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1
Hò, Gia-Gia T., Wiebke Hiemisch, Andreas Pich, Georg M. N. Behrens, Rainer Blasczyk, and Christina Bade-Doeding. "The Loss of HLA-F/KIR3DS1 Ligation Is Mediated by Hemoglobin Peptides." International Journal of Molecular Sciences 21, no. 21 (October 28, 2020): 8012. http://dx.doi.org/10.3390/ijms21218012.
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The human leukocyte antigen (HLA)-Ib molecule, HLA-F, is known as a CD4+ T-cell protein and mediator of HIV progression. While HLA-Ia molecules do not have the chance to select and present viral peptides for immune recognition due to protein downregulation, HLA-F is upregulated. Post HIV infection, HLA-F loses the affinity to its activating receptor KIR3DS1 on NK cells leading to progression of the HIV infection. Several studies aimed to solve the question of the biophysical interface between HLA ligands and their cognate receptors. It became clear that even an invariant HLA molecule can be structurally modified by the variability of the bound peptide. We recently discovered the ability of HLA-F to select and present peptides and the HLA-F allele-specific peptide selection from the proteomic content using soluble HLA (sHLA) technology and a sophisticated MS method. We established recombinant K562 cells that express membrane-bound HLA-F*01:01, 01:03 or 01:04 complexes. While a recombinant soluble form of KIR3DS1 did not bind to the peptide-HLA-F complexes, acid elution of the peptides resulted in the presentation of HLA-F open conformers, and the binding of the soluble KIR3DS1 receptor increased. We used CD4+/HIV− and CD4+/HIV+ cells and performed an MS proteome analysis. We could detect hemoglobin as significantly upregulated in CD4+ T-cells post HIV infection. The expression of cellular hemoglobin in nonerythroid cells has been described, yet HLA-Ib presentation of hemoglobin-derived peptides is novel. Peptide sequence analysis from HLA-F allelic variants featured hemoglobin peptides as dominant and shared. The reciprocal experiment of binding hemoglobin peptide fractions to the HLA-F open conformers resulted in significantly diminished receptor recognition. These results underpin the molecular involvement of HLA-F and its designated peptide ligand in HIV immune escape.
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Hò, Gia-Gia T., Funmilola J. Heinen, Rainer Blasczyk, Andreas Pich, and Christina Bade-Doeding. "HLA-F Allele-Specific Peptide Restriction Represents an Exceptional Proteomic Footprint." International Journal of Molecular Sciences 20, no. 22 (November 8, 2019): 5572. http://dx.doi.org/10.3390/ijms20225572.
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Peptide-dependent engagement between human leucocyte antigens class I (HLA-I) molecules and their cognate receptors has been extensively analyzed. HLA-F belongs to the non-classical HLA-Ib molecules with marginal polymorphic nature and tissue restricted distribution. The three common allelic variants HLA-F*01:01/01:03/01:04 are distinguished by polymorphism outside the peptide binding pockets (residue 50, α1 or residue 251, α3) and are therefore not considered relevant for attention. However, peptide selection and presentation undergoes a most elaborated extraction from the whole available proteome. It is known that HLA-F confers a beneficial effect on disease outcome during HIV-1 infections. The interaction with the NK cell receptor initiates an antiviral downstream immune response and lead to delayed disease progression. During the time of HIV infection, HLA-F expression is upregulated, while its interaction with KIR3DS1 is diminished. The non-polymorphic nature of HLA-F facilitates the conclusion that understanding HLA-F peptide selection and presentation is essential to a comprehensive understanding of this dynamic immune response. Utilizing soluble HLA technology we recovered stable pHLA-F*01:01, 01:03 and 01:04 complexes from K562 cells and analyzed the peptides presented. Utilizing a sophisticated LC-MS-method, we analyzed the complete K562 proteome and matched the peptides presented by the respective HLA-F subtypes with detected proteins. All peptides featured a length of 8 to 24 amino acids and are not N-terminally anchored; the C-terminus is preferably anchored by Lys. To comprehend the alteration of the pHLA-F surface we structurally compared HLA-F variants bound to selected peptides. The peptides were selected from the same cellular content; however, no overlap between the proteomic source of F*01:01, 01:03 or 01:04 selected peptides could be observed. Recognizing the balance between HLA-F expression, HLA-F polymorphism and peptide selection will support to understand the role of HLA-F in viral pathogenesis.
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Bernhard, Oliver K., Joey Lai, John Wilkinson, Margaret M. Sheil, and Anthony L. Cunningham. "Proteomic Analysis of DC-SIGN on Dendritic Cells Detects Tetramers Required for Ligand Binding but No Association with CD4." Journal of Biological Chemistry 279, no. 50 (September 22, 2004): 51828–35. http://dx.doi.org/10.1074/jbc.m402741200.
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DC-SIGN (dendriticcellspecificintracellular adhesion molecule 3grabbingnon-integrin) or CD209 is a type II transmembrane protein and one of several C-type lectin receptors expressed by dendritic cell subsets, which bind to high mannose glycoproteins promoting their endocytosis and potential degradation. DC-SIGN also mediates attachment of HIV to dendritic cells and binding to this receptor can subsequently lead to endocytosis or enhancement of CD4/CCR5-dependent infection. The latter was proposed to be facilitated by an interaction between DC-SIGN and CD4. Endocytosis of HIV virions does not necessarily lead to their complete degradation. A proportion of the virions remain infective and can be later presented to T cells mediating their infectionin trans. Previously, the extracellular domain of recombinant DC-SIGN has been shown to assemble as tetramers and in the current study we use a short range covalent cross-linker and show that DC-SIGN exists as tetramers on the surface of immature monocyte-derived dendritic cells. There was no evidence of direct binding between DC-SIGN and CD4 either by cross-linking or by fluorescence resonance energy transfer measurements suggesting that there is no constitutive association of the majority of these proteins in the membrane. Importantly we also show that the tetrameric complexes, in contrast to DC-SIGN monomers, bind with high affinity to high mannose glycoproteins such as mannan or HIV gp120 suggesting that such an assembly is required for high affinity binding of glycoproteins to DC-SIGN, providing the first direct evidence that DC-SIGN tetramers are essential for high affinity interactions with pathogens like HIV.
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Bram Ednersson, Susanne, Mimmie Stern, Henrik Fagman, Gunilla Enblad, Ulf-Henrik Mellqvist, Herman Nilsson-Ehle, Sverker Hasselblom, and Per-Ola Andersson. "Quantitative Proteomics in Diffuse Large B-Cell Lymphoma Patients Reveal Novel Overexpressed Proteins and Potentially Druggable Targets in the ABC Subtype." Blood 134, Supplement_1 (November 13, 2019): 3967. http://dx.doi.org/10.1182/blood-2019-126387.
