journal
https://read.qxmd.com/read/36951961/intrathecal-aav9-ap4m1-gene-therapy-for-hereditary-spastic-paraplegia-50-shows-safety-and-efficacy-in-preclinical-studies
#1
JOURNAL ARTICLE
Xin Chen, Thomas Dong, Yuhui Hu, Raffaella De Pace, Rafael Mattera, Kathrin Eberhardt, Marvin Ziegler, Terry Pirovolakis, Mustafa Sahin, Juan S Bonifacino, Darius Ebrahimi-Fakhari, Steven J Gray
Spastic paraplegia 50 (SPG50) is an ultrarare childhood-onset neurological disorder caused by biallelic loss-of-function variants in the AP4M1 gene. SPG50 is characterized by progressive spastic paraplegia, global developmental delay and subsequent intellectual disability, secondary microcephaly, and epilepsy. Preclinical studies evaluated an adeno-associated virus (AAV)/AP4M1 gene therapy for SPG50. In vitro studies demonstrated that transduction of patient-derived fibroblasts with AAV2/AP4M1 resulted in phenotypic rescue...
March 23, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36951958/third-party-cmv-viral-specific-t-cells-for-refractory-cmv-viremia-and-disease-after-hematopoietic-transplant
#2
JOURNAL ARTICLE
Susan E Prockop, Aisha N Hasan, Ekaterina Doubrovina, Parastoo B Dahi, M Irene Rodriguez-Sanchez, Michael Curry, Audrey Mauguen, Genovefa A Papanicolaou, Yiqi Su, JinJuan Yao, Maria E Arcila, Farid Boulad, Hugo Castro-Malaspina, Christina Cho, Kevin J Curran, Sergio Giralt, Nancy A Kernan, Guenther Koehne, Ann Jakubowski, Esperanza Papadopoulos, Miguel-Angel Perales, Ioannis Politikos, Keith J Price, Annamalai Selvakumar, Craig S Sauter, Roni Tamari, Teresa Vizconde, James W Young, Richard J O'Reilly
BACKGROUND: Refractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT). METHODS: In Phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after allogeneic hematopoietic cell transplant with adoptive transfer of banked off-the-shelf, 3rd party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least two weeks of induction therapy with a median of 3 antiviral drugs; 84...
March 23, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36951954/durability-of-immune-responses-to-the-booster-mrna-vaccination-against-covid-19
#3
JOURNAL ARTICLE
Prabhu S Arunachalam, Lilin Lai, Hady Samaha, Yupeng Feng, Mengyun Hu, Harold Sai-Yin Hui, Bushra Wali, Madison L Ellis, Meredith E Davis-Gardner, Christopher M Huerta, Kareem Bechnak, Sarah Bechnak, Matthew Lee, Matthew B Litvack, Cecilia Losada, Alba Grifoni, Alessandro Sette, Veronika I Zarnitsyna, Nadine Rouphael, Mehul S Suthar, Bali Pulendran
BACKGROUND: Maintaining durable immunity to vaccination represents a major challenge, but whether booster mRNA vaccination improves durability is unknown. METHODS: We measured antibody responses in 55 healthy adults who received a booster dose of Pfizer-BioNTech or Moderna vaccine against SARS-CoV-2 and calculated the half-life of antibody titers. We also measured memory B and T cell responses in a subset of 28 participants. In 13 volunteers who received a second booster, we measured serum antibody titers, and memory B and T cell responses...
March 23, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36951953/tmem16e-regulates-endothelial-cell-procoagulant-activity-and-thrombosis
#4
JOURNAL ARTICLE
Alec A Schmaier, Papa F Anderson, Siyu M Chen, Emale El-Darzi, Ivan Aivasovsky, Milan P Kaushik, Kelsey D Sack, H Criss Hartzell, Samir M Parikh, Robert Flaumenhaft, Sol Schulman
Endothelial cells (ECs) are constitutively an anticoagulant surface but switch to support coagulation following pathogenic stimuli. This switch promotes thrombotic cardiovascular disease. To generate thrombin at physiologic rates, coagulation proteins assemble on a membrane containing anionic phospholipid, most notably phosphatidylserine (PS). PS can be rapidly externalized to the outer cell membrane leaflet by phospholipid "scramblases", such as TMEM16F. TMEM16F-dependent PS externalization is well-characterized in platelets...
