keyword
https://read.qxmd.com/read/36964178/aiolos-represses-cd4-t-cell-cytotoxic-programming-via-reciprocal-regulation-of-t-fh-transcription-factors-and-il-2-sensitivity
#21
JOURNAL ARTICLE
Kaitlin A Read, Devin M Jones, Srijana Pokhrel, Emily D S Hales, Aditi Varkey, Jasmine A Tuazon, Caprice D Eisele, Omar Abdouni, Abbey Saadey, Melissa R Leonard, Robert T Warren, Michael D Powell, Jeremy M Boss, Emily A Hemann, Jacob S Yount, Gang Xin, Hazem E Ghoneim, Chan-Wang J Lio, Aharon G Freud, Patrick L Collins, Kenneth J Oestreich
During intracellular infection, T follicular helper (TFH ) and T helper 1 (TH 1) cells promote humoral and cell-mediated responses, respectively. Another subset, CD4-cytotoxic T lymphocytes (CD4-CTLs), eliminate infected cells via functions typically associated with CD8+ T cells. The mechanisms underlying differentiation of these populations are incompletely understood. Here, we identify the transcription factor Aiolos as a reciprocal regulator of TFH and CD4-CTL programming. We find that Aiolos deficiency results in downregulation of key TFH transcription factors, and consequently reduced TFH differentiation and antibody production, during influenza virus infection...
March 24, 2023: Nature Communications
https://read.qxmd.com/read/36929172/imid-resistance-in-multiple-myeloma-current-understanding-of-the-underpinning-biology-and-clinical-impact
#22
JOURNAL ARTICLE
Sarah Anne Bird, Charlotte Pawlyn
Immunomodulatory agents (IMiDs) are a cornerstone of treatment for patients with multiple myeloma. IMiDs are used in therapeutic combinations at all stages of disease and are approved as a single agent maintenance treatment after autologous stem cell transplantation. However patients will become resistant to ongoing therapy over time and inevitably relapse. It is only in the last decade that the mechanism of IMiD action has been elucidated; through binding to the cereblon component of the CRL4CRBN E3 ubiquitin ligase a set of neosubstrates is designated for degradation by the proteosome...
March 16, 2023: Blood
https://read.qxmd.com/read/36928053/-not-available
#23
JOURNAL ARTICLE
(no author information available yet)
No abstract text is available yet for this article.
2023: Arerugī, [Allergy]
https://read.qxmd.com/read/36289711/activity-of-a-novel-anti-inflammatory-agent-f-3-6-dithiopomalidomide-as-a-treatment-for-traumatic-brain-injury
#24
JOURNAL ARTICLE
Shih Chang Hsueh, Michael T Scerba, David Tweedie, Daniela Lecca, Dong Seok Kim, Abdul Mannan Baig, Yu Kyung Kim, Inho Hwang, Sun Kim, Warren R Selman, Barry J Hoffer, Nigel H Greig
Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson's disease (PD) and Alzheimer's disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders...
September 30, 2022: Biomedicines
https://read.qxmd.com/read/36284352/autoimmune-gene-expression-profiling-of-fingerstick-whole-blood-in-chronic-fatigue-syndrome
#25
JOURNAL ARTICLE
Zheng Wang, Michelle F Waldman, Tara J Basavanhally, Aviva R Jacobs, Gonzalo Lopez, Regis Y Perichon, Johnny J Ma, Elyse M Mackenzie, James B Healy, Yixin Wang, Sarah A Hersey
BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition that can lead to severe impairment of physical, psychological, cognitive, social, and occupational functions. The cause of ME/CFS remains incompletely understood. There is no clinical diagnostic test for ME/CFS. Although many therapies have been used off-label to manage symptoms of ME/CFS, there are limited, if any, specific therapies or cure for ME/CFS. In this study, we investigated the expression of genes specific to key immune functions, and viral infection status in ME/CFS patients with an aim of identifying biomarkers for characterization and/or treatment of the disease...