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Background: The cell-of-origin (COO) concept, based on gene expression profiling (GEP), dividing diffuse large B-cell lymphoma (DLBCL) patients into germinal center B cell (GCB) or activated B cell (ABC) subtypes, is a well-established subclassification where ABC patients have an inferior survival. The hallmark the ABC-type is constitutive activation of nuclear factor kappa B (NF-κB), often due to mutations in the B-cell receptor (BCR) signaling pathway. This has been the underlying rationale for adding newer drugs, such as bortezomib, ibrutinib or lenalidomide, to R-CHOP for ABC patients. However, none of these combinations studied in phase III trials have shown any clinical benefit. So, the complexity of ABC DLBCL is probably not only explained by genetic alterations and transcriptional changes as gene expression not necessarily correlate with protein expression, and protein action and dynamics are not caught by genomics-based techniques. Instead, using methods to measure global protein expression and interactions could offer new insights into the ABC subtype and possibly aid in the identification of novel drug targets. Aim: To study possible differences in global protein expression between ABC and GCB DLBCL subtypes using quantitative proteomics. Patients: A total of 213 adult DLBCL patients in western Sweden diagnosed between 1/1 2004 and 31/12 2016, were included. All patients received immunochemotherapy (R-CHOP). Primary mediastinal large B-cell lymphoma, primary CNS lymphoma, HIV-related lymphoma and transformed lymphoma were excluded. From archived formalin-fixed, paraffin-embedded (FFPE) tissue sections, from the time of diagnosis, a core biopsy (1 mm diameter) were obtained from each patient sample. Methods: COO was determined using the Hans immunohistochemistry algorithm. For 92 of the 213 patients, COO was also determined using the gene expression Lymph2cx chip: 14% changed subtype group from either non-GCB to GCB (n=8), GCB to ABC (n=4) or GCB to unclassified (n=1). From the FFPE samples a proteomic analysis was performed. In short, peptides were labelled using tandem mass tag (TMT) according to the manufacturer instructions and samples were analysed on an Orbitrap Fusion Tribrid mass spectrometer. The data files were merged for identification and relative quantification using Proteome Discoverer version 1.4.The search used the Human Swissprot Database version August 2016 using Mascot 2.3 as a search engine. The differentially expressed proteins were analysed using STRING version 10.0, for pathway analysis we used the Reactome database resource, and for potentially druggable proteins we used the Human Protein Atlas website which holds protein information of the current FDA approved drugs directed to 672 separate human proteins. Results: In all, 3078 proteins could be identified in all patients and 793 proteins were differentially expressed (p<0.05 adjusted for mass significance according to Benjamin-Hochberg) between ABC and GCB patients. Of these, 410 proteins were overexpressed in the ABC group. Among the most expressed proteins were several well-known ABC-associated proteins (such as IRF4/MUM1, HSP90B1, CCDC50 and STAT3) in addition to a large number of proteins previously not described in ABC DLBCL, e.g. neudesin, BLNK, MPST, BPGM, SUB1, SP140, PCK2, PARP4, SRP54, SRP68, SRP72, TRPV2, IGF2R and FGD2. A majority of the 410 proteins were closely linked with an enrichment p-value < 1x10-16(Fig. 1) and the most enriched pathways were immune system (FDR rate 3.3 x 10-27), interferon signaling (2.9 x 10-7), antigen processing (8.8 x 10-7) and down-modulation of cell surface receptors (4.7 x 10-5). Most interestingly, we also found that 16 proteins overexpressed in the ABC group could be potential drug targets for an FDA approved drug, e.g. high affinity immunoglobulin gamma Fc receptor I, CD47, HDAC2, ELANE and carbonic anhydrase 1. Conclusions: In this large proteomic study we found a number of overexpressed proteins in the ABC subtype, previously not described in DLBCL. Even though functional studies aimed at individual proteins and protein interactions to evaluate potential clinical effect are needed, our findings reveal novel proteins that could be potential druggable targets in ABC DLBCL patients. Figure 1 Disclosures Enblad: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Mellqvist:Amgen, Janssen, Oncopeptides, Sanofi, Sandoz, Takeda: Honoraria. Andersson:Abbvie and Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead, Janssen and Roche: Consultancy; Gilead: Research Funding.
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Pham, Lan, Juan Chen, Archie Tamayo, Jerry Bryant, David Yang, and Richard J. Ford. "Cannabinoid Receptor Signaling As a Target for Personalized Therapy in Aggressive B Cell Lymphomas." Blood 128, no. 22 (December 2, 2016): 4181. http://dx.doi.org/10.1182/blood.v128.22.4181.4181.
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Abstract Non-Hodgkin Lymphoma (NHL) is the most common hematological malignancy, with B-cell lymphoma (NHL-B) accounting for 85% of all lymphomas. In the United States, there are ~500,000 lymphoma patients currently living with this disease and ~20,000 lymphoma-related deaths occur annually. The current overall cure rate for B-cell lymphoma is estimated at ~30%, indicating that new innovative therapeutic approaches are needed to significantly reduce the high mortality rate, particularly of relapsed/refractory (r/r) NHL-B. The poor quality of life in patients suffering from chronic diseases like cancer has forced many patients to pursue alternative treatment options, including medicinal cannabinoids (CB), in order to improve their clinical prospect/outcomes. Medicinal cannabinoids have been legalized in 23 states and DC for several medical conditions such as cachexia, chronic pain, epilepsy and other similar disorders characterized by seizures, glaucoma, HIV- AIDS, Multiple Sclerosis, muscle spasticity and GI enteritis. Lately however, cannabis has been shown to have a broader biologic activity spectrum with various cannabis compounds functioning as ligands binding the two principle cannabinoid-specific G protein-coupled receptors (GPCR) CB1 (in neural cells), and CB2, in immune lymphoid, particularly B cells, but have also been identified, showing aberrant expression in a wide variety of important human cancers. This suggests not only a wider spectrum of cellular usage of cannabinoids and their cognate receptors, but also their potential utility as novel therapeutic targets. Gene expression profiling data has demonstrated, however, that B-cell lymphoma is one of the top three cancers (glioma and gastric are the other two) showing high expression of CB1 and CB2 receptors. Our studies showed that CB1 receptor is highly expressed in aggressive NHL-B, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) cells in comparison to normal unstimulated (G0) B cells, and that targeting CB1 using an siRNA approach leads to cell growth inhibition. Furthermore, pharmacological approaches targeting CB1 with small molecule antagonists (Rimonabant and Otenabant) inhibited lymphoma cell viability, leading to the induction of apoptosis and G2M cell cycle arrest. Using proteomic approach via reverse-phase protein array (RPPA), we have demonstrated that lymphoma cells treated with the CB1 antagonist Rimonabant showed a robust effect on apoptosis (increases in caspase 3 and 7, Bad, and bak), cell cycle (increases in p27 and cyclin D1), DNA damage (increases in gH2AX), and autophagy (increases in LC3A) associated proteins. In addition, Rimonabant treatment also inhibited several growth and survival pathways, including STAT3, SRC, and b-catenin, while enhancing the PI3K/ATK pathway. Of note, Rimonabant treatment also activated the DNA damage response (DDR) pathway through stimulating two checkpoint kinases (Chk1 and Chk2). Blocking Rimonabant-induced Chk1 and Chk2 with a selective ATP-competitive inhibitor of Chk1 and Chk2 leads to a robust synergistic effect on cell growth inhibition and apoptotic induction, suggesting that blocking the DDR pathway with Chk kinase inhibitors prevents cells recovering from rimonabant-induced DNA damage. These findings suggest that targeting the cannabinoid receptors and the DDR pathway represents a new therapeutic strategy against resistant r/r NHL-B cells. Disclosures Pham: Vyripharm Biopharmaceuticals: Research Funding. Bryant:Vyripharm Biopharmaceuticals: Equity Ownership. Yang:Vyripharm Biopharmaceuticals: Employment.
