tbuckley/cabot-search huggingface dataset:
Preexisting maternal immunity to AAV but not Cas9 impairs in utero gene editing in mice
Authors: John S. Riley, Valerie L. Luks, Cara L. Berkowitz, Ana Maria Dumitru, Nicole J. Kus, Apeksha Dave, Pallavi Menon, Monique E. De Paepe, Rajan Jain, Li Li, Lorraine Dugoff, Christina Paidas Teefey, Mohamad-Gabriel Alameh, Philip W. Zoltick, William H. Peranteau
Journal: Journal of Clinical Investigation (2024)

In utero gene editing (IUGE) is a potential treatment for inherited diseases that cause pathology before or soon after birth. Preexisting immunity to adeno-associated virus (AAV) vectors and Cas9 endonuclease may limit postnatal gene editing. The tolerogenic fetal immune system minimizes a fetal immune barrier to IUGE. However, the ability of maternal immunity to limit fetal gene editing remains a question. We investigated whether preexisting maternal immunity to AAV or Cas9 impairs IUGE. Using a combination of fluorescent reporter mice and a murine model of a metabolic liver disease, we demonstrated that maternal anti-AAV IgG antibodies were efficiently transferred from dam to fetus and impaired IUGE in a maternal titer–dependent fashion. By contrast, maternal cellular immunity was inefficiently transferred to the fetus, and neither maternal cellular nor humoral immunity to Cas9 impaired IUGE. Using human umbilical cord and maternal blood samples collected from mid- to late-gestation pregnancies, we demonstrated that maternal-fetal transmission of anti-AAV IgG was inefficient in midgestation compared with term, suggesting that the maternal immune barrier to clinical IUGE would be less relevant at midgestation. These findings support immunologic advantages for IUGE and inform maternal preprocedural testing protocols and exclusion criteria for future clinical trials.
HIF-2α expression and metabolic signaling require ACSS2 in clear cell renal cell carcinoma
Authors: Zachary A. Bacigalupa, Emily N. Arner, Logan M. Vlach, Melissa M. Wolf, Whitney A. Brown, Evan S. Krystofiak, Xiang Ye, Rachel A. Hongo, Madelyn Landis, Edith K. Amason, Kathryn E. Beckermann, W. Kimryn Rathmell, Jeffrey C. Rathmell
Journal: Journal of Clinical Investigation (2024)

Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has potential therapeutic benefit. Acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2α and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2α. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF-2α expression and stability. While HIF-2α protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHL-independent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α-targeted therapies and deplete pathogenically stabilized HIF-2α.
Crizanlizumab for retinal vasculopathy with cerebral leukoencephalopathy in a phase II clinical study
Authors: Wilson X. Wang, Dan Spiegelman, P. Kumar Rao, Andria L. Ford, Rajendra S. Apte
Journal: Journal of Clinical Investigation (2024)

BackgroundRetinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare, autosomal dominant, universally fatal disease without effective treatment options. This study explores the safety and preliminary efficacy of crizanlizumab, a humanized monoclonal antibody against P-selectin approved for the prevention of sickle cell crises, in slowing retinal nonperfusion and preserving vision in patients with RVCL-S.METHODSEleven patients with RVCL-S with confirmed exonuclease 3 prime repair exonuclease 1 (TREX1) mutations received monthly crizanlizumab infusions over 2 years. The study measured the nonperfusion index within 3 retinal zones and the total retina with fluorescein angiography, visual acuity, intraocular pressure (IOP), and optical coherence tomography central subfield thickness (CST) at baseline, 1 year, and 2 years. A mixed repeated-measures analysis was performed to assess the progression rates and changes from baseline.RESULTSEleven participants received crizanlizumab infusions. All of the participants tolerated crizanlizumab well, with 8 of 11 (72.7%) reporting mild adverse effects such as nausea, fatigue, and gastrointestinal symptoms. The change in total retinal nonperfusion was 7.22% [4.47, 9.97] in year 1 and -0.69% [-4.06, 2.68] in year 2 (P < 0.001). In the mid periphery, the change in nonperfusion was 10.6% [5.1, 16.1] in year 1 and -0.68% [-3.98, 5.35] in year 2 (P < 0.01), demonstrating a reduction in progression of nonperfusion in the second year of treatment. Visual acuity, IOP, and CST remained stable.CONCLUSIONCrizanlizumab has an acceptable safety profile. These results show promising potential for examining crizanlizumab in larger studies of RVCL-S and similar small-vessel diseases and for using the retina as a biomarker for systemic disease.Trial registrationClinicalTrials.gov NCT04611880.FUNDINGThe Clayco Foundation; DeNardo Education and Research Foundation Grant; Jeffrey T. Fort Innovation Fund; Siteman Retina Research Fund; unrestricted grant from Research to Prevent Blindness Inc.; National Heart,Lung, and Blood Institute (NHLBI), NIH (R01HL129241); National Institute of Neurological Disorders and Stroke (NINDS), NIH (RF1NS116565).
Frameshift variants in C10orf71 cause dilated cardiomyopathy in human, mouse, and organoid models
Authors: Yang Li, Ke Ma, Zhujun Dong, Shijuan Gao, Jing Zhang, Shan Huang, Jie Yang, Guangming Fang, Yujie Li, Xiaowei Li, Carrie Welch, Emily L. Griffin, Prema Ramaswamy, Zaheer Valivullah, Xiuying Liu, Jianzeng Dong, Dao Wen Wang, None Du, Wendy K. Chung, Yulin Li
Journal: Journal of Clinical Investigation (2024)

Research advances over the past 30 years have confirmed a critical role for genetics in the etiology of dilated cardiomyopathies (DCMs). However, full knowledge of the genetic architecture of DCM remains incomplete. We identified candidate DCM causal gene, C10orf71, in a large family with 8 patients with DCM by whole-exome sequencing. Four loss-of-function variants of C10orf71 were subsequently identified in an additional group of492 patients with sporadic DCM from 2 independent cohorts. C10orf71 was found to be an intrinsically disordered protein specifically expressed in cardiomyocytes. C10orf71-KO mice had abnormal heart morphogenesis during embryonic development and cardiac dysfunction as adults with altered expression and splicing of contractile cardiac genes. C10orf71-null cardiomyocytes exhibited impaired contractile function with unaffected sarcomere structure. Cardiomyocytes and heart organoids derived from human induced pluripotent stem cells with C10orf71 frameshift variants also had contractile defects with normal electrophysiological activity. A rescue study using a cardiac myosin activator, omecamtiv mecarbil, restored contractile function in C10orf71-KO mice. These data support C10orf71 as a causal gene for DCM by contributing to the contractile function of cardiomyocytes. Mutation-specific pathophysiology may suggest therapeutic targets and more individualized therapy.
Reply: The importance of disrupting complement activation in acute lung injury
Authors: Simon J. Cleary, Mark R. Looney
Journal: Journal of Clinical Investigation (2024)

We appreciate the letter from Kapur and colleagues and are glad to be in agreement on the importance of the complement cascade in experimental transfusion-related acute lung injury (TRALI) (1).We have also measured increased complement activation in clinical TRALI (2), but as complement deposition and lung injury occur within a few minutes in mouse models of TRALI (2, 3), and various mitigation strategies have been effective in preventing clinical TRALI (4), we struggle to take an optimistic view on therapeutic or prophylactic use of complement inhibitors to ameliorate or prevent TRALI.We are hopeful that recombinant IgG Fc hexamers or complement therapeutics might improve outcomes in patients at high risk of developing antibody-mediated rejection (AbMR) following solid-organ transplantation or in other diseases, such as COVID-19.Recent approvals of therapeutics targeting IgG (imlifidase for desensitization to prevent AbMR, ref.5) or C1s (sutimlimab for cold agglutinin disease, ref. 6) demonstrate that inhibiting "upstream" antibody effectors is feasible, and these approaches would be expected to preserve some of the immune protection mediated by membrane attack complexes.Determining the importance of IgG Fc-Fc interactions and different complement components in antibody-mediated diseases will help to improve diagnostics and therapeutics.
STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma
Authors: Hinda Najem, Spencer T. Lea, Shashwat Tripathi, Lisa Hurley, Chao-Hsien Chen, Ivana William, Moloud Sooreshjani, Michelle Bowie, Genevieve Hartley, Corey Dussold, Sebastian Pacheco, Crismita Dmello, Catalina Lee-Chang, Kathleen McCortney, Alicia Steffens, Jordain Walshon, Martina Ott, Jun Wei, Anantha Marisetty, Irina Balyasnikova, Roger Stupp, Rimas V. Lukas, Jian Hu, Charles David James, Craig M. Horbinski, Maciej S. Lesniak, David M. Ashley, Waldemar Priebe, Leonidas C. Platanias, Michael A. Curran, Amy B. Heimberger
Journal: Journal of Clinical Investigation (2024)

