journal
https://read.qxmd.com/read/37788110/a-splice-switching-oligonucleotide-treatment-ameliorates-glycogen-storage-disease-type-1a-with-g6pc-c-648g-t
#1
JOURNAL ARTICLE
Kentaro Ito, Go Tajima, Chikako Kamisato, Miyuki Tsumura, Mitsuhiro Iwamoto, Yukiko Sekiguchi, Yukinobu Numata, Kyoko Watanabe, Yoshiyuki Yabe, Satomi Kanki, Yusuke Fujieda, Koichi Goto, Yoshitaka Sogawa, Masataka Oitate, Hiroyuki Nagase, Shinnosuke Tsuji, Tomohiro Nishizawa, Masayo Kakuta, Takeshi Masuda, Yoshiyuki Onishi, Makoto Koizumi, Hidefumi Nakamura, Satoshi Okada, Masafumi Matsuo, Kiyosumi Takaishi
Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-alpha (G6Pase-α, encoded by G6PC), primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves the life expectancy, patients still suffer from intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno-associated virus and mRNA with lipid nanoparticles are under development for GSD1a, but potentially require complicated glycemic management throughout life...
October 3, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37788109/engineered-hydrogel-reveals-contribution-of-matrix-mechanics-to-esophageal-adenocarcinoma-and-identifies-matrix-activated-therapeutic-targets
#2
JOURNAL ARTICLE
Ricardo Cruz-Acuña, Secunda W Kariuki, Kensuke Sugiura, Spyros Karaiskos, Eleanor M Plaster, Claudia Loebel, Gizem Efe, Tatiana A Karakasheva, Joel T Gabre, Jianhua Hu, Jason A Burdick, Anil K Rustgi
Increased extracellular matrix (ECM) stiffness has been implicated in esophageal adenocarcinoma (EAC) progression, metastasis, and resistance to therapy. However, the underlying pro-tumorigenic pathways are yet to be defined. Additional work is needed to develop physiologically relevant in vitro 3D culture models that better recapitulate the human tumor microenvironment and can be used to dissect the contributions of matrix stiffness to EAC pathogenesis. Here, we describe a modular, tumor ECM-mimetic hydrogel platform with tunable mechanical properties, defined presentation of cell-adhesive ligands, and protease-dependent degradation that supports robust in vitro growth and expansion of patient-derived EAC 3D organoids (EAC PDOs)...
October 3, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37788096/recruitment-of-na%C3%A3-ve-cd4-t-cells-by-the-recombinant-zoster-vaccine-correlates-with-persistent-immunity
#3
JOURNAL ARTICLE
Kerry J Laing, Emily S Ford, Michael J Johnson, Myron J Levin, David M Koelle, Adriana Weinberg
Herpes zoster (HZ) is a substantial problem for people with decreased cell-mediated immunity, including older adults. The first vaccine approved for HZ prevention, the zoster vaccine live (ZVL), which provided limited and short-lived protection, has been supplanted by the superior recombinant zoster vaccine (RZV), which provides robust and durable protection. To understand the mechanisms underlying the differential immunologic characteristics of the two vaccines, we used T cell receptor beta sequencing and peptide-MHC class II tetramer staining to analyze gE-specific CD4+ T cell clonotypes in RZV and ZVL recipients...
October 3, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37788092/usp47-inhibits-m6a-dependent-c-myc-translation-to-maintain-regulatory-t-cell-metabolic-and-functional-homeostasis
#4
JOURNAL ARTICLE
Aiting Wang, Haiyan Huang, Jian-Hong Shi, Xiaoyan Yu, Rui Ding, Yuerong Zhang, Qiaoqiao Han, Zhi-Yu Ni, Xia Li, Ren Zhao, Qiang Zou
The functional integrity of Treg cells is interwoven with cellular metabolism; however, the mechanisms governing Treg cell metabolic programs remain elusive. Here, we identified that the deubiquitinase USP47 inhibited RNA m6A reader YTHDF1-mediated c-Myc translation to maintain Treg cell metabolic and functional homeostasis. USP47 positively correlated with the tumor-infiltrating Treg cell signature in colorectal cancer and gastric cancer patient samples. USP47 ablation compromised Treg cell homeostasis and function in vivo, resulting in the development of inflammatory disorders, and boosted antitumor immune responses...