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Lemma, Mahlet, Stefan Petkov, Yonas Bekele, Beyene Petros, Rawleigh Howe, and Francesca Chiodi. "Profiling of Inflammatory Proteins in Plasma of HIV-1-Infected Children Receiving Antiretroviral Therapy." Proteomes 8, no. 3 (September 7, 2020): 24. http://dx.doi.org/10.3390/proteomes8030024.
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Treatment of HIV-1-infected patients results in improved clinical and immunological conditions, but severe non-AIDS-related conditions still persist. Novel proteomic platforms have identified inflammatory proteins where abundance is dysregulated in adult treated patients, whereas limited data are available in treated HIV-1 infection of children. Using a proteomic plasma profiling approach comprising 92 inflammation-related molecules, we analyzed specimens from 43 vertically HIV-1-infected children receiving antiretroviral treatment (ART) and matched controls in Ethiopia. The infected children were analyzed as a group and separately, according to age of treatment initiation. Proteins displaying a significantly different abundance between groups were hierarchically clustered and presented in heat maps. Random forest analysis was performed to pin-point proteins discriminating between groups; five proteins (STAMBP, CD5, TFG-α, TRANCE, AXIN1) were the strongest prediction factors for treated HIV-1 infection. TRANCE was previously linked to reduced bone mass levels in HIV-1-infected children. CCL4 chemokine, ligand to HIV-1 co-receptor CCR5, was the most critical protein for successful classification between children who initiated ART at different time points. Our data provide evidence that a dysregulated expression of proteins linked to immunological abnormalities and bone metabolism can be found in HIV-1-infected children with prolonged exposure to ART.
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Carlin, Eric, Braxton Greer, Kelsey Lowman, Alexandra Duverger, Frederic Wagner, David Moylan, Alexander Dalecki, et al. "Extensive proteomic and transcriptomic changes quench the TCR/CD3 activation signal of latently HIV-1 infected T cells." PLOS Pathogens 17, no. 1 (January 19, 2021): e1008748. http://dx.doi.org/10.1371/journal.ppat.1008748.
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The biomolecular mechanisms controlling latent HIV-1 infection, despite their importance for the development of a cure for HIV-1 infection, are only partially understood. For example, ex vivo studies have recently shown that T cell activation only triggered HIV-1 reactivation in a fraction of the latently infected CD4+ T cell reservoir, but the molecular biology of this phenomenon is unclear. We demonstrate that HIV-1 infection of primary T cells and T cell lines indeed generates a substantial amount of T cell receptor (TCR)/CD3 activation-inert latently infected T cells. RNA-level analysis identified extensive transcriptomic differences between uninfected, TCR/CD3 activation-responsive and -inert T cells, but did not reveal a gene expression signature that could functionally explain TCR/CD3 signaling inertness. Network analysis suggested a largely stochastic nature of these gene expression changes (transcriptomic noise), raising the possibility that widespread gene dysregulation could provide a reactivation threshold by impairing overall signal transduction efficacy. Indeed, compounds that are known to induce genetic noise, such as HDAC inhibitors impeded the ability of TCR/CD3 activation to trigger HIV-1 reactivation. Unlike for transcriptomic data, pathway enrichment analysis based on phospho-proteomic data directly identified an altered TCR signaling motif. Network analysis of this data set identified drug targets that would promote TCR/CD3-mediated HIV-1 reactivation in the fraction of otherwise TCR/CD3-reactivation inert latently HIV-1 infected T cells, regardless of whether the latency models were based on T cell lines or primary T cells. The data emphasize that latent HIV-1 infection is largely the result of extensive, stable biomolecular changes to the signaling network of the host T cells harboring latent HIV-1 infection events. In extension, the data imply that therapeutic restoration of host cell responsiveness prior to the use of any activating stimulus will likely have to be an element of future HIV-1 cure therapies.
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Douglas, Janet L., Kasinath Viswanathan, Matthew N. McCarroll, Jean K. Gustin, Klaus Früh, and Ashlee V. Moses. "Vpu Directs the Degradation of the Human Immunodeficiency Virus Restriction Factor BST-2/Tetherin via a βTrCP-Dependent Mechanism." Journal of Virology 83, no. 16 (June 10, 2009): 7931–47. http://dx.doi.org/10.1128/jvi.00242-09.
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ABSTRACT The primary roles attributed to the human immunodeficiency virus type 1 (HIV-1) Vpu protein are the degradation of the viral receptor CD4 and the enhancement of virion release. With regard to CD4 downregulation, Vpu has been shown to act as an adapter linking CD4 with the ubiquitin-proteasome machinery via interaction with the F-box protein βTrCP. To identify additional cellular βTrCP-dependent Vpu targets, we performed quantitative proteomics analyses using the plasma membrane fraction of HeLa cells expressing either wild-type Vpu or a Vpu mutant (S52N/S56N) that does not bind βTrCP. One cellular protein, BST-2 (CD317), was consistently underrepresented in the membrane proteome of cells expressing wild-type Vpu compared to the proteome of cells expressing the Vpu mutant. To verify the biological relevance of this phenotype for HIV pathogenesis, we showed that in T cells infected with HIV-1, BST-2 downregulation occurred in a Vpu-dependent manner. Recently, BST-2 has been identified as the interferon-inducible cellular factor Tetherin, which restricts HIV virion release in the absence of Vpu. We address here the unresolved mechanism of Vpu-mediated BST-2 downregulation. Our data show that the presence of wild-type Vpu reduced cell surface and total steady-state BST-2 levels, whereas that of the mutant Vpu had no effect. In addition, treatment of cells with the lysosome acidification inhibitor concanamycin A, but not treatment with the proteasome inhibitor MG132, reduced BST-2 downregulation by wild-type Vpu, thereby suggesting that the presence of Vpu leads to the degradation of BST-2 via an endosome-lysosome degradation pathway. The importance of βTrCP in this process was confirmed by demonstrating that in the absence of βTrCP, BST-2 levels were restored despite the presence of Vpu. Taken together, these data support the hypothesis that, in similarity to its role in CD4 degradation, Vpu acts as an adapter molecule linking BST-2 to the cellular ubiquitination machinery via βTrCP. However, in contrast to the proteasome-dependent degradation of CD4, which occurs in the endoplasmic reticulum, Vpu appears to interact with BST-2 in the trans-Golgi network or in early endosomes, leading to lysosomal degradation of BST-2. Via this action, Vpu could counter the tethering function of BST-2, resulting in enhanced HIV-1 virion release. Interestingly, although HIV-2 does not express Vpu, an isolate known to exhibit enhanced viral egress can downregulate surface BST-2 by an as-yet-unknown mechanism that does not appear to involve degradation. Understanding the molecular mechanisms of both Vpu-dependent and -independent mediated antagonism of BST-2 will be critical for therapeutic strategies that exploit this novel viral function.
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Kimbro, K. S., and J. W. Simons. "Hypoxia-inducible factor-1 in human breast and prostate cancer." Endocrine-Related Cancer 13, no. 3 (September 2006): 739–49. http://dx.doi.org/10.1677/erc.1.00728.