October 25, 2022: Journal of Translational Medicine
https://read.qxmd.com/read/36164087/abcl-412-clinical-activity-of-cc-99282-a-novel-oral-small-molecule-cereblon-e3-ligase-modulator-celmod-agent-in-patients-with-relapsed-refractory-non-hodgkin-lymphoma-r-r-nhl-results-from-cc-99282-nhl-001-nct03930953-a-first-in-human-phase-1-open-label-multicenter
#26
MULTICENTER STUDY
Julio C Chavez, Jean-Marie Michot, Cecilia Carpio, Silvia Ferrari, Tatyana A Feldman, Daniel Morillo, John Kuruvilla, Antonio Pinto, Vincent Ribrag, Emmanuel Bachy, Tonia J Buchholz, Soraya Carrancio, Wen-Chi Chou, Carla Guarinos, Fan Wu, Shaoyi Li, Poliana Patah, Michael Pourdehnad, Loretta Nastoupil
CC-99282, a CELMoD® agent, co-opts cereblon to induce targeted degradation of Ikaros/Aiolos. In preclinical studies, CC-99282 exhibited stronger antiproliferative, apoptotic, and immunostimulatory activities compared with lenalidomide and other CELMoD agents. Here we present results of CC-99282 monotherapy in patients with R/R NHL. This 2-part study comprises CC-99282 monotherapy dose escalation (part A) and expansion ± combination partners (part B). Part A includes patients with R/R diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) that progressed after ≥2 lines of therapy (LOTs) and patients with R/R DLBCL unfit for transplant who have received ≥1 standard LOT...
October 2022: Clinical Lymphoma, Myeloma & Leukemia
https://read.qxmd.com/read/36163884/cll-240-frequency-of-ikzf3-l162r-mutation-in-b-cell-lymphoproliferative-disorders
#27
JOURNAL ARTICLE
Assia Taleb, Carole Fleury, Florence Cymbalista, Fanny Baran-Marszak, Gregory Lazarian
A mutation of AIOLOS/IKZF3, a member of the IKAROS family transcription factors has been identified as a putative driver of chronic lymphocytic leukemia (CLL) through large-scale WES studies of CLL patients, with a frequency of ~3% CLLs. The mutation has been detected uniquely as a hotspot mutation (L162R), localized within the DNA binding domain, conferring a gain-of-function by altering DNA binding specificity and expression of IKZF3 target genes, resulting in overexpression of B-cell receptor (BCR) signaling genes...
October 2022: Clinical Lymphoma, Myeloma & Leukemia
https://read.qxmd.com/read/36077711/ck1%C3%AE-runx2-axis-in-the-bone-marrow-microenvironment-a-novel-therapeutic-target-in-multiple-myeloma
#28
JOURNAL ARTICLE
Anna Fregnani, Lara Saggin, Ketty Gianesin, Laura Quotti Tubi, Marco Carraro, Gregorio Barilà, Greta Scapinello, Giorgia Bonetto, Maria Pesavento, Tamara Berno, Antonio Branca, Carmela Gurrieri, Renato Zambello, Gianpietro Semenzato, Livio Trentin, Sabrina Manni, Francesco Piazza
Multiple myeloma (MM) is a malignant plasma cell (PC) neoplasm, which also displays pathological bone involvement. Clonal expansion of MM cells in the bone marrow causes a perturbation of bone homeostasis that culminates in MM-associated bone disease (MMABD). We previously demonstrated that the S/T kinase CK1α sustains MM cell survival through the activation of AKT and β-catenin signaling. CK1α is a negative regulator of the Wnt/β-catenin cascade, the activation of which promotes osteogenesis by directly stimulating the expression of RUNX2 , the master gene regulator of osteoblastogenesis...
August 29, 2022: Cancers
https://read.qxmd.com/read/36007246/redirecting-the-neo-substrate-specificity-of-cereblon-targeting-protacs-to-helios
#29
JOURNAL ARTICLE
Alyssa L Verano, Inchul You, Katherine A Donovan, Nada Mageed, Hong Yue, Radosław P Nowak, Eric S Fischer, Eric S Wang, Nathanael S Gray
Immunomodulatory imide drugs (IMiDs), such as thalidomide and its analogues, are some of the most commonly utilized E3 ligase ligands for the development of proteolysis targeting chimeras (PROTACs). While the canonical neo-substrates of IMiDs (i.e., Ikaros and Aiolos) are often considered to be unwanted targets of PROTACs, maintaining the degradation of these neo-substrates also provides the opportunity to synergistically degrade multiple proteins with a single compound. Here, we report the development of ALV-07-082-03, a CDK4/CDK6/Helios triple degrader that consists of palbociclib, an FDA-approved CDK4/6 inhibitor, conjugated to DKY709, a novel IMiD-based Helios degrader...
