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JOURNAL ARTICLE
Yuening Chen, Wanlin Liu, Xiaohan Xu, Hongying Zhen, Bo Pang, Zhe Zhao, Yanan Zhao, Hongxiao Liu
Ankylosing spondylitis (AS) is a common chronic progressive inflammatory autoimmune disease. T helper 17 (Th17) cells are the major effector cells mediating AS inflammation. Histone 3 Lys 27 trimethylation (H3K27me3) is an inhibitory histone modification that silences gene transcription and plays an important role in Th17 differentiation. The objective of this study was to investigate the expression of H3K27me3 in patients with AS and to explore its epigenetic regulation mechanism of Th17 differentiation during AS inflammation...
March 22, 2024: Inflammation
#22
JOURNAL ARTICLE
Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms.
Tomohiko Sato, Kenichi Yoshida, Tsutomu Toki, Rika Kanezaki, Kiminori Terui, Ryunosuke Saiki, Masami Ojima, Yotaro Ochi, Seiya Mizuno, Masaharu Yoshihara, Tamayo Uechi, Naoya Kenmochi, Shiro Tanaka, Jun Matsubayashi, Kenta Kisai, Ko Kudo, Kentaro Yuzawa, Yuka Takahashi, Tatsuhiko Tanaka, Yohei Yamamoto, Akie Kobayashi, Takuya Kamio, Shinya Sasaki, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Hideki Muramatsu, Asahito Hama, Daisuke Hasegawa, Atsushi Sato, Katsuyoshi Koh, Shuhei Karakawa, Masao Kobayashi, Junichi Hara, Yuichi Taneyama, Chihaya Imai, Daiichiro Hasegawa, Naoto Fujita, Masahiro Yoshitomi, Shotaro Iwamoto, Genki Yamato, Satoshi Saida, Nobutaka Kiyokawa, Takao Deguchi, Masafumi Ito, Hidemasa Matsuo, Souichi Adachi, Yasuhide Hayashi, Takashi Taga, Akiko Moriya Saito, Keizo Horibe, Kenichiro Watanabe, Daisuke Tomizawa, Satoru Miyano, Satoru Takahashi, Seishi Ogawa, Etsuro Ito
Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse, and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing...
March 21, 2024: Blood
#23
JOURNAL ARTICLE
Lingyun Wang, Yunus Yukselten, Julius Nuwagaba, Richard E Sutton
CCR5 serves as R5-tropic HIV co-receptor. Knocking out CCR5 in HIV patients, which has occurred <10 times, is believed important for cure. JAK/STAT inhibitors tofacitinib and ruxolitinib inhibit CCR5 expression in HIV+ viremic patients. We investigated the association of JAK/STAT signaling pathway with CCR5/CCR2 expression in human primary CD4+ T cells and confirmed its importance. Six of nine JAK/STAT inhibitors that reduced CCR5/CCR2 expression were identified. Inhibitor-treated CD4+ T cells were relatively resistant, specifically to R5-tropic HIV infection...
March 22, 2024: Science Advances
#24
JOURNAL ARTICLE
Sara van Gennep, Ivan C N Fung, Djuna C de Jong, Rishand K Ramkisoen, Esmé Clasquin, Jitteke de Jong, Leonie C S de Vries, Wouter J de Jonge, Krisztina B Gecse, Mark Löwenberg, John C Woolcott, Aart Mookhoek, Geert R D'Haens
BACKGROUND AND AIMS: Histological outcomes and JAK-STAT signaling were assessed in a prospective ulcerative colitis (UC) patient cohort after 8 weeks treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor. METHODS: Forty UC patients received tofacitinib 10 mg twice daily for 8 weeks. Treatment response was defined as histo-endoscopic mucosal improvement (HEMI). Histological remission was defined as a Robarts Histopathology Index (RHI) ≤3 points and histological response as 50% decrease in RHI...
March 20, 2024: Journal of Crohn's & Colitis
#25
JOURNAL ARTICLE
Yan Yang, Xinmeng Wang, Jie Zhang
BACKGROUND: Pirfenidone and nintedanib were approved by the Food and Drug Administration (FDA) for the treatment of idiopathic pulmonary fibrosis (IPF). These two drugs can slow the progression of the disease, but the specific mechanisms are not fully understood. In the current study, bleomycin (BLM) induced pulmonary fibrosis in mice was accompanied by high p-JAK2 expression in lung tissue, mainly in the nucleus. The expression of p-JAK2 significantly decreased after intragastric administration of pirfenidone and nintedanib...
