Despite the systemic impact of both cancer and the associated immune response, immuno-PET is predominantly centered on assessment of the immune milieu within the tumor microenvironment. The aim of this study was to assess the value of [F]F-AraG PET imaging as a noninvasive method for evaluation of system-wide immune status of patients with non-small cell lung cancer before starting immunotherapy. Eleven patients with advanced non-small cell lung cancer were imaged with [F]F-AraG before starting immunotherapy.
View Article and Find Full Text PDFFront Immunol
September 2024
Macrophages play a multifaceted role in maintaining tissue homeostasis, fighting infections, and regulating cold-induced thermogenesis. The brown adipose tissue (BAT) is crucial for maintaining body temperature during cold exposure. Cold stress triggers the sympathetic nervous system to release norepinephrine (NE), which activates BAT via β3-adrenergic receptors, initiating lipolysis and glycolysis.
View Article and Find Full Text PDFPurpose: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, F-labeled 2'-deoxy-2'-F-fluoro-9-β-d-arabinofuranosylguanine ([F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI.
View Article and Find Full Text PDFBrown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue.
View Article and Find Full Text PDFPurpose: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, F-labeled 2'-deoxy-2'-F-fluoro-9-β-d-arabinofuranosylguanine ([F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI.
View Article and Find Full Text PDFDiamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome associated with severe anemia, congenital malformations, and an increased risk of developing cancer. The chromatin-binding special AT-rich sequence-binding protein-1 (SATB1) is downregulated in megakaryocyte/erythroid progenitors (MEPs) in patients and cell models of DBA, leading to a reduction in MEP expansion. Here we demonstrate that SATB1 expression is required for the upregulation of the critical erythroid factors heat shock protein 70 (HSP70) and GATA1 which accompanies MEP differentiation.
View Article and Find Full Text PDFCryogenic electron microscopy (cryo-EM) has emerged as a viable structural tool for molecular therapeutics development against human diseases. However, it remains a challenge to determine structures of proteins that are flexible and smaller than 30 kDa. The 11 kDa KIX domain of CREB-binding protein (CBP), a potential therapeutic target for acute myeloid leukemia and other cancers, is a protein which has defied structure-based inhibitor design.
View Article and Find Full Text PDFThe 90 kDa Ribosomal S6 Kinase (RSK) drives cell proliferation and survival in cancers, although its oncogenic mechanism has not been well characterized. Phosphorylated level of RSK (T573) was increased in acute myeloid leukemia (AML) patients and associated with poor survival. To examine the role of RSK in AML, we analyzed apoptosis and the cell cycle profile following treatment with BI-D1870, a potent inhibitor of RSK.
View Article and Find Full Text PDFAcute myeloid leukemia (AML) is a clinically and genetically heterogenous malignancy of myeloid progenitor cells that affects patients of all ages. Despite decades of research and improvement in overall outcomes, standard therapy remains ineffective for certain subtypes of AML. Current treatment is intensive and leads to a number of secondary effects with varying results by patient population.
View Article and Find Full Text PDFDisruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction.
View Article and Find Full Text PDFDasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR ALL.
View Article and Find Full Text PDFCREB (cAMP Response Element Binding protein) is a transcription factor that is overexpressed in primary acute myeloid leukemia (AML) cells and associated with a decreased event-free survival and increased risk of relapse. We recently reported a small molecule inhibitor of CREB, XX-650-23, which inhibits CREB activity in AML cells. Structure-activity relationship analysis for chemical compounds with structures similar to XX-650-23 led to the identification of the anthelminthic drug niclosamide as a potent anti-leukemic agent that suppresses cell viability of AML cell lines and primary AML cells without a significant decrease in colony forming activity of normal bone marrow cells.
View Article and Find Full Text PDFThe transcription factor CREB (cAMP Response Element Binding Protein) is an important determinant in the growth of Acute Myeloid Leukemia (AML) cells. CREB overexpression increases AML cell growth by driving the expression of key regulators of apoptosis and the cell cycle. Conversely, CREB knockdown inhibits proliferation and survival of AML cells but not normal hematopoietic cells.