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation.
Dicarboxylic acids counteract the metabolic effects of a Western diet by boosting energy expenditure
Authors: Lidia Castagneto-Gissey, Stefan R. Bornstein, Geltrude Mingrone
Journal: Journal of Clinical Investigation (2024)

Obesity has reached pandemic proportion not only in the West but also in other countries around the world; it is now one of the leading causes of death worldwide. A Western diet is rich in saturated fats and provides more calories than necessary, contributing to the rise of the obesity rate. It also promotes the development of liver steatosis, insulin resistance, hyperglycemia, and hyperlipidemia. In this issue of the JCI, Goetzman and colleagues describe the effects of consuming dicarboxylic acids (DAs) as an alternative source of dietary fat. The 12-carbon dicarboxylic acid (DC12) was administered to mice at 20% of their daily caloric intake for nine weeks in place of triglycerides. Notably, the change in diet increased the metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. These findings highlight DAs as useful energy nutrients for combatting obesity and treating various metabolic disorders.
Licit use of illicit drugs for treating depression: the pill and the process
Authors: Alejandro Torrado Pacheco, Bita Moghaddam
Journal: Journal of Clinical Investigation (2024)

Psilocybin, MDMA, and ketamine have emerged as potentially effective treatments for rapid amelioration of the symptoms of mood and related psychiatric disorders. All clinical data collected so far with regard to psilocybin or MDMA, which have reported positive outcomes for treating depression, anxiety, posttraumatic stress disorder, and drug or alcohol use disorders, have involved clinician-assisted intervention. While the case for ketamine is assumed to be different, the first report of the successful use of ketamine in psychiatry for treating depression was in combination with psychotherapy, and an emerging literature suggests that the subjective state of individual experiences with ketamine predicts clinical outcome. This Review will focus on (a) a brief review of the literature, showing that the context or the process of drug administration has been an integrative component of published work; (b) the importance of clinical trials to compare the efficacy of the drug ("pill") as a stand-alone treatment versus drug in combination with clinician-assisted psychological support ("process"); and (c) suggestions for future approaches in animal models that take into account the role of systems and behavioral neuroscience in explaining a potential role for context, experience, and expectancy in drug effect.
Linvoseltamab for Treatment of Relapsed/Refractory Multiple Myeloma
Authors: Naresh Bumma, Joshua Richter, Sundar Jagannath, Hans C. Lee, James E. Hoffman, Attaya Suvannasankha, Jeffrey A. Zonder, Mansi R. Shah, Suzanne Lentzsch, Rachid Baz, Joseph J. Maly, Swathi Namburi, Matthew J. Pianko, Jing Christine Ye, Ka Lung Wu, Rebecca Silbermann, Chang-Ki Min, Marie-Christiane Vekemans, Markus Munder, Ja Min Byun, Joaquín Martínez-Lopez, Kaniel Cassady, Michelle DeVeaux, Dhruti Chokshi, Anita Boyapati, Anasuya Hazra, George D. Yancopoulos, L. Andres Sirulnik, Karen Rodriguez Lorenc, Glenn S. Kroog, Yariv Houvras, Madhav V. Dhodapkar
Journal: Journal of Clinical Oncology (2024)

