrast, in Th2 dominant OVA-induced allergic airway disease (AAD), B-IL-4KO mice had 3x decrease in total lymphocyte infiltrate, 5x decrease CD4 T cells and 8x decrease eosinophils in BAL fluid vs. controls. CD4+ T cells from whole lung tissue produced 2x less IL-4 and 3x less IL-5 vs. controls. Hence, IL-4 production by B cells is important for both Breg induction and Th2 polarization and absence of B cell IL-4/IL-13 promotes allograft rejection yet reduces AAD.
Salvia miltiorrhiza inhibits allospecific memory CD8+ T cell generation and allograft rejection in mice
Authors: Dai Zhenhua , Liu Huazhen , Qiu Feifei , Chen Yuchao 
Published: January 2023

Abstract
It’s well known that memory T cells pose a threat to long-term allograft survival. The objective of this study is to suppress generation of donor-specific memory T cells via short-term treatment with a natural and non-cytotoxic herb. Previous studies have demonstrated that Chinese herb Salvia miltiorrhiza (Danshen) regulates immune responses. In this study, B6 mice were transplanted with BALB/c islets and treated with Danshen and/or low doses of rapamycin (0.25 mg/kg/day). To generate allospecific memory T cells, Thy1.1+ CD8+CD44low T cells were sorted by FACSAria and injected into B6 recipients one day before transplantation. Graft-infiltrating T cell proliferation was determined by BrdU staining while the memory cells were enumerated via FACS.
We found that Danshen alone significantly extended islet allograft survival (MST = 28 vs. 13 days, n=9, P&lt;0.05). Interestingly, administration of both Danshen and low doses of rapamycin further prolonged islet allograft survival (MST = 83 versus 28 days), with 44% of recipients achieving long-term islet graft survival (&gt;100 days). Moreover, Danshen suppressed generation of memory CD8+ T cells compared to control two months after transplantation (Thy1.1+CD8+CD44high cell numbers: 1.3±0.2 vs. 2.5±0.3, ×104/LN, P&lt;0.05 and 4.3±0.6 vs. 8.5±0.9, ×105/spleen, P&lt;0.05) while Danshen plus rapamycin further reduced CD8+ memory T cells compared to Danshen alone (0.7±0.1 vs. 1.3±0.2/LN, P&lt;0.05 and 2.6±0.4 vs. 4.3±0.6,/spleen, P&lt;0.05). Finally, Danshen alone inhibited graft-infiltrating T cell proliferation at one week (52±4 vs. 35±3 %, P&lt;0.05). Thus, Danshen inhibited donor-specific memory CD8+ T cell generation and promoted induction of long-term murine allograft survival.
Peroxiredoxin 1 controls β-catenin activity and Epstein-Barr Virus-encoded MicroRNA in Nasopharyngeal Carcinoma
Authors: Noh Minhye , Gong Eun-Yeung , Akinleye Temitope Michael , Rajbongshi Lata , Kim Yeong Seok , Hur Dea Young 
Published: January 2023

Abstract

BACKGROUND
Nasopharyngeal Carcinoma(NPC) is a rare tumor in the world, but high in some countries such as southern China, Mediterranean Africa and Middle East. According to studies, Epstein-Barr virus is affected more aggressive in NPC. In NPC, EBV-miR-BARTs have been demonstrated, especially EBV-miR-BART17 have relation to β-catenin activity but the studies are still unclear. Peroxiredoxin 1 (Prdx1) is an antioxidant enzyme and is highly susceptible to oxidative stress.

METHODS
To study the roles of Prdx1 and EBV-miR-BART17-5p in NPC C666-1 and HK1 cells, it is transfected to siRNA of Prdx1 and then it is measured using RT-PCR for RNA level and western blot for protein level. Colony forming assay and Wound-healing assay were used to detect the cell proliferation in NPC cells.

RESULT
EBV-miR-BART17-5p expression was higher in C666-1 than HK1 cells. The expression of Prdx1 is different between C666-1 and HK1 cells because of EBV genes. EBV-miR-BART17 expression was found to relate to cell proliferation through targeting NF-κB signaling pathway.