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The tumor microenvironment is best characterized as a fluctuation of hypoxia and nutrient deprivation, which leads to epigenetic and genetic adaptation of clones and increased invasiveness and metastasis. In turn, these hypoxic adaptations make the tumors more difficult to treat and confer increased resistance to current therapies. Part of this adaptation is the regulation of gene products in response to hypoxia. Many of these hypoxia-regulated genes are mediated by the hypoxia-inducible factor 1 (HIF-1) complex, which is composed of a heterodimer pair of HIF-1α and HIF-1β. This heterodimer binds to the promoter of hypoxia-responsive genes, while interacting with other transcription factors, such as p300, signal and transducer of transcription 3, and Redox effector factor 1/apurinic/apyrimidinic endonuclease. HIF-1α levels itself can be regulated by hypoxia transcriptionally and post-translationally through ubiquitination; but the magnitude of the response is modulated by several other pathways, including free radicals that affect crosstalk with HIF-1α/HIF-1β transcriptional activities. HIF-1α has emerged as an important transcription factor in breast cancer and prostate cancer biology, and is expressed in the early stages of mammary and prostate carcinogenesis. Its expression is correlated with diagnostic and prognostic indicators for early relapse and metastatic disease, thus making HIF-1α a potential prognostic biomarker in proteomic assessments of breast and prostate cancers. The importance of HIF-1α in tumor progression makes it a logical target for chemoprevention strategies in patients at higher genetic risk of breast and prostate cancer with Cox 2 inhibitors or 2-methoxyestradiol, as well as a target for new approaches to inhibiting angiogenesis. The crosstalk between estrogen signaling pathways and HIF-1α is still not fully defined in breast cancer, but downstream estrogen receptor signaling may be a candidate for estrogen modulation of HIF-1α levels. In prostate cancer, androgens upregulate HIF-1α through androgen-regulated autocrine receptor tyrosine kinase receptor signaling. This review will put into perspective the role of HIF-1α in endocrine oncology and present new data on HIF-1α signaling and the potential for targeted therapies, including combinatory hormonal therapies.
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Lal, Kerri, Yuwadee Phuang-Ngern, Suchada Suhkumvittaya, Edwin Leeansyah, Aljawharah Alrubayyi, Joana Dias, Adam Waickman, et al. "Longitudinal Analysis of Peripheral and Colonic CD161+ CD4+ T Cell Dysfunction in Acute HIV-1 Infection and Effects of Early Treatment Initiation." Viruses 12, no. 12 (December 11, 2020): 1426. http://dx.doi.org/10.3390/v12121426.
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CD161 expression on CD4+ T cells is associated with a Th17 functional phenotype, as well as with an innate capacity to respond to interleukin (IL)-12 and IL-18 without T cell receptor (TCR) stimulation. Chronic HIV-1 infection is associated with loss of the CD161+ CD4 T cell population, and non-human primate studies suggest that their depletion is associated with disease progression. However, the dynamics of the CD161+ CD4+ T cell population during acute HIV-1 infection remains unknown. In this study, we characterize peripheral blood CD161+ CD4+ T cells in detail, and examine how they are affected during the earliest stages of HIV-1 infection. Unbiased surface proteome screening and principal component analysis indicated that CD161+ CD4+ T cells are relatively phenotypically homogeneous between donors, and are intermediates between conventional CD4 T cells and innate-like T cells. In acute untreated HIV-1 infection, the circulating CD161+ CD4+ T cell population decreased in frequency, as did absolute cell counts starting from peak viral load, with elevated levels of activation and exhaustion markers expressed throughout acute HIV-1 infection. The capacity of these cells to respond to stimulation with IL-12 and IL-18 was also reduced. Early initiation of anti-retroviral treatment (ART) during acute HIV-1 infection restored the functionality of peripheral blood CD161+ CD4+ T cells, but not their frequency. In contrast, early ART initiation prevented the decline of colonic CD161+ CD4+ T cells that otherwise started during acute infection. Furthermore, loss of peripheral and colonic CD161+ CD4+ T cells in untreated infection was associated with levels of viral load. These results suggest that acute HIV-1 infection has profound effects on the CD161+ CD4+ T cell population that could not be completely prevented by the initiation of ART.
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Jana, Sirsendu, Michael R. Heaven, and Abdu I. Alayash. "Cell-Free Hemoglobin Does Not Attenuate the Effects of SARS-CoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells." International Journal of Molecular Sciences 22, no. 16 (August 22, 2021): 9041. http://dx.doi.org/10.3390/ijms22169041.
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SARS-CoV-2 primarily infects epithelial airway cells that express the host entry receptor angiotensin-converting enzyme 2 (ACE2), which binds to the S1 spike protein on the surface of the virus. To delineate the impact of S1 spike protein interaction with the ACE2 receptor, we incubated the S1 spike protein with human pulmonary arterial endothelial cells (HPAEC). HPAEC treatment with the S1 spike protein caused disruption of endothelial barrier function, increased levels of numerous inflammatory molecules (VCAM-1, ICAM-1, IL-1β, CCL5, CXCL10), elevated mitochondrial reactive oxygen species (ROS), and a mild rise in glycolytic reserve capacity. Because low oxygen tension (hypoxia) is associated with severe cases of COVID-19, we also evaluated treatment with hemoglobin (HbA) as a potential countermeasure in hypoxic and normal oxygen environments in analyses with the S1 spike protein. We found hypoxia downregulated the expression of the ACE2 receptor and increased the critical oxygen homeostatic signaling protein, hypoxia-inducible factor (HIF-1α); however, treatment of the cells with HbA yielded no apparent change in the levels of ACE2 or HIF-1α. Use of quantitative proteomics revealed that S1 spike protein-treated cells have few differentially regulated proteins in hypoxic conditions, consistent with the finding that ACE2 serves as the host viral receptor and is reduced in hypoxia. However, in normoxic conditions, we found perturbed abundance of proteins in signaling pathways related to lysosomes, extracellular matrix receptor interaction, focal adhesion, and pyrimidine metabolism. We conclude that the spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in HPAEC, and that treatment with HbA failed to reverse the vast majority of these spike protein-induced changes.
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Han, Jang Mi, Jae Kyung Sohng, Woo-Haeng Lee, Tae-Jin Oh, and Hye Jin Jung. "Identification of Cyclophilin A as a Potential Anticancer Target of Novel Nargenicin A1 Analog in AGS Gastric Cancer Cells." International Journal of Molecular Sciences 22, no. 5 (March 1, 2021): 2473. http://dx.doi.org/10.3390/ijms22052473.