October 3, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37788087/endothelial-adam10-utilization-defines-a-molecular-pathway-of-vascular-injury-in-mice-with-bacterial-sepsis
#5
JOURNAL ARTICLE
Danielle N Alfano, Mark J Miller, Juliane Bubeck Wardenburg
The endothelium plays a critical role in the host response to infection, and has been a focus of investigation in sepsis. While it is appreciated that intravascular thrombus formation, severe inflammation, and loss of endothelial integrity impair tissue oxygenation during sepsis, the precise molecular mechanisms that lead to endothelial injury remain poorly understood. We demonstrate herein that endothelial ADAM10 is essential for the pathogenesis of Staphylococcus aureus sepsis, contributing to a-toxin (Hla)-mediated microvascular thrombus formation and lethality...
October 3, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37768734/regulation-of-epithelial-transitional-states-in-murine-and-human-pulmonary-fibrosis
#6
JOURNAL ARTICLE
Fa Wang, Christopher Ting, Kent A Riemondy, Michael T Douglas, Kendall M Foster, Nisha Patel, Norihito Kaku, Alexander E Linsalata, Jean Nemzek, Brian M Varisco, Erez Cohen, Jasmine A Wilson, David Wh Riches, Elizabeth F Redente, Diana M Toivola, Xiaofeng Zhou, Bethany B Moore, Pierre A Coulombe, M Bishir Omary, Rachel L Zemans
Idiopathic Pulmonary Fibrosis (IPF) is a progressive scarring disease arising from impaired regeneration of the alveolar epithelium after injury. During regeneration, type 2 alveolar epithelial cells (AEC2s) assume a transitional state that upregulates multiple keratins, and ultimately differentiate into AEC1s. In IPF, transitional AECs accumulate with ineffectual AEC1 differentiation. However, whether and how transitional cells cause fibrosis, whether keratins regulate transitional cell accumulation and fibrosis, and why transitional AECs and fibrosis resolve in mouse models but accumulate in IPF are unclear...
September 28, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37751307/the-catalytic-subunit-of-dna-pk-regulates-transcription-and-splicing-of-ar-in-advanced-prostate-cancer
#7
JOURNAL ARTICLE
Beth Adamson, Nicholas Brittain, Laura Walker, Ruaridh Duncan, Sara Luzzi, Pasquale Rescigno, Graham R Smith, Suzanne McGill, Richard Js Burchmore, Elaine Willmore, Ian Hickson, Craig N Robson, Denisa Bogdan, Juan M Jimenez-Vacas, Alec Paschalis, Jonathan Welti, Wei Yuan, Stuart R McCracken, Rakesh Heer, Adam Sharp, Johann de Bono, Luke Gaughan
Aberrant androgen receptor (AR) signalling drives prostate cancer (PC) and is a key therapeutic target. Although initially effective, the generation of alternatively spliced AR variants (AR-Vs) compromises efficacy of treatments. In contrast to full-length AR (AR-FL), AR-Vs constitutively activate androgenic signalling and are refractory to the current repertoire of AR-targeting therapies, which together drives disease progression. There is an unmet clinical need therefore to develop more durable PC therapies that can attenuate AR-V function...
September 26, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37751301/the-effect-of-glucagon-like-peptide-1-receptor-blockade-on-islet-secretion-and-glucose-metabolism-in-humans
#8
JOURNAL ARTICLE
Andrew A Welch, Rahele A Farahani, Aoife M Egan, Marcello C Laurenti, Maya Zeini, Max Vella, Kent R Bailey, Claudio Cobelli, Chiara Dalla Dalla Man, Aleksey Matveyenko, Adrian Vella
BACKGROUND: Proglucagon can be processed to Glucagon-Like Peptide-1 (GLP-1) within the islet but its contribution to islet function in humans remains unknown. We sought to understand whether 'pancreatic' GLP-1 alters islet function in humans and whether this is affected by type 2 diabetes. METHODS: We therefore studied individuals with and without type 2 diabetes on 2 occasions in random order. On one occasion exendin 9-39, a competitive antagonist of the GLP-1 Receptor (GLP1R), was infused, while on the other saline was infused...