March 23, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36951944/sphingolipid-desaturase-degs1-is-essential-for-mitochondria-associated-membrane-integrity
#5
JOURNAL ARTICLE
Laura Planas-Serra, Nathalie Launay, Leire Goicoechea, Bénédicte Heron, Cristina Jou, Natalia Juliá-Palacios, Montserrat Ruiz, Stéphane Fourcade, Carlos Casasnovas, Carolina De La Torre, Antoinette Gelot, Maria Marsal, Pablo Loza-Alvarez, Àngels García-Cazorla, Ali Fatemi, Isidre Ferrer, Manuel Portero-Otin, Estela Area-Gómez, Aurora Pujol
Sphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase DEGS1 acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18, OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane (MAM)-resident enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only...
March 23, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36951943/memory-t-cells-possess-an-innate-like-function-in-local-protection-from-mucosal-infection
#6
JOURNAL ARTICLE
Tanvi Arkatkar, Veronica A Davé, Irene Cruz Talavera, Jessica B Graham, Jessica L Swarts, Sean M Hughes, Timothy A Bell, Pablo Hock, Joe Farrington, Ginger D Shaw, Anna C Kirby, Michael Fialkow, Meei-Li Huang, Keith R Jerome, Martin T Ferris, Florian Hladik, Joshua T Schiffer, Martin Prlic, Jennifer M Lund
Mucosal infections pose a significant global health burden. Antigen-specific tissue resident T cells are critical to maintaining barrier immunity. Previous studies in the context of systemic infection suggest that memory CD8 T cells may also provide innate-like protection against antigenically unrelated pathogens independent of TCR engagement. Whether "bystander T cell activation" is also an important defense mechanism in the mucosa is poorly understood. Here, we investigated if innate-like memory CD8 T cells could protect against a model mucosal virus infection, herpes simplex virus 2 (HSV-2)...
March 23, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36951942/il-18-secreting-car-t-cells-targeting-dll3-are-highly-effective-in-small-cell-lung-cancer-models
#7
JOURNAL ARTICLE
Janneke E Jaspers, Jonathan F Khan, William D Godfrey, Andrea V Lopez, Metamia Ciampricotti, Charles M Rudin, Renier J Brentjens
Patients with small cell lung cancer (SCLC) generally have a poor prognosis and a median overall survival of only about 13 months, indicating the urgent need for novel therapies. Delta-like protein 3 (DLL3) has been identified as a tumor-specific cell surface marker on neuroendocrine cancers including SCLC. In this study, we developed a chimeric antigen receptor (CAR) against DLL3 that displays antitumor efficacy in xenograft and murine SCLC models. CAR T cell expression of the proinflammatory cytokine interleukin-18 (IL-18) greatly enhanced the potency of DLL3-targeting CAR T cell therapy...
March 23, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36943408/il-6-in-the-infarcted-heart-is-preferentially-formed-by-fibroblasts-and-is-modulated-by-purinergic-signaling
#8
JOURNAL ARTICLE
Christina Alter, Anne Sophie Henseler, Christoph Owenier, Julia Hesse, Zhaoping Ding, Tobias Lautwein, Jasmin Bahr, Sikander Hayat, Rafael Kramann, Eva Kostenis, Jürgen Scheller, Jürgen Schrader
Plasma IL-6 is elevated after myocardial infarction (MI) and is associated with increased morbidity and mortality. Which cardiac cell type preferentially contributes to IL-6 and how its production is regulated is largely unknown. Here, we studied the cellular source and purinergic regulation of IL-6 formation in a murine MI model. IL-6, measured in various cell types in post MI hearts by qPCR, RNAscope and at protein level, was preferentially formed by fibroblasts (CFs). scRNAseq in infarcted mouse and human hearts confirmed this finding...