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We recently discovered a novel nargenicin A1 analog, 23-demethyl 8,13-deoxynargenicin (compound 9), with potential anti-cancer and anti-angiogenic activities against human gastric adenocarcinoma (AGS) cells. To identify the key molecular targets of compound 9, that are responsible for its biological activities, the changes in proteome expression in AGS cells following compound 9 treatment were analyzed using two-dimensional gel electrophoresis (2-DE), followed by MALDI/TOF/MS. Analyses using chemical proteomics and western blotting revealed that compound 9 treatment significantly suppressed the expression of cyclophilin A (CypA), a member of the immunophilin family. Furthermore, compound 9 downregulated CD147-mediated mitogen-activated protein kinase (MAPK) signaling pathway, including c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) by inhibiting the expression of CD147, the cellular receptor of CypA. Notably, the responses of AGS cells to CypA knockdown were significantly correlated with the anticancer and antiangiogenic effects of compound 9. CypA siRNAs reduced the expression of CD147 and phosphorylation of JNK and ERK1/2. In addition, the suppressive effects of CypA siRNAs on proliferation, migration, invasion, and angiogenesis induction of AGS cells were associated with G2/M cell cycle arrest, caspase-mediated apoptosis, inhibition of MMP-9 and MMP-2 expression, inactivation of PI3K/AKT/mTOR pathway, and inhibition of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression. The specific interaction between compound 9 and CypA was also confirmed using the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA) approaches. Moreover, in silico docking analysis revealed that the structure of compound 9 was a good fit for the cyclosporin A binding cavity of CypA. Collectively, these findings provide a novel molecular basis for compound 9-mediated suppression of gastric cancer progression through the targeting of CypA.
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Miura, Norimasa, Junichi Hasegawa, and Goshi Shiota. "Serum Messenger RNA as a Biomarker and its Clinical Usefulness in Malignancies." Clinical medicine. Oncology 2 (January 2008): CMO.S379. http://dx.doi.org/10.4137/cmo.s379.
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A number of biomarkers are used clinically and many protein-based assay methods are available. Improvements in the method to utilize specific antibodies have led to remarkable progress in clinical diagnosis using biomarkers. Proteomics studies to identify better biomarkers have been performed worldwide by using a protein-based comprehensive method. The detection rate of conventional biomarkers can not improve further. Now is a time that a breakthrough is needed. We previously proposed mRNA, which is circulating in the body, as a novel material for biomarkers. mRNA is an unexpectedly useful molecule, not only because it can detect genes with a low expression level in protein, but also because it can detect the expression from non-coding RNA precursor genes or gene products with limited secretion from the cells. Circulating mRNA has been thought to be unstable in blood containing RNase. We confirm that mRNA remains at the same level for 24 hours after blood sampling. Unlike DNA, the RNA molecule can reflect events in the human body which occurred within a day, resulting in an early diagnosis of diseases. We report the possibility to detect and quantify cancer-derived mRNAs circulating in human vessels. We introduce the detection of serum mRNA as a useful biomarker of human malignancies. Abbreviations hTERT: human telomerase reverse transcriptase protein; HCC: hepatocellular carcinoma; hTR: human telomerase RNA template; HCV: hepatitis C virus; HBV: hepatitis B virus; AH: adenomatous hyperplasia; AAH: atypical adenomatous hyperplasia; LC: liver cirrhosis; CH: chronic hepatitis; AFP: α-fetoprotein; DCP; des-γ-carboxy prothrombin; ALT: alanine aminotransferase; Alb: albumin; EGFR: Epidermal growth factor receptor; non-small cell lung cancer; NSCLC: non-small cell lung cancer; small cell lung cancer; SCLC; ADC: adenocarcinoma; SCC: squamous cell carcinoma antigen; SqCC: squamous cell carcinoma; CEA: carcinoembryonic antigen; CYFRA (21–1): cytokeratin 19 fragment; CNA: circulating nucleic acids.
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Balasubramanian, Krishnan. "Mathematical and Computational Techniques for Drug Discovery: Promises and Developments." Current Topics in Medicinal Chemistry 18, no. 32 (March 5, 2019): 2774–99. http://dx.doi.org/10.2174/1568026619666190208164005.
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We review various mathematical and computational techniques for drug discovery exemplifying some recent works pertinent to group theory of nested structures of relevance to phylogeny, topological, computational and combinatorial methods for drug discovery for multiple viral infections. We have reviewed techniques from topology, combinatorics, graph theory and knot theory that facilitate topological and mathematical characterizations of protein-protein interactions, molecular-target interactions, proteomics, genomics and statistical data reduction procedures for a large set of starting chemicals in drug discovery. We have provided an overview of group theoretical techniques pertinent to phylogeny, protein dynamics especially in intrinsically disordered proteins, DNA base permutations and related algorithms. We consider computational techniques derived from high level quantum chemical computations such as QM/MM ONIOM methods, quantum chemical optimization of geometries complexes, and molecular dynamics methods for providing insights into protein-drug interactions. We have considered complexes pertinent to Hepatitis Virus C non-structural protein 5B polymerase receptor binding of C5-Arylidebne rhodanines, complexes of synthetic potential vaccine molecules with dengue virus (DENV) and HIV-1 virus as examples of various simulation studies that exemplify the utility of computational tools. It is demonstrated that these combinatorial and computational techniques in conjunction with experiments can provide promising new insights into drug discovery. These techniques also demonstrate the need to consider a new multiple site or allosteric binding approach to drug discovery, as these studies reveal the existence of multiple binding sites.
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Hsieh, James J., Valerie H. Le, Toshinao Oyama, Christopher J. Ricketts, Thai Huu Ho, and Emily H. Cheng. "Chromosome 3p Loss–Orchestrated VHL, HIF, and Epigenetic Deregulation in Clear Cell Renal Cell Carcinoma." Journal of Clinical Oncology 36, no. 36 (December 20, 2018): 3533–39. http://dx.doi.org/10.1200/jco.2018.79.2549.
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Clear cell renal cell carcinoma (ccRCC) is the most common renal cell carcinoma subtype, and metastatic ccRCC is associated with 5-year survival rates of 10% to 20%. Genetically, ccRCC originates from sequential losses of multiple tumor suppressor genes. Remarkably, chromosome 3p loss occurs in more than 90% of sporadic ccRCCs. This results in concurrent one-copy loss of four tumor suppressor genes that are also mutated individually at high frequency in ccRCC (ie, VHL, 80%; PBRM1, 29% to 46%; BAP1, 6% to 19%; and SETD2, 8% to 30%). Pathogenically, 3p loss probably represents the first genetic event that occurs in sporadic ccRCC and the second genetic event in VHL-mutated hereditary ccRCC. VHL constitutes the substrate recognition module of the VCB-Cul2 E3 ligase that degrades HIF1/2α, whereas PBRM1, BAP1, and SETD2 are epigenetic modulators that regulate gene transcription. Because 3p loss and VHL inactivation are nearly universal truncal events in ccRCC, the resulting HIF1/2 signaling overdrive and accompanied tumor hypervascularization probably underlie the therapeutic benefits observed with vascular endothelial growth factor receptor inhibitors, including sorafenib, sunitinib, pazopanib, axitinib, bevacizumab, cabozantinib, and lenvatinib. Furthermore, recent marked advances in ccRCC genomics, transcriptomics, proteomics, metabolomics, molecular mechanisms, mouse models, prognostic and predictive biomarkers, and clinical trials have rendered invaluable translational insights concerning precision kidney cancer therapeutics. With an armamentarium encompassing 13 drugs that exploit seven unique therapeutic mechanisms (ie, cytokines, vascular endothelial growth factor receptor, mTORC1, cMET/AXL, fibroblast growth factor receptor, programmed cell death-1 and programmed death-ligand 1, and cytotoxic T-cell lymphocyte associated-4) to treat metastatic renal cell carcinoma, one of the imminent clinical questions concerning care of patients with metastatic ccRCC is how a personalized treatment strategy, through rationally combining and sequencing different therapeutic modalities, can be formulated to offer the best clinical outcome for individual patients. Here, we attempt to integrate recent discoveries of immediate translational impacts and discuss future translational challenges and opportunities.