February 29, 2024: Journal of Thoracic Disease
#26
JOURNAL ARTICLE
Vikas Gupta, Stephen Oh, Timothy Devos, Viviane Dubruille, John Catalano, Tim C P Somervaille, Uwe Platzbecker, Pilar Giraldo, Hiroshi Kosugi, Tomasz Sacha, Jiri Mayer, Arpad Illes, Catherine Ellis, Zhaohui Wang, Francisco J Gonzalez Carreras, Bryan Strouse, Ruben Mesa
A key hallmark of myelofibrosis is anemia, which ranges from mild to severe based on hemoglobin levels. To more clearly define outcomes with the Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib by anemia severity, we performed a descriptive post hoc exploratory analysis of the double-blind, randomized, phase 3 SIMPLIFY-1 study (NCT01969838; N = 432, JAK inhibitor naive, momelotinib vs. ruxolitinib); subgroups were defined by baseline hemoglobin: <10 (moderate/severe), ≥10 to <12 (mild), or ≥12 g/dL (nonanemic)...
March 19, 2024: Leukemia & Lymphoma
#27
REVIEW
Siva Prasad Panda, Adarsh Kesharwani, Samaresh Datta, D S N B K Prasanth, Sunil Kumar Panda, Ajay Guru
Neurodegenerative diseases (NDDs) are a collection of incapacitating disorders in which neuroinflammation and neuronal apoptosis are major pathological consequences due to oxidative stress. Neuroinflammation manifests in the impacted cerebral areas as a result of pro-inflammatory cytokines stimulating the Janus Kinase2 (JAK2)/Signal Transducers and Activators of Transcription3 (STAT3) pathway via neuronal cells. The pro-inflammatory cytokines bind to their respective receptor in the neuronal cells and allow activation of JAK2...
March 14, 2024: European Journal of Pharmacology
#28
JOURNAL ARTICLE
Shuang Chen, Caihua Li, Zeng Tu, Tao Cai, Xinying Zhang, Lei Wang, Ruoyuan Tian, Jinglan Huang, Yuxuan Gong, Xiaotong Yang, Zetong Wu, Sirong He, Wenyan He, Dan Wang
As an inflammatory disease with a disrupted immune system, cytokine disorders in atopic dermatitis (AD) are closely related to the abnormal activation of JAK-STAT signal pathway. The critical relevance of the JAK-STAT signaling pathway to the pathogenesis of AD provides a strong rationale for JAK inhibitor research. Baricitinib, a small-molecule oral JAK inhibitor, has been proven to inhibit JAK-STAT signaling in a variety of diseases, including AD. It is currently available in China for off-label use. However, its efficacy in China and its mechanism are rarely reported...
2024: Frontiers in Pharmacology
#29
JOURNAL ARTICLE
Tim Kong, Nicole Gaudin, Karyn Gordon, Maggie J Cox, Amy W Zhou, Stephen T Oh
Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214)...
2024: Therapeutic Advances in Hematology
#30
REVIEW
Eric Morand, Joseph F Merola, Yoshiya Tanaka, Dafna Gladman, Roy Fleischmann
Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family of intracellular signalling molecules. By participating in signalling pathways downstream of type I interferons, IL-12, IL-23 and IL-10, TYK2 elicits a distinct set of immune events to JAK1, JAK2 and JAK3. TYK2 polymorphisms have been associated with susceptibility to various rheumatic diseases including systemic lupus erythematosus and dermatomyositis. In vitro and animal studies substantiate these findings, highlighting a role for TYK2 in diseases currently managed by antagonists of cytokines that signal through TYK2...
March 11, 2024: Nature Reviews. Rheumatology
#31
JOURNAL ARTICLE
Giulia Rotta, Ettore Gilardoni, Domenico Ravazza, Jacqueline Mock, Frauke Seehusen, Abdullah Elsayed, Emanuele Puca, Roberto De Luca, Christian Pellegrino, Thomas Look, Tobias Weiss, Markus G Manz, Cornelia Halin, Dario Neri, Sheila Dakhel Plaza
Cytokine-based therapeutics have been shown to mediate objective responses in certain tumor entities but suffer from insufficient selectivity, causing limiting toxicity which prevents dose escalation to therapeutically active regimens. The antibody-based delivery of cytokines significantly increases the therapeutic index of the corresponding payload but still suffers from side effects associated with peak concentrations of the product in blood upon intravenous administration. Here we devise a general strategy (named "Intra-Cork") to mask systemic cytokine activity without impacting anti-cancer efficacy...