CONCLUSION
These data suggested that Prdx1 and EBV-miR-BART17-5p play roles in inducing β-catenin activity in NPC cells. Our findings suggest that the regulating of Prdx1 is an important therapeutic target for NPC.
Nanoparticles as potential therapeutics for acute myeloid leukemia
Authors: Simmet Thomas , Gaiser Ann Kathrin , Schmiech Michael , Syrovets Tatiana 
Published: January 2023

Abstract
Acute myeloid leukemia (AML) is associated with an unfavourable prognosis. Hence, new therapeutic agents with higher specificity and lower general cytotoxicity are urgently required.
We synthesized biocompatible engineered nanoparticles and used various physico-chemical methods for their characterization. Cell viability was assessed by analysis of activities of mitochondrial dehydrogenases and colony-formation assay. Intracellular targets were identified by Western immunoblotting, fluorescent microscopy, flow cytometry, and various functional tests.
We have previously shown that amino-functionalized polystyrene nanoparticles (PS-NH2) induce autophagy in leukemia cells and are selectively cytotoxic to leukemia cells compared to human macrophages and PBMC. We created now biocompatible amino-functionalized nanoparticles with an inert metallic gold core, Au-NH2, which were selectively highly cytotoxic towards different AML cell lines and PBMC from acute myeloid leukemia patients, but not to PBMC from healthy donors. We show that in leukemia cells, Au-NH2 treatment induces BID cleavage to tBID, increases mitochondrial superoxide levels, inhibits activity of complexes I, III, IV of the mitochondrial electron transport chain, and induces loss of the mitochondrial membrane potential as well as cytochrome c release from the mitochondrial intermembrane space and caspase 3 activation. Likewise, Au-NH2 treatment induces a rapid decrease in mTOR pathway activity, induces lysosomal rupture in THP-1 and HL-60 leukemia cells but not so in macrophages and PBMC. Thus, this engineered material holds great promise as a novel nanotherapeutic for treatment of acute myeloid leukemia independent of cytogenetic profile.
The Ikaros1, IKZF1, risk locus for Acute Lymphoblastic Leukemia (ALL) at chromosome 7p12.2 regulates the expression of the FIGNL1 gene
Authors: Laurynenka Viktoryia , Ho Danielle , Huang Yongbo , Parameswaran Sreeja , Kottyan Leah C. , Weirauch Matthew T. , Perentesis John , Kaufman Kenneth M. , Mizukawa Benjamin , Harley John B. 
Published: January 2023

Abstract
ALL, the most common pediatric cancer, originates from progenitor B-cells in ~85% of cases. IKAROS Family Zinc Finger 1 (IKZF1) is an important locus for ALL. Our goal was to identify the functional variants, thereby nominating a potential causal mechanism for ALL.
We evaluated all 27 genetic polymorphisms in disequilibrium at r2&gt;0.8 with the tag, the most highly associated risk variant at IKZF1 locus. They map to intron 7, 3′ UTR and 3′ flanking sequence of IKZF1. Fidgetin-like protein 1 (FIGNL1) is 45,524 bases from the tag variant and is nominated by eQTL and DNA looping data along with IKZF1 as possible targets. Epstein-Barr virus (EBV) transformed GM12878 cells were transduced with lentiviral vectors for stable expression of fusion proteins dead (d) Cas9-VP64 and activator MS2-p65-HSF1 (synergistic activation mediator (SAM) system). We designed 27 single guide (sg) RNAs, one for each of the 27 variants and evaluated expression perturbation in cells transfected with pools and individual sgRNA. Expression of FIGNL1, but not IKZF1, was convincingly altered in this system. The reduction of FIGNL1 expression by ~50% was isolated to two neighboring variants separated by 1 kb. The risk allele at these variants increases FIGNL1 expression in wild type cells, however in EBV transformed B-cells FIGNL1 expression is decreased. Other data show that the EBV encoded DNA binding co-factor EBNA3C binds at or very near this locus in EBV transformed B cells.
Our results nominate two closely located SNPs in the last intron of IKZF1 as potentially causal variants, controlling the expression of FIGNL1, which ordinarily participates in homologous recombination during DNA double-strand break repair, maintenance of genomic stability and prevention of cancer.
B cell transcription factors define a novel tumor suppressor gene network In ALL
Authors: Heltemes Harris Lynn M , Hubbard Gregory , LaRue Rebecca , Munro Sarah A. , Yang Rendong , Henzler Christine , Sarver Aaron , Farrar Michael A 
Published: January 2023