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Tong, Jun, Yuanmeng Jin, Qinjie Weng, Shuwen Yu, Hafiz Muhammad Jafar Hussain, Hong Ren, Jing Xu, et al. "Glomerular Transcriptome Profiles in Focal Glomerulosclerosis: New Genes and Pathways for Steroid Resistance." American Journal of Nephrology 51, no. 6 (2020): 442–52. http://dx.doi.org/10.1159/000505956.
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Background: Patients with focal segmental glomerulosclerosis (FSGS) characterized by steroid-resistant nephrotic syndrome (SRNS) are prone to progress to ESRD. Mechanism for the FSGS patients’ response to steroid treatment is still unknown and currently, it is impossible to predict the steroid resistance before treatment of patients with FSGS. Methods: To identify biomarkers and potential therapeutic targets of FSGS patients with SRNS, patients diagnosed as kidney biopsy-proven FSGS and nephrotic syndrome (NS) were prospectively enrolled. They were divided into 2 groups, steroid-sensitive NS and SRNS based on their treatment response. Cortical regions were selected from biopsied renal tissues, and glomeruli were isolated under an inverted microscope. RNA was prepared from the isolated glomeruli and further used for microarray analysis. Followed by multiple analyses, the top 6 highest and lowest, and a selected panel of differentially expressed genes obtained and their related pathways were validated via real-time PCR, western blot, and measurement of reactive oxygen species (ROS). Results: In SRNS group, we discovered that the most significant up-regulated pathway was primarily related to cellular amino acid and derivative metabolic process. Meanwhile, the most significant down-regulated pathway was primarily involved in anatomical structure morphogenesis. Moreover, we found NADPH oxidase 4 (NOX4), one of the key regulators of renal ROS, at a much higher level in SRNS both at transcriptomic and proteomic levels. We also found the levels of ROS, p-p38 MAPK and matrix metalloproteinase (MMP)-2, which were all regulated by NOX4, were also higher in glomeruli isolated from SRNS patients. At last, we detected stimulated by retinoic acid gene 6 homolog (STRA6), a cell surface receptor formerly known as a gene preventing podocytes from over-proliferative lesion induced by HIV infection and was up-regulated by retinoic acid, expressed at a much higher level in SRNS kidneys. Conclusion: We found 2 potential mechanisms underline the SRNS, NOX4/ROS/P38 MAPK/MMP-2 pathway and STRA6. Our findings provided new insights into the steroid resistance.
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Tarasova, G., A. Volkov, A. Iakovlev, T. Ghazudin, and I. Shcherbakova. "P016 Efficiency of evaluating the expression of Toll-like receptors 2, 4, 6 and proteins proteomic profiling as integral indicators for predicting the risk of early relapse of ulcerative colitis." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S138. http://dx.doi.org/10.1093/ecco-jcc/jjz203.145.
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Abstract Background Success was made in the study of TLR in congenital and adaptive immunity, which determined a new look at immune processes at ulcerative colitis (UC). Modern achievements of proteomic methods of analysis research allow to define molecular characteristics of the inflammation in colon mucosa of patients with UC. Methods The study included 86 patients with UC, an average age of 39.0 ± 1.4 years. Groups: 1–15 (17.4%) patients with distal form of UC, 2–42 (48%) left-sided form, 3–29 (33.7%) patients with total UC. The expression of TLR on peripheral blood monocytes was determined in the immunofluorescence test. Two-colour analysis was performed on a flowthrough laser cytofluorimeter (Cytomics FC500, Beckman Coulte). The percentage of monocytes (CD14 + cells) carrying TLR2, TLR4, and TLR6 on their surface was assessed. The separation of proteins of colon mucosa was based on technologies of IEF, SDS–PAGE, 2DPAGE, by standard sets (MB-HIC C8 Kit, MB-IMAC Cu, MB-Wax Kit, Bruker, USA). The getting of mass spectrogram was determined by matrix-assisted laser desorption-ionisation time-of-flight mass spectrometry (MALDI-TOF-MS/MS, Ultraflex II, Bruker, USA). Statistical analysis was performed using the software Statistica 10.0 (Statsoft). Results The direct average relationship was established between the number of monocytes expressing CD14 + CD282 +, CD14 + CD284 +, CD14 + CD286 + and the area of inflammation (r = 0.49, r = 0.55, r = 0.42, p < 0.05). The nonlinear regression equation was used. Calculation example: the risk of recurrence UC = exp (−26.1 + (0.4) × TLR 2)/(1 + exp (−26.1 + (0.4) × TLR 2)), χ2 = 130, 59, p < 0.0001. Thus, when the number of monocytes expressing TLR2 is not more than 60%, the risk of recurrence of the UC is not more than 11%, with values above 70%, the probability of recurrence exceeds 80%. We identified potentially new molecular markers of the early relapse of ulcerative colitis: SMAD2 activates the transcription of TFG1β and leads to development of fibrosis in colon submucosa in patients with UC; significant decrease of the expression of PPARγ promotes the activation of STAT and AP-1 signalling pathways that promotes the increase of the synthesis of IL-2, 6, 8, 12, TNFα, the activity of immune and inflammation processes in colon mucosa; the reduction of expression of β-defensin-1 in cells of colon mucosa is accompanied with increased expression of CCR6 that promotes the formation of inflammatory infiltrates in colonic submucosa in UC. Conclusion Expression of TLR 2, 4, 6 in blood monocytes (the risk of recurrence UC ratio) and new protein molecular markers of colon mucosa (SMAD2, PPARγ, and apoС-III) can be used as a tool for prediction of early relapse UC.
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Stanley, Takara Leah, Lindsay T. Fourman, Lai Ping Wong, Ruslan Sadreyev, James T. Billingsley, Meghan N. Feldpausch, Autumn Boutin, et al. "Growth Hormone Releasing Hormone Reduces Plasma Markers of Immune Activation and Hepatic Immune Pathways in Nonalcoholic Fatty Liver Disease." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A628—A629. http://dx.doi.org/10.1210/jendso/bvab048.1282.