March 6, 2024: EMBO Molecular Medicine
#32
JOURNAL ARTICLE
Camille Keenan, Sabrin Albeituni, Ninad Oak, Alexa N Stroh, Heather Tillman, Yingzhe Wang, Burgess B Freeman, Silvia Alemán-Arteaga, Lauren K Meyer, Rolanda Woods, Katherine C Verbist, Yinmei Zhou, Cheng Cheng, Kim E Nichols
Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK/STAT pathway. Indeed, the JAK1/2 inhibitor ruxolitinib has demonstrated efficacy in pre-clinical studies and early-phase clinical trials in HLH. Nevertheless, concerns remain for ruxolitinib-induced cytopenias, which are postulated to result from the blockade of JAK2-dependent hematopoietic growth factors. To explore the therapeutic effects of selective JAK inhibition in mouse models of HLH, we carried out studies incorporating the JAK1 inhibitor itacitinib, the JAK2 inhibitor fedratinib and the JAK1/2 inhibitor ruxolitinib...
March 6, 2024: Blood
#33
REVIEW
Sandy El Bitar, Murat O Arcasoy
The treatment landscape for BCR/ABL-negative myeloproliferative neoplasms (MPNs), driven by JAK2, CALR, and MPL mutations, has evolved significantly over the last decade. Recent regulatory approvals in polycythemia vera (PV) include the JAK inhibitor ruxolitinib, and more recently, a novel recombinant interferon alfa-2 (IFN-α) therapeutic agent. Many clinical trials have documented the safety and efficacy of IFN-α therapy in PV and essential thrombocythemia, the classical BCR/ABL-negative MPNs. Used off-label for more than 30 years as a cytoreductive agent, IFN-α therapy promotes significant clinical, hematologic, and molecular responses...
March 2024: Clinical Advances in Hematology & Oncology: H&O
#34
JOURNAL ARTICLE
Nadia Munir, Tahir Ali Chohan, Aisha Qayyum, Talha Ali Chohan, Fakhra Batool, Mian Waqar Mustafa, Sirajudheen Anwar, Fawaz Alheibshy, Weiam Hussein, Ahmed Alafnan, Umair Khurshid, Anjum Khursheed, Hammad Saleem
Janus kinase 2(JAK2) is a potential target for anticancer drugs in the treatment of numerous myeloproliferative diseases due to its central role in the JAK/STAT signaling cascade. In this study, the binding behavior of 2 amino-pyridine derivatives as JAK2 inhibitors was investigated by using multifaceted strategies including 3D-QSAR, molecular docking, Fingerprint analysis, MD simulations, and MM-PBSA calculations. A credible COMFA ( q 2 = 0.606 and r 2 = 0.919) and COMSIA ( q 2 = 0.641 and r 2 = 0.992) model was developed, where the internal and external validation revealed that the obtained 3D-QSAR models could be capable of predicting bioactivities of JAK2 inhibitors...
March 6, 2024: Journal of Biomolecular Structure & Dynamics
#35
JOURNAL ARTICLE
Min-Yung Kuo, Wen-Chyi Dai, Jie-Li Chang, Jo-Shu Chang, Tse-Min Lee, Chia-Che Chang
Melanoma is the most lethal skin malignancy. Fucoxanthin is a marine carotenoid with significant anticancer activities. Intriguingly, Fucoxanthin's impact on human melanoma remains elusive. Signal Transducer and Activator of Transcription 3 (STAT3) represents a promising target in cancer therapy due to its persistent activation in various cancers, including melanoma. Herein, we revealed that Fucoxanthin is cytotoxic to human melanoma cell lines A2758 and A375 while showing limited cytotoxicity to normal human melanocytes...