September 26, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37751299/hyperphosphorylation-of-bcl-2-family-proteins-underlies-functional-resistance-to-venetoclax-in-lymphoid-malignancies
#9
JOURNAL ARTICLE
Stephen Jun Fei Chong, Fen Zhu, Olga Dashevsky, Rin Mizuno, Jolin Xh Lai, Liam Hackett, Christine E Ryan, Mary C Collins, J Bryan Iorgulescu, Romain Guièze, Johany Penailillo, Ruben Carrasco, Yeonjoo C Hwang, Denise P Muñoz, Mehdi Bouhaddou, Yaw Chyn Lim, Catherine J Wu, John N Allan, Richard R Furman, Boon Cher Goh, Shazib Pervaiz, Jean-Philippe Coppé, Constantine S Mitsiades, Matthew S Davids
The BCL-2 inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B-cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL-2 mutations have been described, this likely only explains a subset of resistant cases. Using two complementary functional precision medicine techniques -- BH3-profiling and high throughput-kinase activity mapping -- we found that hyperphosphorylation of BCL-2 family proteins, including anti-apoptotic MCL-1 and BCL-2 and pro-apoptotic BAD and BAX, underlies functional mechanisms of both intrinsic and acquired resistance of venetoclax in CLL and DLBCL...
September 26, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37751296/type-i-interferon-signature-and-cycling-lymphocytes-in-macrophage-activation-syndrome
#10
JOURNAL ARTICLE
Zhengping Huang, Kailey E Brodeur, Liang Chen, Yan Du, Holly Wobma, Evan E Hsu, Meng Liu, Joyce C Chang, Margaret H Chang, Janet Chou, Megan Day-Lewis, Fatma Dedeoglu, Olha Halyabar, James A Lederer, Tianwang Li, Mindy S Lo, Meiping Lu, Esra Meidan, Jane W Newburger, Adrienne G Randolph, Mary Beth F Son, Robert P Sundel, Maria L Taylor, Huaxiang Wu, Qing Zhou, Scott W Canna, Kevin Wei, Lauren A Henderson, Peter A Nigrovic, Pui Y Lee
BACKGROUND: Macrophage activation syndrome (MAS) is a life-threatening complication of Still's disease (SD) characterized by overt immune cell activation and cytokine storm. We aimed to further understand the immunologic landscape of SD and MAS. METHOD: We profiled peripheral blood mononuclear cells (PBMC) from healthy controls and patients with SD with or without MAS using bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq). We validated and expanded the findings by mass cytometry, flow cytometry and in vitro studies...
September 26, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37733448/a-paracrine-circuit-of-il-1%C3%AE-il-1r1-between-myeloid-and-tumor-cells-drives-genotype-dependent-glioblastoma-progression
#11
JOURNAL ARTICLE
Zhihong Chen, Bruno Giotti, Milota Kaluzova, Montserrat Puigdelloses Vallcorba, Kavita Rawat, Gabrielle Price, Cameron J Herting, Gonzalo Piñero, Simona Cristea, James L Ross, James Ackley, Victor Maximov, Frank Szulzewsky, Wes Thomason, Mar Marquez-Ropero, Angelo Angione, Noah Nichols, Nadejda M Tsankova, Franziska Michor, Dmitry M Shayakhmetov, David H Gutmann, Alexander M Tsankov, Dolores Hambardzumyan
Monocytes and monocyte-derived macrophages (MDM) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here we show that PDGFB-driven GBM cells induce the expression of the potent pro-inflammatory cytokine IL-1β in MDM, which engages IL-1R1 in tumor cells, activates the NF-kB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression...