August 25, 2022: ACS Chemical Biology
https://read.qxmd.com/read/35895319/discovery-of-a-first-in-class-degrader-for-nuclear-receptor-binding-set-domain-protein-2-nsd2-and-ikaros-aiolos
#30
JOURNAL ARTICLE
Fanye Meng, Chenxi Xu, Kwang-Su Park, H Ümit Kaniskan, Gang Greg Wang, Jian Jin
Overexpression of nuclear receptor binding SET domain protein 2 (NSD2) is frequent in multiple myeloma (MM). However, existing NSD2 inhibitors are largely ineffective in suppressing MM cell proliferation. Here, we report the discovery of a first-in-class NSD2 proteolysis targeting chimera (PROTAC) degrader, 9 (MS159), and two structurally similar controls, 17 (MS159N1) and 18 (MS159N2), with diminished binding to the cereblon (CRBN) E3 ligase and NSD2, respectively. Compound 9 , but not 17 and 18 , effectively degraded NSD2 in a concentration-, time-, CRBN-, and proteasome-dependent manner...
August 11, 2022: Journal of Medicinal Chemistry
https://read.qxmd.com/read/35883614/regulatory-t-cells-from-patients-with-rheumatoid-arthritis-are-characterized-by-reduced-expression-of-ikaros-zinc-finger-transcription-factors
#31
JOURNAL ARTICLE
Mara Dittrich-Salamon, Anja Meyer, Shuaifeng Yan, Eva Steinbach-Knödgen, Konstantin Kotschenreuther, David Stahl, Carola Tho Pesch, Joanna Schiller, Franziska Byrtus, Dorothee Jochimsen, Viktoria Golumba-Nagy, David M Kofler
Regulatory T (Treg) cells play an important role in immune tolerance and contribute to the prevention of autoimmune diseases, including rheumatoid arthritis (RA). The differentiation, function and stability of Treg cells is controlled by members of the Ikaros zinc finger transcription factor family. In this study, we aimed to reveal how the expression of Ikaros transcription factors is affected by disease activity in RA. Therefore, we analyzed the ex vivo expression of Ikaros, Helios, Aiolos and Eos in Treg cells, Th17 cells and Th1 cells from RA patients by flow cytometry...
July 11, 2022: Cells
https://read.qxmd.com/read/35831638/ikaros-aiolos-and-other-moving-targets-to-treat-sle
#32
JOURNAL ARTICLE
Afroditi Boulougoura, George C Tsokos
No abstract text is available yet for this article.
July 13, 2022: Nature Reviews. Rheumatology
https://read.qxmd.com/read/35831190/-development-of-novel-cereblon-modulators-and-their-target-molecules
#33
REVIEW
Takumi Ito
Thalidomide was developed as a sedative drug during the 1950s. Unfortunately, it has serious teratogenic properties. When pregnant women ingested thalidomide, their infants developed serious malformations such as short limbs. However, thalidomide is now recognized as a clinically useful drug, with several countries approving it as an anti-myeloma treatment. Although the direct target of thalidomide was largely debated until recently, our groups discovered cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase as a primary target of thalidomide in 2010...
2022: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://read.qxmd.com/read/35717803/structure-activity-relationship-analysis-of-novel-gspt1-degraders-based-on-benzotriazinone-scaffold-and-its-antitumor-effect-on-xenograft-mouse-model
#34
JOURNAL ARTICLE
Akshay D Takwale, Eun Yeong Kim, Yerin Jang, Dong Ho Lee, Seulgi Kim, Yuri Choi, Jin Hwan Kim, Da Yeon Lee, Yeongrin Kim, So Myoung Lee, Heung Kyoung Lee, Hye Jin Nam, Joo-Youn Lee, Jin Hwa Cho, Jeong Hee Moon, Ga Seul Lee, Jeong-Hoon Kim, Pilho Kim, Chi Hoon Park, Jong Yeon Hwang
Molecular glue degraders, such as lenalidomide and pomalidomide, bind to cereblon (CRBN) E3 ligase and subsequently recruit neosubstrate proteins, Ikaros (IKZF1) and Aiolos (IKZF3), for the ubiquitination-proteasomal degradation process. In this study, we explored structure-activity relationship analysis for novel GSPT1 degraders utilizing a benzotriazinone scaffold previously discovered as a novel CRBN binder. In particular, we focused on the position of the ureido group on the benzotriazinone scaffold, substituent effect on the phenylureido group, and methyl substitution on the benzylic position of benzotriazinone...
October 2022: Bioorganic Chemistry
https://read.qxmd.com/read/35704067/-iberdomide-against-aiolos-and-ikaros-in-systemic-lupus-erythematosus
#35
JOURNAL ARTICLE
Johanna Mucke
No abstract text is available yet for this article.