March 5, 2024: Environmental Toxicology
#36
JOURNAL ARTICLE
Garima Pandey, Lucia Mazzacurati, Tegan M Rowsell, Nathan P Horvat, Narmin E Amin, Guolin Zhang, Afua A Akuffo, Christelle M Colin-Leitzinger, Eric B Haura, Andrew T Kuykendall, Ling Zhang, Pearlie K Epling-Burnette, Gary W Reuther
Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, are clonal hematopoietic neoplasms driven by mutationally activated signaling by the JAK2 tyrosine kinase. Although JAK2 inhibitors can improve MPN patients' quality of life, they do not induce complete remission as disease-driving cells persistently survive therapy. ERK activation has been highlighted as contributing to JAK2 inhibitor persistent cell survival. As ERK is a component of signaling by activated RAS proteins and by JAK2 activation, we sought to inhibit RAS activation to enhance responses to JAK2 inhibition in preclinical MPN models...
March 5, 2024: American Journal of Hematology
#37
JOURNAL ARTICLE
Zhang Yaqin, Wu Kehan, Zhu Yi, Wang Naijian, Qiu Wei, Mao Fei
The role of O-linked N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) in the pathogenesis of inflammatory bowel disease (IBD) has been increasingly highlighted in recent studies. It's been reported that signal transducer and activator of transcription 3 (STAT3) O-GlcNAcylation can affect the activity of the Janus kinase2 (JAK2)/STAT3 pathway.Our recent study showed that resveratrol repairsIBDin mice.On this basis,the present study aimed to explore whether the mechanism of IBD repair by resveratrol is associated with STAT3 O-GlcNAcylation...
March 2, 2024: Toxicology and Applied Pharmacology
#38
JOURNAL ARTICLE
Junya Zeng, Ziman Lin, Jiangyu Tang, Xingxiang Chen, Kehe Huang, Fang Gan
Deoxynivalenol (DON) as a mycotoxin was commonly found in food and cereals which can affect immune function and inflammatory response. The majority of foods contain DON at levels below the official limit. This study aimed to evaluate the effects of non-cytotoxic concentration of DON on inflammation and its mechanisms using the IL-10 gene-silenced RAW264.7 cell model. The results showed that a non-cytotoxic concentration of DON at 25 ng/ml aggravated IL-10 knockdown-induced inflammation, which was manifested by increasing IL-1β and TNF-α mRNA expression, migration and phagocytosis, decreasing IL-10 mRNA expression, and enhancing JAK2/STAT3 phosphorylation...
March 1, 2024: Food and Chemical Toxicology
#39
JOURNAL ARTICLE
Kathryn A F Pennel, Phimmada Hatthakarnkul, Colin S Wood, Guang-Yu Lian, Sara S F Al-Badran, Jean A Quinn, Assya Legrini, Jitwadee Inthagard, Peter G Alexander, Hester van Wyk, Ahmad Kurniawan, Umar Hashmi, Michael A Gillespie, Megan Mills, Aula Ammar, Jennifer Hay, Ditte Andersen, Colin Nixon, Selma Rebus, David K Chang, Caroline Kelly, Andrea Harkin, Janet Graham, David Church, Ian Tomlinson, Mark Saunders, Tim Iveson, Tamsin R M Lannagan, Rene Jackstadt, Noori Maka, Paul G Horgan, Campbell S D Roxburgh, Owen J Sansom, Donald C McMillan, Colin W Steele, Nigel B Jamieson, James H Park, Antonia K Roseweir, Joanne Edwards
Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids...
March 1, 2024: Journal of Experimental & Clinical Cancer Research: CR
#40
JOURNAL ARTICLE
Zhengyang Hu, Qihai Sui, Xing Jin, Guangyao Shan, Yiwei Huang, Yanjun Yi, Dejun Zeng, Mengnan Zhao, Cheng Zhan, Qun Wang, Zongwu Lin, Tao Lu, Zhencong Chen
BACKGROUND: Lung cancer is one of the most common tumors in the world, and metastasis is one of the major causes of tumor-related death in lung cancer patients. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and are frequently associated with tumor metastasis in human cancers. However, the regulatory mechanisms of TAMs in lung cancer metastasis remain unclear. METHODS: Single-cell sequencing analysis of lung cancer and normal tissues from public databases and from 14 patients who underwent surgery at Zhongshan Hospital was performed...
February 29, 2024: Journal of Experimental & Clinical Cancer Research: CR
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