September 21, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37733443/initial-productive-and-latent-hiv-infections-originate-in-vivo-by-infection-of-resting-t-cells
#12
JOURNAL ARTICLE
Stephen W Wietgrefe, Jodi Anderson, Lijie Duan, Peter J Southern, Paul Zuck, Guoxin Wu, Bonnie J Howell, Cavan Reilly, Eugène Kroon, Suthat Chottanapund, Supranee Buranapraditkun, Carlo Sacdalan, Nicha Tulmethakaan, Donn J Colby, Nitiya Chomchey, Peeriya Prueksakaew, Suteeraporn Pinyakorn, Rapee Trichavaroj, Julie L Mitchell, Lydie Trautmann, Denise C Hsu, Sandhya Vasan, Sopark Manasnayakorn, Mark de Souza, Sodsai Tovanabutra, Alexandra Schuetz, Merlin L Robb, Nittaya Phanuphak, Jintanat Ananworanich, Timothy W Schacker, Ashley T Haase
Productively infected cells are generally thought to arise by HIV infection of activated CD4+ T cells, and these infected activated cells are also thought to be a recurring source of latently infected cells when a portion of the population transitions to a resting state. We discovered and report here that productively and latently infected cells can instead originate by direct infection of resting CD4+ T cell populations in lymphoid tissues in Fiebig I, the earliest stage of detectable HIV infection. We found that direct infection of resting CD4+ T cells was correlated with the availability of susceptible target cells in lymphoid tissues restricted to resting CD4+ T cells and expression of pTEFb in these resting cells to enable productive infection, and we documented persistence of HIV producing resting T cells during ART...
September 21, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37733441/population-level-single-cell-genomics-reveals-conserved-gene-programs-in-systemic-juvenile-idiopathic-arthritis
#13
JOURNAL ARTICLE
Emely L Verweyen, Kairavee Thakkar, Sanjeev Dhakal, Elizabeth J Baker, Kashish Chetal, Daniel Schnell, Scott W Canna, Alexei A Grom, Nathan Salomonis, Grant S Schulert
Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared amongst distinct patient subsets. Here, we performed single-cell RNA-Seq of PBMCs of systemic juvenile idiopathic arthritis (SJIA) patients with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD)...
September 21, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37731359/alphafold-developers-demis-hassabis-and-john-jumper-share-the-2023-albert-lasker-basic-medical-research-award
#14
JOURNAL ARTICLE
Tobin R Sosnick
No abstract text is available yet for this article.
September 21, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37731358/optical-coherence-tomography-when-a-picture-is-worth-a-million-words
#15
JOURNAL ARTICLE
Simone Tzaridis, Martin Friedlander
No abstract text is available yet for this article.
September 21, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37725435/tumor-derived-biomarkers-predict-efficacy-of-b7h3-antibody-drug-conjugate-treatment-in-metastatic-prostate-cancer-models
#16
JOURNAL ARTICLE
Supreet Agarwal, Lei Fang, Kerry McGowen, JuanJuan Yin, Joel Bowman, Anson T Ku, Aian Neil Alilin, Eva Corey, Martine P Roudier, Lawrence D True, Ruth F Dumpit, Ilsa Coleman, John K Lee, Peter S Nelson, Brian J Capaldo, Aida Mariani, Clare E Hoover, Ilya S Senatorov, Michael Beshiri, Adam G Sowalsky, Elaine M Hurt, Kathleen Kelly
Antibody-drug conjugates(ADCs) are promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer(mPC) models...