March 21, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36943390/murine-models-of-hras-mediated-cutaneous-skeletal-hypophosphatemia-syndrome-suggest-bone-as-the-fgf23-excess-source
#9
JOURNAL ARTICLE
Diana Ovejero, Zachary Michel, Christophe Cataisson, Amanda Saikali, Rebeca Galisteo, Stuart H Yuspa, Michael T Collins, Luis F de Castro
Cutaneous Skeletal Hypophosphatemia Syndrome (CSHS) is a mosaic RASopathy characterized by the association of dysplastic skeletal lesions, congenital skin nevi of epidermal and/or melanocytic origin, and fibroblast growth factor-23 (FGF23)-mediated hypophosphatemia. The primary physiological source of circulating FGF23 is bone cells. However, several reports have suggested skin lesions as the source of excess FGF23 in CSHS. Consequently, without convincing evidence of efficacy, many patients with CSHS have undergone painful removal of cutaneous lesions in an effort to normalize blood phosphate levels...
March 21, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36928314/rb1-deficient-prostate-tumor-growth-and-metastasis-are-vulnerable-to-ferroptosis-induction-via-the-e2f-acsl4-axis
#10
JOURNAL ARTICLE
Mu-En Wang, Jiaqi Chen, Yi Lu, Alyssa R Bawcom, Jinjin Wu, Jianhong Ou, John M Asara, Andrew J Armstrong, Qianben Wang, Lei Li, Yuzhuo Wang, Jiaoti Huang, Ming Chen
Inactivation of the RB1 tumor suppressor gene is common in several types of therapy-resistant cancers, including metastatic castration-resistant prostate cancer, and predicts poor clinical outcomes. Effective therapeutic strategies against RB1-deficient cancers, however, remain elusive. Here we showed that RB1-loss/E2F activation sensitized cancer cells to ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, by upregulating expression of ACSL4 and enriching ACSL4-dependent arachidonic acid-containing phospholipids, which are key components of ferroptosis execution...
March 16, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36928190/persistent-fasting-lipogenesis-links-impaired-ketogenesis-with-citrate-synthesis-in-humans-with-non-alcoholic-fatty-liver
#11
JOURNAL ARTICLE
Xiaorong Fu, Justin A Fletcher, Stanisław Deja, Melissa Inigo-Vollmer, Shawn C Burgess, Jeffrey D Browning
BACKGROUND: Hepatic de novo lipogenesis (DNL) and β-oxidation are tightly coordinated, and their dysregulation is thought to contribute to the pathogenesis of non-alcoholic fatty liver (NAFL). Fasting normally relaxes DNL-mediated inhibition of hepatic β-oxidation, dramatically increasing ketogenesis and decreasing reliance on the TCA cycle. Thus, we tested whether aberrant oxidative metabolism in fasting NAFL subjects is related to the inability to halt fasting DNL. METHODS: Forty consecutive non-diabetic individuals with and without a history of NAFL were recruited for this observational study...
March 16, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36928177/aurora-a-kinase-inhibition-elevates-pd-l1-expression-and-compromises-its-anti-tumor-efficacy
#12
JOURNAL ARTICLE
Xiaobo Wang, Jing Huang, Fenglin Liu, Qian Yu, Ruina Wang, Jiaqi Wang, Zewen Zhu, Juan Yu, Jun Hou, Joong Sup Shim, Wei Jiang, Zengxia Li, Yuanyuan Zhang, Yongjun Dang
Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. Aurora A inhibitors showed remarkable antitumor effects in preclinical studies, but unsatisfactory outcomes in clinical trials have greatly limited their development. In this study, the Aurora A inhibitor alisertib upregulated PD-L1 expression in a panel of tumor cells both in vitro and in vivo. The upregulation of the checkpoint protein PD-L1 reduced antitumor immunity in immune-competent mice, paradoxically inhibiting the antitumor effects of alisertib...