Abstract
The transcription factors EBF1 and PAX5 are frequently mutated in B cell acute lymphoblastic leukemia (B-ALL). We demonstrated that Pax5+/− x Ebf1+/− compound heterozygous mice develop leukemia with high penetrance. Similar results were seen in Pax5+/− x Ikzf1+/− and Ebf1+/− x Ikzf1+/− mice for B-ALL, or in Tcf1+/− x Ikzf1+/− mice for T cell leukemia. To identify genetic defects that cooperate with Pax5 and Ebf1 compound heterozygosity to initiate leukemia, we carried out a Sleeping Beauty transposon screen. This screen identified a number of cooperating partners including gain-of-function mutations in Stat5 (~65%) and Jak1(~68%), as well as loss-of-function mutations in Cblb (61%)and Myb (32%). These findings highlight the key role of JAK/STAT5 signaling in cooperating with Pax5 and Ebf1 compound haploinsufficiency to drive B cell transformation. Moreover, these studies pointed to unexpected roles for loss of function mutations in CBL-b and MYB in B cell transformation. Subsequent RNA-Seq studies on WT, Pax5+/−, Ebf1+/−, Pax5+/− x Ebf1+/− pre-leukemic, Pax5+/− x Ebf1+/− leukemic cells and Pax5+/− x Ebf1+/− Sleeping Beauty leukemic cells demonstrated upregulation of a PDK1&gt;PLK1&gt;MYC pathway; treatment of Pax5+/− x Ebf1+/− leukemias with PDK1 specific inhibitors blocked their proliferation in vitro. Finally, we identified conserved transcriptional variation in a subset of genes between human leukemias and our mouse B-ALL models. Thus, compound haploinsufficiency for B cell transcription factors likely plays a critical role in transformation of human B cells and suggest that newly developed PDK1 inhibitors may be effective for treating patients characterized by such defects.
Multivariate Gene Expression Analysis Identifies Novel Signatures and Therapeutic Targets for CLL Relapse
Authors: Griffen Tiara L , Dammer Eric D , Dill Courtney D , Carey Kaylin M , Young Corey D , Nunez Sha’Kayla K , Lillard James W 
Published: January 2023

Abstract
Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy of immature B cells that is characterized by episodes of relapse. CLL relapse is supported by pro-survival factors, such as chemokines, secreted CLL cells of the CLL microenvironment. The CXCL13-CXCR5 axis has been previously shown to contribute to the progression of several malignancies and possibly CLL relapse. CXCR5 is highly expressed by CLL cells and CXCL13 serum levels were found to be significantly higher in CLL patients versus healthy donors. There is a gap in the understanding of the molecular mechanisms following CXCL13-CXCR5 interactions during CLL. The presence of CXCR5, CXCL13, and associated genes were investigated by using a novel weighted gene co-expression network analysis (WGCNA) method as well as examining overrepresentation of upstream regulators and biological functions found in the transcriptomes (24,658 genes) of CLL patients (n = 203). The WGCNA-designated yellow (p = 0.003), brown (p = 0.05), purple (p &lt; 0.001), black (p = 0.006), and salmon (p = 0.001) modules were significantly correlated with relapse. The fourth-largest, yellow co-expression module contained CXCR5 and 1,315 other genes. The biological processes associated with this module included lipid metabolism, protein catabolism, positive regulation of cell cycle arrest, and cell cycle checkpoint signal transduction. Systems pharmacology analysis revealed drugs targeting ATPases, proteasomes, and microtubules, could disrupt CLL relapse signatures, found in the yellow module. Taken together, the relapse associated gene networks have provided new insights on the complex biology of CLL and identified new targets for the treatment CLL relpase.
The role of the splenic microenvironment in Chronic Lymphocytic Leukemia
Authors: Bondada Subbarao , Collard James P. , McKenna Mary Kathryn , Noothi Sunil K. , Alhakeem Sara S. , Rivas Jacqueline R. , Broeking Shelbi 
Published: January 2023