September 19, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37721853/glut3-promotes-macrophage-signaling-and-function-via-ras-mediated-endocytosis-in-atopic-dermatitis-and-wound-healing
#17
JOURNAL ARTICLE
Dong-Min Yu, Jiawei Zhao, Eunice E Lee, Dohun Kim, Ruchika Mahapatra, Elysha K Rose, Zhiwei Zhou, Calvin R Hosler, Abdullah El-Kurdi, Jun-Yong Choe, E Dale Abel, Gerta Hoxhaj, Kenneth D Westover, Raymond J Cho, Jeffrey B Cheng, Richard C Wang
The facilitative GLUT1 and GLUT3 hexose transporters are expressed abundantly in macrophages, but whether they have distinct functions remains unclear. We confirmed that GLUT1 expression increased after M1 polarization stimuli and found that GLUT3 expression increased after M2 stimulation in macrophages. Conditional deletion of Glut3 (LysM-Cre Glut3fl/fl) impaired M2 polarization of bone marrow derived macrophages. Alternatively activated macrophages from the skin of atopic dermatitis patients showed increased GLUT3 expression, and a calcipotriol-induced model of atopic dermatitis was rescued LysM-Cre Glut3fl/fl mice...
September 14, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37707957/cap2-promotes-gastric-cancer-metastasis-by-mediating-the-interaction-between-tumor-cells-and-tumor-associated-macrophages
#18
JOURNAL ARTICLE
Guohao Zhang, Zhaoxin Gao, Xiangyu Guo, Ranran Ma, Xiaojie Wang, Pan Zhou, Chunlan Li, Zhiyuan Tang, Ruinan Zhao, Peng Gao
The metastasis of cancer cells is the main cause of death for patients with gastric cancer (GC). Mounting evidence has demonstrated the vital importance of tumor-associated macrophages in promoting tumor invasion and metastasis; however, the interaction between tumor cells and macrophages in GC is largely unknown. In this study, we demonstrated that cyclase-associated protein 2 (CAP2) was upregulated in GC, especially in cases with lymph node metastasis, and was correlated with a poorer prognosis. The transcription factor JUN directly bound to the promoter region of CAP2 and activated CAP2 transcription...
September 14, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37707954/a-cyclic-pyrrole-imidazole-polyamide-reduces-pathogenic-rna-in-cag-ctg-triplet-repeat-neurological-disease-models
#19
JOURNAL ARTICLE
Susumu Ikenoshita, Kazuya Matsuo, Yasushi Yabuki, Kosuke Kawakubo, Sefan Asamitsu, Karin Hori, Shingo Usuki, Yuki Hirose, Toshikazu Bando, Kimi Araki, Mitsuharu Ueda, Hiroshi Sugiyama, Norifumi Shioda
Expansion of CAG and CTG (CWG) triplet repeats causes several inherited neurological diseases. The CWG repeat diseases are thought to involve complex pathogenic mechanisms through expanded CWG repeat-derived RNAs in a non-coding and polypeptides in a coding region, respectively. However, an effective therapeutic approach has not been established for the CWG repeat diseases. Here, we show that a CWG repeat DNA-targeting compound, cyclic pyrrole¬-imidazole polyamide (CWG-cPIP), suppresses the pathogenesis of coding and non-coding CWG repeat diseases...
September 14, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37698938/plk1-inhibition-dampens-nlrp3-inflammasome-elicited-response-in-inflammatory-disease-models
#20
JOURNAL ARTICLE
Marta Baldrighi, Christian Doreth, Yang Li, Xiaohui Zhao, Emily F Warner, Hannah Chenoweth, Kamal Kishore, Yagnesh Umrania, David-Paul Minde, Sarah Winkler, Xian Yu, Yuning Lu, Alice Knapton, James Harrison, Murray Ch Clarke, Eicke Latz, Guillermo de Cárcer, Marcos Malumbres, Bernhard Ryffel, Clare E Bryant, Jinping Liu, Kathryn S Lilley, Ziad Mallat, Xuan Li
Unabated activation of NLRP3 inflammasome activation is linked with the pathogenesis of various inflammatory disorders. PLK1 has been widely studied for its role in mitosis. Here, employing both pharmacological and genetic approaches, we demonstrated that PLK1 promoted NLRP3 inflammasome activation at cell interphase. Using an unbiased Bio-ID screen for PLK1 interactome in macrophages, we showed an enhanced proximal association of NLRP3 with PLK1 upon NLRP3 inflammasome activation. We further confirmed the interaction between PLK1 and NLRP3, and identified the interacting domains...
September 12, 2023: Journal of Clinical Investigation
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