June 15, 2022: Zeitschrift Für Rheumatologie
https://read.qxmd.com/read/35631536/3-6-and-1-6-dithiopomalidomide-mitigate-ischemic-stroke-in-rats-and-blunt-inflammation
#36
JOURNAL ARTICLE
Yan-Rou Tsai, Dong Seok Kim, Shih-Chang Hsueh, Kai-Yun Chen, John Chung-Che Wu, Jia-Yi Wang, Yi-Syue Tsou, Inho Hwang, Yukyung Kim, Dayeon Gil, Eui Jung Jo, Baek-Soo Han, David Tweedie, Daniela Lecca, Michael T Scerba, Warren R Selman, Barry J Hoffer, Nigel H Greig, Yung-Hsiao Chiang
( 1 ) Background: An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. ( 2 ) Methods: Two novel pomalidomide derivatives, 3,6'-dithiopomalidomide (3,6'-DP) and 1,6'-dithiopomalidomide (1,6'-DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti-inflammatory actions were characterized...
April 27, 2022: Pharmaceutics
https://read.qxmd.com/read/35585966/pomalidomide-and-dexamethasone-based-regimens-in-the-treatment-of-refractory-relapsed-multiple-myeloma
#37
REVIEW
Despina Fotiou, Maria Gavriatopoulou, Evangelos Terpos, Meletios A Dimopoulos
Pomalidomide is a potent immunomodulatory agent that is currently a standard of care backbone for the treatment of multiple myeloma (MM) patients in the relapsed/refractory setting after exposure to lenalidomide and a proteasome inhibitor. The present review addresses current knowledge regarding the clinical use of pomalidomide in relapsed myeloma patients. Pomalidomide has direct myeloma cell tumoricidal effects by activating proteasomal degradation of Ikaros and Aiolos transcription factors and also indirect effects by modulation of immune responses, interaction with bone marrow stromal cells, and inhibition of angiogenesis...
2022: Therapeutic Advances in Hematology
https://read.qxmd.com/read/35583604/interactome-of-aiolos-ikaros-reveals-combination-rationale-of-cereblon-modulators-with-hdac-inhibitors-in-dlbcl
#38
JOURNAL ARTICLE
Patrick R Hagner, Hsiling Chiu, Vivek S Chopra, Martino Colombo, Nisha Patel, Maria Ortiz Estevez, Michelle F Waldman, Remco Loos, Fadi Towfic, Anita K Gandhi
PURPOSE: Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of the small molecules lenalidomide (Len) and avadomide (Ava). Upon binding of the drugs, Aiolos and Ikaros are recruited to the E3 ligase, ubiquitylated and subsequently degraded. In DLBCL cells, Aiolos and Ikaros are direct transcriptional repressors of interferon stimulated genes (ISG) and degradation of these substrates results in increased ISG protein levels resulting in decreased proliferation and apoptosis...
May 18, 2022: Clinical Cancer Research
https://read.qxmd.com/read/35477518/biological-impact-of-iberdomide-in-patients-with-active-systemic-lupus-erythematosus
#39
JOURNAL ARTICLE
Peter E Lipsky, Ronald van Vollenhoven, Thomas Dörner, Victoria P Werth, Joan T Merrill, Richard Furie, Milan Petronijevic, Benito Velasco Zamora, Maria Majdan, Fedra Irazoque-Palazuelos, Robert Terbrueggen, Nikolay Delev, Michael Weiswasser, Shimon Korish, Mark Stern, Sarah Hersey, Ying Ye, Allison Gaudy, Zhaohui Liu, Robert Gagnon, Shaojun Tang, Peter H Schafer
OBJECTIVES: Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros ( IKZF1 ) and Aiolos ( IKZF3 ). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE). METHODS: Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81)...
April 27, 2022: Annals of the Rheumatic Diseases
https://read.qxmd.com/read/35444653/aiolos-variants-causing-immunodeficiency-in-human-and-mice
#40
REVIEW
Motoi Yamashita, Tomohiro Morio
AIOLOS is encoded by IKZF3 and is a member of the IKAROS zinc finger transcription factor family. Heterozygous missense variants in the second zinc finger of AIOLOS have recently been reported to be found in the families of patients with inborn errors of immunity. The AIOLOSG159R variant was identified in patients with B-lymphopenia and familial Epstein-Barr virus-associated lymphoma. Early B-cell progenitors were significantly reduced in the bone marrow of patients with AIOLOSG159R . Another variant, AIOLOSN160S was identified in the patients presented with hypogammaglobulinemia, susceptibility to Pneumocystis jirovecii pneumonia, and chronic lymphocytic leukemia...
2022: Frontiers in Immunology
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