March 16, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36928117/keratinocytes-sense-and-eliminate-crispr-dna-through-sting-ifn-%C3%AE%C2%BA-activation-and-apobec3g-induction
#13
JOURNAL ARTICLE
Mrinal K Sarkar, Ranjitha Uppala, Chang Zeng, Allison C Billi, Lam C Tsoi, Austin Kidder, Xianying Xing, Bethany E Perez White, Shuai Shao, Olesya Plazyo, Sirisha Sirobhushanam, Enze Xing, Yanyun Jiang, Katherine A Gallagher, John J Voorhees, J Michelle Kahlenberg, Johann E Gudjonsson
CRISPR-Cas9 has been proposed as a treatment for genetically inherited skin disorders. Here we report that CRISPR transfection activates STING-dependent antiviral responses in keratinocytes, resulting in heightened endogenous interferon (IFN) responses through induction of IFN-κ leading to decreased plasmid stability secondary to induction of the cytidine deaminase APOBEC3G. Notably, CRISPR-generated KO keratinocytes had permanent suppression of IFN-κ and IFN-stimulated gene (ISG) expression, secondary to hypermethylation of the IFNK promoter region by the DNA methyltransferase DNMT3B...
March 16, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36928090/kras-oncogene-ablation-prevents-resistance-in-advanced-lung-adenocarcinoma
#14
JOURNAL ARTICLE
Marina Salmón, Ruth Álvarez-Díaz, Coral Fustero-Torre, Oksana Brehey, Carmen G Lechuga, Manuel Sanclemente, Fernando Fernández-García, Alejandra López-García, María Carmen Martín-Guijarro, Sandra Rodríguez-Perales, Emily Bousquet-Mur, Lucía Morales-Cacho, Francisca Mulero, Fátima Al-Shahrour, Lola Martínez, Orlando Domínguez, Eduardo Caleiras, Sagrario Ortega, Carmen Guerra, Monica Musteanu, Matthias Drosten, Mariano Barbacid
KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited anti-tumor response similar to that observed in the clinic, including the rapid onset of resistance...
March 16, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36927960/rip140-deficiency-enhances-cardiac-fuel-metabolism-and-protects-mice-from-heart-failure
#15
JOURNAL ARTICLE
Tsunehisa Yamamoto, Santosh K Maurya, Elizabeth Pruzinsky, Kirill Batmanov, Yang Xiao, Sarah M Sulon, Tomoya Sakamoto, Yang Wang, Ling Lai, Kendra S McDaid, Swapnil V Shewale, Teresa C Leone, Timothy R Koves, Deborah M Muoio, Pieterjan Dierickx, Mitchell A Lazar, E Douglas Lewandowski, Daniel P Kelly
During development of heart failure, capacity for cardiomyocyte fatty acid oxidation (FAO) and ATP production is progressively diminished contributing to pathologic cardiac hypertrophy and contractile dysfunction. Receptor interacting protein 140 (RIP140; Nrip1) has been shown to function as a transcriptional co-repressor of oxidative metabolism. We found that mice with striated muscle deficiency of RIP140 (strNrip1-/-) exhibit increased expression of a broad array of genes involved in mitochondrial energy metabolism and contractile function in heart and skeletal muscle...
March 16, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36927693/intrinsic-rig-i-restrains-stat5-activation-to-modulate-anti-tumor-activity-of-cd8-t-cells
#16
JOURNAL ARTICLE
Xinyi Jiang, Jian Lin, Chengfang Shangguan, Xiaoyao Wang, Bin Xiang, Juan Chen, Hezhou Guo, Wu Zhang, Jun Zhang, Yan Shi, Jiang Zhu, Hui Yang
Anti-tumor activity of CD8+ T cells is potentially restrained by a variety of negative regulatory pathways that are triggered in tumor microenvironment, yet exact mechanisms remain incompletely defined. Here we report that intrinsic RIG-I in CD8+ T cells represents such a factor, as evidenced by observations that tumor-restricting effect of endogenous or adoptively transferred CD8+ T cells was enhanced by intrinsic Rig-I deficiency or inhibition, with the increased accumulation, survival, and cytotoxicity of tumor-infiltrating CD8+ T cells...