View Article and Find Full Text PDFRhoH is a hematopoietic-specific, GTPase-deficient member of the Rho GTPase family that was first identified as a hypermutable gene in human B lineage lymphomas. RhoH remains in a constitutively active state and thus its effects are regulated by expression levels or post-translational modifications. Similar to other small GTPases, intracellular localization of RhoH is dependent upon the conserved "CAAX" box and surrounding sequences within the carboxyl (C) terminus.
View Article and Find Full Text PDFIdentification of new anti-apoptotic genes is important for understanding the molecular mechanisms underlying apoptosis and tumorigenesis. The present study identified a novel anti-apoptotic gene named AREL1, which encodes a HECT (homologous to E6-AP carboxyl terminus) family E3 ubiquitin ligase. AREL1 interacted with and ubiquitinated IAP antagonists such as SMAC, HtrA2, and ARTS.
View Article and Find Full Text PDFWhile most somatic cells undergoing induced pluripotent stem (iPS) cell reprogramming with Yamanaka factors accumulate at stable partially reprogrammed stages, the molecular mechanisms required to achieve full reprogramming are unknown. MicroRNAs (miRNAs) fine-tune mRNA translation and are implicated in reprogramming, but miRNA functional targets critical for complete iPS cell reprogramming remain elusive. We identified methyl-DNA binding domain protein 2 (MBD2) as an epigenetic suppressor, blocking full reprogramming of somatic to iPS cells through direct binding to NANOG promoter elements preventing transcriptional activation.
View Article and Find Full Text PDFWe previously reported that the p53 tumor suppressor protein plays an essential role in the induction of tetraploid G1 arrest in response to perturbation of the actin cytoskeleton, termed actin damage. In this study, we investigated the role of p53, ataxia telangiectasia mutated protein (ATM), and catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in tetraploid G1 arrest induced by actin damage. Treatment with actin- damaging agents including pectenotoxin-2 (PTX-2) increases phosphorylation of Ser-15 and Ser-37 residues of p53, but not Ser-20 residue.
View Article and Find Full Text PDFMolecular mechanisms of how energy metabolism affects embryonic stem cell (ESC) pluripotency remain unclear. AMP-activated protein kinase (AMPK), a key regulator for controlling energy metabolism, is activated in response to ATP-exhausting stress. We investigated whether cellular energy homeostasis is associated with maintenance of self-renewal and pluripotency in mouse ESCs (mESCs) by using 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) as an activator of AMPK.
View Article and Find Full Text PDFWe previously reported that CDK2/Cyclin A can phosphorylate and activate the transcription factor NF-Y. In this study, we investigated a potential regulatory role for NF-Y in the transcription of Cyclin A and other cell cycle regulatory genes. Gel-shift assays demonstrate that NF-Y binds to CCAAT sequences in the Cyclin A promoter, as well as to those in the promoters of cell cycle G2 regulators such as CDC2, Cyclin B and CDC25C.
View Article and Find Full Text PDFRhoH is an hematopoietic-specific, GTPase-deficient Rho GTPase that plays a role in T development. We investigated the mechanisms of RhoH function in TCR signaling. We found that the association between Lck and CD3ζ was impaired in RhoH-deficient T cells, due to defective translocation of both Lck and ZAP-70 to the immunological synapse.
View Article and Find Full Text PDFSilent mating type information regulation 2 homolog 1 (SIRT1) plays a critical role in reactive oxygen species-triggered apoptosis in mouse embryonic stem (mES) cells. Here, we investigated a possible role for the PTEN/Akt/JNK pathway in the SIRT1-mediated apoptosis pathway in mES cells. Akt was activated by removal of anti-oxidant 2-mercaptoethanol in SIRT1(-/-) mES cells.
View Article and Find Full Text PDFSIRT1 is a founding member of a sirtuin family of 7 proteins and histone deacetylases. It is involved in cellular resistance to stress, metabolism, differentiation, aging, and tumor suppression. SIRT1(-/-) mice demonstrate embryonic and postnatal development defects.
View Article and Find Full Text PDFGr1(+)CD11b(+) cells are characterized as myeloid-derived suppressor cells potentially involved in angiogenesis. We demonstrate that Gr1(+)CD11b(+) cells isolated from ischemic muscle in a hind-limb ischemic C57BL/6 mouse model play a role in vessel formation after ischemic injury. Gr1(dim)CD11b(+) cells, a subpopulation of Gr1(+)CD11b(+) cells, within skeletal muscle were increased in context of ischemia.
View Article and Find Full Text PDF