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Abstract Introduction: The GH/IGF-1 axis affects multiple metabolic pathways, and animal models demonstrate that it also modulates immune function. Little is known, however, regarding effects of augmenting GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and immune-related gene pathways in the liver in people with HIV (PWH) and NAFLD. We hypothesized that tesamorelin would decrease circulating markers of immune activation in conjunction with previously reported reductions in visceral fat and hepatic triglyceride. Methods: 92 biomarkers associated with immune function (Olink Immuno-Oncology panel) were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized, 12-month trial of tesamorelin versus identical placebo. Proteins differentially altered by tesamorelin at a false discovery rate < 0.1 were considered significantly changed. Gene set enrichment analysis targeted to immune pathways was subsequently performed on liver tissue from serial biopsies. Results: Compared to placebo, tesamorelin decreased circulating concentrations of 13 proteins, including four chemokines (C-C Motif Chemokine Ligands 3 [CCL3, effect size -0.38 Log2 fold change], 4 [CCL4, -0.36 Log2 fold change], and 13 [CCL13 or MCP4, -0.42 Log2 fold change] and interleukin-8 [-0.50 Log2 fold change]), two cytokines (interleukin-10 [-0.32 Log2 fold change] and cytokine stimulating factor 1 [-0.22 Log2 fold change]), and four T-cell associated molecules (CD8A [-0.37 Log2 fold change], Cytotoxic And Regulatory T Cell Molecule [CRTAM, -0.47 Log2 fold change], granzyme A [-0.53 Log2 fold change], and adhesion G protein-coupled receptor G1 [ADGRG1, -0.54 Log2 fold change]), as well as arginase-1 [-0.95 Log2 fold change], galectin-9 [-0.26 Log2 fold change], and hepatocyte growth factor [-0.30 Log2 fold change]. No proteins in the panel were significantly increased by tesamorelin. Network analysis indicated close interaction among the gene pathways responsible for the reduced proteins, with imputational analyses suggesting down regulation of a closely related cluster of immune pathways. Targeted transcriptomics using tissue from liver biopsy confirmed an end-organ signal of down-regulated immune pathways, including pathways involved in antigen presentation, complement activation, toll like receptor and inflammatory signaling, and T-cell activation. Conclusions: Long-term treatment with tesamorelin decreased circulating markers of T-cell and monocyte/macrophage activity, with corresponding downregulation of immune pathways in the liver. These findings suggest that augmenting pulsatile GH may ameliorate immune activation in a population with metabolic dysregulation and systemic inflammation.
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Miharada, Kenichi, Göran Karlsson, Matilda Rehn, Emma Rörby, Kavitha Siva, Jörg Cammenga, and Stefan Karlsson. "Cripto Regulates Hematopoietic Stem Cells As a Hypoxic Niche Related Factor Through the Cell Surface Receptor GRP78." Blood 118, no. 21 (November 18, 2011): 2332. http://dx.doi.org/10.1182/blood.v118.21.2332.2332.
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Abstract Abstract 2332 Cripto is a member of the EGF-CFC soluble protein family and has been identified as an important factor for the proliferation/self-renewal of embryonic stem (ES) and several types of tumor cells. The role for Cripto in the regulation of hematopoietic cells (HSCs) has been unknown. We have reported that Cripto increases colony formation and maintains reconstitution ability of HSCs after growth in vitro and that this signaling is mediated through association of Cripto with cell surface receptor GRP78 which is expressed on a subset of HSCs (Miharada et al, Blood abstract, 2010). Here we show that Cripto/GRP78 signaling is important to sustain HSCs in the hypoxic niche. In order to clarify what pathway(s) are activated by Cripto/GRP78 signaling, we performed proteomics analysis using the HSC-like Lhx2 cell line. Two dimentional electrophoresis (2D-DIGE) of proteins was used to analyze Cripto stimulated- and unstimulated-Lhx2 cells. The findings show that several glycolytic metabolism-related proteins were up-regulated and/or phosphorylated by Cripto treatment, e.g. Pyruvate kinase, Phosphoglycerate kinase 1, and Triosephosphate isomerase. Glycolysis is active under hypoxia and it is known that HSC located in the endosteal area of bones are in a hypoxic environment. We therefore separately analyzed central HSCs (cHSCs) and endosteal HSCs (eHSCs) and their hypoxic/metabolic properties. The findings show that eHSCs exhibit a larger proportion of GRP78+HSCs than cHSC and are more dormant (18.9±4.3% of eHSCs and 5.2±3.2% of cHSCs). GRP78+HSCs exhibit a higher content of Pimonidazole high positive cells indicating more hypoxic cells (37.4±13.2% in GRP78+ and 10.2±6.4% in GRP78−, p=0.001), and they also have a higher proportion of MitoTracker (MT) low cells which indirectly represents higher glycolytic activity (0.29±0.02 in GRP78+ and 0.42±0.07 in GRP78−, as relative MFI, p=0.011). It is noteworthy that after 3 days culture with Cripto, GRP78+HSCs showed significantly lower increase in MT intensity relative to the control condition (7,993±3,223 with Cripto and 14,952±2,857 without Cripto, as MFI, p=0.018). To see how Cripto/GRP78 signaling is important in vivo, we analyzed endosteal niche cells. An endosteal cell analysis revealed that part of ALCAM+ and Sca-I+ cells which have been shown to have supportive ability for HSCs, expressed cell membrane associated Cripto on their cell surface. Moreover, injection of anti-GRP78 blocking antibody led to displacement of GRP78+HSCs from the endosteal area to the central marrow (16.9±5.2% with control IgG and 9.6±3.8% with blocking antibody, in eHSCs, p=0.023). Hypoxia-inducible factor 1α (HIF-1α) null mice, have been shown to exhibit failure in the maintenance of functional HSCs even though the immunophenotypic percentage of HSCs is normal. Since the Cripto promoter region has HIF-1 complex binding sites, we analyzed whether HIF-1α null mice exhibit alterations in the Cripto/GRP78 pathway. Analysis of HIF-1α null mice demonstrated a reduced number of GRP78+HSCs within the eHSC compartment (13.8±1.6% in Mx-Cre control and 5.3±2.5% in HIF-1α null mice, p=0.001) and decreased number of cell surface Cripto+ endosteal niche cells. Taken together, our study strongly suggests that the Cripto/GRP78 pathway is an important signal, as an intermediary of HIF-1 regulation, to maintain HSCs in the hypoxic environment of the endosteal niche, by inducing glycolytic metabolism in dormant HSCs. Disclosures: No relevant conflicts of interest to declare.
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Hoff, Fieke W., Peter P. Ruvolo, Yihua Qiu, Michael Andreeff, Eveline S. de Bont, Terzah M. Horton, and Steven M. Kornblau. "AXL Expression in Pediatric AML Is Associated with Putative LSC and Correlates with a Distinct Set of Proteins Associated with Cell Metabolism, Cell Cycle, and Unfolded Protein Response." Blood 132, Supplement 1 (November 29, 2018): 2686. http://dx.doi.org/10.1182/blood-2018-99-112555.