March 16, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36917196/an-igfbp7high-endothelial-cell-subset-drives-t-cell-extravasation-in-psoriasis-via-endothelial-glycocalyx-degradation
#17
JOURNAL ARTICLE
Qingyang Li, Shuai Shao, Zhenlai Zhu, Jiaoling Chen, Junfeng Hao, Yaxing Bai, Bing Li, Erle Dang, Gang Wang
Dysfunction of vascular endothelial cells (ECs) facilitates imbalanced immune responses and tissue hyperinflammation. However, the heterogeneous functions of skin ECs and their underlying mechanism in dermatoses remain to be solved. Here, focusing on the pathogenic role of skin ECs in psoriasis, we characterized the molecular and functional heterogeneity of skin ECs from healthy individuals and psoriasis patients at the single-cell level. We found that endothelial glycocalyx destruction, a major feature of EC dysfunction in psoriasis, was a driving force during the process of T cell extravasation...
March 14, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36917193/elevated-prelimbic-cortex-to-basolateral-amygdala-circuit-activity-mediates-comorbid-anxiety-like-behaviors-in-chronic-pain
#18
JOURNAL ARTICLE
Feng Gao, Jie Huang, Guo-Bin Huang, Qiang-Long You, Shan Yao, Shen-Ting Zhao, Jian Liu, Cui-Hong Wu, Gui-Fu Chen, Shi-Min Liu, Zongyan Yu, Yan-Ling Zhou, Yu-Ping Ning, Shenquan Liu, Bing-Jie Hu, Xiang-Dong Sun
Chronic pain could cause both hyperalgesia and anxiety symptoms. How the two components are encoded in the brain remains unclear. The prelimbic cortex (PrL), a critical brain region for both nociceptive and emotional modulations, serves as an ideal medium for comparing the encoding of the two components. We report that PrL neurons projecting to the basolateral amygdala (PrLBLA) and those projecting to the ventrolateral periaqueductal gray (PrLl/vlPAG) were segregated and displayed elevated and reduced neuronal activity, respectively, during pain chronicity...
March 14, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36917188/monoclonal-antibody-y01-prevents-tauopathy-progression-induced-by-lysine280-acetylated-tau-in-cell-and-mouse-models
#19
JOURNAL ARTICLE
Ha-Lim Song, Na-Young Kim, Jaewan Park, Meong Il Kim, Yu-Na Jeon, Se-Jong Lee, Kwangmin Cho, Young-Lim Shim, Kyoung-Hye Lee, Yeon-Seon Mun, Jung-A Song, Min-Seok Kim, Chan-Gi Pack, Minkyo Jung, Hyemin Jang, Duk L Na, Minsun Hong, Dong-Hou Kim, Seung-Yong Yoon
The spatiotemporal pattern of the spread of pathologically modified tau through brain regions in Alzheimer's disease (AD) can be explained by prion-like cell-to-cell seeding and propagation of misfolded tau aggregates. Hence, to develop targeted therapeutic antibodies, it is important to identify the seeding- and propagation-competent tau species. The hexapeptide 275VQIINK280 of tau is a critical region for tau aggregation, and K280 is acetylated in various tauopathies including AD. However, the mechanism that links tau acetylated on lysine 280 (tau-acK280) to subsequent progression to neurodegenerative disease remains unclear...
March 14, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/36917177/human-iapp-is-a-contributor-to-painful-diabetic-peripheral-neuropathy
#20
JOURNAL ARTICLE
Mohammed Mh Albariqi, Sabine Versteeg, Elisabeth M Brakkee, J Henk Coert, Barend Ow Elenbaas, Judith Prado, C Erik Hack, Jo Wm Höppener, Niels Eijkelkamp
Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage pancreatic islet β-cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth and increased levels of mitochondrial reactive oxygen species. Transgenic hIAPP mice that have elevated plasma hIAPP levels without hyperglycemia developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intra-epidermal nerve fiber (IENF) density...
March 14, 2023: Journal of Clinical Investigation
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