Abstract
Chronic Lymphocytic Leukemia (CLL), the most prevalent adult leukemia, is characterized by the clonal expansion of CD5+ CD19+ B cells within lymphoid organs and accumulation of quiescent cells in the blood. Eμ-Tcl1 transgenic mice expressing the Tcl1 oncogene in a B cell-specific manner develop CLL and adoptive transfer of CLL cells from these mice induces CLL growth in C57BL/6 mice. These models typically cause splenomegaly as the CLL burden increases, and CLL cells localize mainly in the spleen within the first 10 days post-injection. We hypothesized that the splenic microenvironment is vital for CLL expansion. Accordingly, we found that splenectomy significantly delayed and decreased CD5+ CD19+ CLL cell burden. The role of the splenic microenvironment was further explored by isolating splenic stromal cells from Eμ-Tcl1 mice and establishing stable cell lines (EMST cells). In cell culture, CLL cells divide poorly and remain mostly quiescent. The EMST cells induced proliferation in a majority of mouse and human CLL cells without the addition of any cytokines or growth factors commonly used to accomplish in vitro proliferation of CLL cells. They do not express CD40L, an important stimulatory molecule for B cell proliferation. EMST cells lack conventional immune cell markers, but they express the cytokines and chemokines BAFF, CCL2, CXCL12, and Wnt4. CCL2 levels dramatically increased upon co-culture with CLL. EMST cells also enhance IL-10 secretion by the CLL cells and thus may enhance an immunosuppressive environment to prevent anti-CLL immunity from developing. Our studies support the hypothesis that the spleen is vital for the establishment of CLL and EMST cells produce specific factors that may play a role in CLL growth.
Elucidating nurse-like cell development as a new therapeutic strategy for chronic lymphocytic leukemia
Authors: Reyes Giovanna Merchand , Santhanam Ramasamy , Weigel Christoph , Woyach Jennifer , Tridandapani Susheela , Oakes Christopher , Butchar Jonathan P 
Published: January 2023

Abstract
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, with the NIH estimating 20,720 new cases and 3,930 deaths in 2019. Despite advances in treatment, some patients still relapse (eg. up to 10 to 18% of ibrutinib-treated patients). CLL cells depend on interactions with supportive cells for survival, and nurse-like cells (NLCs) are the major such cell type. However, little is known about how NLCs develop. Thus, our objective is to elucidate NLC development for the purpose of identifying novel therapeutic targets that may aid in the treatment of CLL.
We examined DNA methylation patterns of NLCs and found unusually strong MAPK and AP-1 transcription factor signatures. qPCR showed upregulation of MAF, MAFF and JUN in NLCs, supporting this epigenetics analysis. To test the role of the high MAPK signature we treated NLC cultures with inhibitors of Mek, p38 or Jnk. Results showed that Mek inhibition dramatically reduced NLC development. Of note, we did not detect phosphorylated Erk in CLL cells within treated or control cultures, suggesting that the Mek inhibitor acted directly against the CD14+-derived cells. We then tested Mek inhibition in vivo with the Eμ-TCL1 mouse model of CLL and found that it led to significantly longer survival time and lower white-blood-cell counts.
In conclusion, we found that NLC development is dependent on Mek signaling and that Mek inhibition extends survival in vivo. This suggests that targeting the Mek/Erk pathway may be an effective treatment strategy for CLL.