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Abstract Background: The receptor tyrosine kinase AXL is emerging as a critical regulator of survival signaling and cell cycle regulators in AML. Our previous work using AXL inhibitor ONO-7475 in treating AML cells demonstrated that the drug reduced proteins associated with cell cycle regulation such as CDK1 and PLK1 and PI3K/AKT/mTOR signaling (Ruvolo et al Haematologica 2017). PI3K/AKT/mTOR signaling supports cell survival from stress challenge including response to unfolded protein (UPR). CDK1 and PLK1 have also been implicated as having survival roles during UPR stress. At present an understanding of AXL expression in primary pediatric AML samples is unknown. Reverse phase protein analysis (RPPA) is a powerful proteomic tool that allows for the measurement of protein expression in clinical samples. Methods: ± the proteasome inhibitor bortezomib. Bioinformatic analysis was performed by calculating the Pearson correlation coefficients. Proteins were identified as significantly positively correlated with AXL or significantly negatively correlated with AXL based on p < 0.05 & r ≥ 0.25 or r ≤ -0.25, respectively. All p-values were Bonferroni corrected (0.05 / 291 = 0.0002). String analysis to determine protein: protein interactions was performed on sets associated with positive and negative correlation. Results: Expression of AXL appears to be lower in AML cells compared to healthy donor CD34+ cells (p < 0.001). The expression of AXL was not prognostic for clinical outcome . AXL expression was higher in AML patients with favorable cytogenetics category (p < 0.001) and in low risk pediatric patients (p = 0.002). AXL expression was significantly different in cytogenetic categories with AXL expression elevated in inv(16) and monosomy 7 and lower in 11q23 (p = 0.0014) . AXL expression is higher in putative leukemia stem cell (LSC) population (CD34+ CD38 -) compared to bulk AML (CD34+,CD38+)(p < 0.001). AXL expression in the pediatric AML cells was compared to 290 proteins by RPPA. Fifty-five protein displayed positive correlation with AXL including the immune checkpoint inhibitor protein PD-L1. Other proteins positively correlated with AXL included PLK1 and FOXM1. Our previous study using the ONO-7475 AXL inhibitor demonstrated reduction of PLK1 in cells treated with the inhibitor. Positive association of FOXM1 and PLK1 with AXL would be consistent with a regulatory network where AXL regulates PLK1 via FOXM1. Thirty-three proteins were negatively correlated with AXL expression including HNRNPK, STAT3, XPO1, and phosphorylated EIF2S1. Phosphorylation of EIF2S suppresses protein translation during stress events including unfolded protein response (UPR). String analysis to determine protein: protein interactions determined high interaction (p < 10 e-16) in both positively correlated and negatively correlated sets. KEGG pathways associated with proteins correlated with AXL include mTOR signaling (Pathway ID 4150), PI3K/AKT signaling (Pathway ID 4151), HIF signaling (Pathway ID 4066), and focal adhesion (Pathway ID 4510). Biological pathways associated with AXL networks included regulation of cellular metabolism (Pathway ID GO.0031325), regulation of gene expression (Pathway ID GO.0010604), and cellular response to unfolded protein (Pathway ID G0:0034620). Conclusions: These results suggest that AXL may be prominently expressed in putative LSC in pediatric AML. Though AXL expression appears to be associated with favorable risk cytogenetics, the correlation of AXL with PD-L1 suggests it may be involved in how the AML cell responds to immune surveillance. Finally, a distinct set of proteins are clearly associated with AXL expression and represent a number of different survival pathways including regulation of cell metabolism, cell cycle, and UPR that could contribute to AML cell survival. Disclosures Andreeff: AstraZeneca: Research Funding.
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Rasheed, Suraiya, Jasper S. Yan, Adil Hussain, and Bruce Lai. "Proteomic characterization of HIV-modulated membrane receptors, kinases and signaling proteins involved in novel angiogenic pathways." Journal of Translational Medicine 7, no. 1 (August 27, 2009). http://dx.doi.org/10.1186/1479-5876-7-75.
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Ruiz-Riol, M., D. Berdnik, A. Llano, B. Mothe, C. Gálvez, S. Pérez-Álvarez, B. Oriol-Tordera, et al. "Identification of Interleukin-27 (IL-27)/IL-27 Receptor Subunit Alpha as a Critical Immune Axis for In Vivo HIV Control." Journal of Virology 91, no. 16 (June 7, 2017). http://dx.doi.org/10.1128/jvi.00441-17.
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ABSTRACT Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/β-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC. IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and the blood is a key conduit for transporting such factors. Investigating the communication factors promoting effective immune responses and having potentially antiviral functions against HIV using a novel focused omics approach (“communicome”) has the potential to significantly improve our knowledge of effective host immunity and accelerate the HIV cure agenda. Including 140 subjects with variable viral loads and measuring the plasma levels of >600 soluble proteins, our data highlight the importance of Th17 cells and Wnt/β-catenin signaling in HIV control and especially identify the IL-27/IL-27 receptor subunit alpha (IL-27RA) axis as a predictor of plasma viral load and proviral copy number in the peripheral blood. These data may provide important guidance to therapeutic approaches in the HIV cure agenda.
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Shannon, Casey P., Travis M. Blimkie, Rym Ben-Othman, Nicole Gladish, Nelly Amenyogbe, Sibyl Drissler, Rachel D. Edgar, et al. "Multi-Omic Data Integration Allows Baseline Immune Signatures to Predict Hepatitis B Vaccine Response in a Small Cohort." Frontiers in Immunology 11 (November 30, 2020). http://dx.doi.org/10.3389/fimmu.2020.578801.
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BackgroundVaccination remains one of the most effective means of reducing the burden of infectious diseases globally. Improving our understanding of the molecular basis for effective vaccine response is of paramount importance if we are to ensure the success of future vaccine development efforts.MethodsWe applied cutting edge multi-omics approaches to extensively characterize temporal molecular responses following vaccination with hepatitis B virus (HBV) vaccine. Data were integrated across cellular, epigenomic, transcriptomic, proteomic, and fecal microbiome profiles, and correlated to final HBV antibody titres.ResultsUsing both an unsupervised molecular-interaction network integration method (NetworkAnalyst) and a data-driven integration approach (DIABLO), we uncovered baseline molecular patterns and pathways associated with more effective vaccine responses to HBV. Biological associations were unravelled, with signalling pathways such as JAK-STAT and interleukin signalling, Toll-like receptor cascades, interferon signalling, and Th17 cell differentiation emerging as important pre-vaccination modulators of response.ConclusionThis study provides further evidence that baseline cellular and molecular characteristics of an individual’s immune system influence vaccine responses, and highlights the utility of integrating information across many parallel molecular datasets.
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Genera, Mariano, Barbara Quioc-Salomon, Antonin Nourisson, Baptiste Colcombet-Cazenave, Ahmed Haouz, Ariel Mechaly, Mariette Matondo, et al. "Molecular basis of the interaction of the human tyrosine phosphatase PTPN3 with the hepatitis B virus core protein." Scientific Reports 11, no. 1 (January 13, 2021). http://dx.doi.org/10.1038/s41598-020-79580-9.
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AbstractInteractions between the hepatitis B virus core protein (HBc) and host cell proteins are poorly understood, although they may be essential for the propagation of the virus and its pathogenicity. HBc has a C-terminal PDZ (PSD-95, Dlg1, ZO-1)-binding motif (PBM) that is responsible for interactions with host PDZ domain-containing proteins. In this work, we focused on the human protein tyrosine phosphatase non-receptor type 3 (PTPN3) and its interaction with HBc. We solved the crystal structure of the PDZ domain of PTPN3 in complex with the PBM of HBc, revealing a network of interactions specific to class I PDZ domains despite the presence of a C-terminal cysteine in this atypical PBM. We further showed that PTPN3 binds the HBc protein within capsids or as a homodimer. We demonstrate that overexpression of PTPN3 significantly affects HBV infection in HepG2 NTCP cells. Finally, we performed proteomics studies on both sides by pull-down assays and screening of a human PDZ domain library. We identified a pool of human PBM-containing proteins that might interact with PTPN3 in cells and that could be in competition with the HBc PBM during infection, and we also identified potential cellular partners of HBc through PDZ-PBM interactions. This study opens up many avenues of future investigations into the pathophysiology of HBV.