PURPOSE We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody in relapsed/refractory multiple myeloma (RRMM). METHODS Phase II eligible patients had RRMM that either progressed on/after ≥three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody or was triple-class (PI/IMiD/anti-CD38) refractory. Phase II treatment was once a week through week 14 and then once every 2 weeks. Phase II 200 mg patients who achieved a ≥very good partial response by week 24 received linvoseltamab once every 4 weeks. The primary end point in phase II was overall response rate (ORR). RESULTS Among the 117 patients treated with 200 mg, the median age was 70 years, 39% had high-risk cytogenetics, and 28% had penta-refractory disease. At a median follow-up of 14.3 months, the ORR was 71%, with 50% achieving ≥complete response (CR). In 104 patients treated with 50 mg at a median follow-up of 7.4 months, the ORR was 48%, with 21% achieving ≥CR. The median duration of response (DOR) for 200 mg patients (n = 83) was 29.4 months (95% CI, 19.2 to not evaluable). Among 200 mg patients, the most common adverse events included cytokine release syndrome (35.0% Gr1, 10.3% Gr2, 0.9% Gr3), neutropenia (0.9% Gr2, 18.8% Gr3, 23.1% Gr4), and anemia (3.4% Gr1, 4.3% Gr2, 30.8% Gr3). Immune effector cell-associated neurotoxicity syndrome occurred in 7.7% of patients (2.6% each Gr1, Gr2, Gr3). Infections were reported in 74.4% of patients (33.3% Gr3, 2.6% Gr4); infection frequency and severity declined over time. CONCLUSION Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable safety profile.
Advances in Vascular Diagnostics using Magnetic Particle Imaging (MPI) for Blood Circulation Assessment
Authors: Marisa O Pacheco, Isabelle K Gerzenshtein, Whitney L Stoppel, Carlos M Rinaldi‐Ramos
Journal: Advanced Healthcare Materials (2024)

Abstract Rapid and accurate assessment of conditions characterized by altered blood flow, cardiac blood pooling, or internal bleeding is crucial for diagnosing and treating various clinical conditions. While widely used imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound offer unique diagnostic advantages, they fall short for specific indications due to limited penetration depth and prolonged acquisition times. Magnetic particle imaging (MPI), an emerging tracer‐based technique, holds promise for blood circulation assessments, potentially overcoming existing limitations with reduction in background signals and high temporal and spatial resolution, below the millimeter scale. Successful imaging of blood pooling and impaired flow necessitates tracers with diverse circulation half‐lives optimized for MPI signal generation. Recent MPI tracers show potential in imaging cardiovascular complications, vascular perforations, ischemia, and stroke. The impressive temporal resolution and penetration depth also position MPI as an excellent modality for real‐time vessel perfusion imaging via functional MPI (fMPI). This review summarizes advancements in optimized MPI tracers for imaging blood circulation and analyzes the current state of pre‐clinical applications. This work discusses perspectives on standardization required to transition MPI from a research endeavor to clinical implementation and explore additional clinical indications that may benefit from the unique capabilities of MPI.
Structural basis of neuropeptide Y signaling through Y<sub>1</sub> and Y<sub>2</sub> receptors
Authors: Siyuan Shen, Yue Deng, Chenglong Shen, Haidi Chen, Lin Cheng, Chao Wu, Chang Zhao, Zhiqian Yang, Hanlin Hou, Kexin Wang, Zhenhua Shao, Cheng Deng, Feng Ye, Wei Yan
Journal: MedComm (2024)

Abstract Neuropeptide Y (NPY), a 36‐amino‐acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor subfamily. Notably, NPY analogs display varying selectivity and exert diverse physiological effects through their interactions with this receptor family. [Pro 34 ]–NPY and [Leu 31 , Pro 34 ]–NPY, mainly acting on Y 1 R, reportedly increases blood pressure and postsynaptically potentiates the effect of other vasoactive substances above all, while N‐terminal cleaved NPY variants in human body primary mediates angiogenesis and neurotransmitter release inhibition through Y 2 R. However, the recognition mechanisms of Y 1 R and Y 2 R with specific agonists remain elusive, thereby hindering subtype receptor‐selective drug development. In this study, we report three cryo‐electron microscopy (cryo‐EM) structures of Gi2‐coupled Y 1 R and Y 2 R in complexes with NPY, as well as Y 1 R bound to a selective agonist [Leu 31 , Pro 34 ]–NPY. Combined with cell‐based assays, our study not only reveals the conserved peptide‐binding mode of NPY receptors but also identifies an additional sub‐pocket that confers ligand selectivity. Moreover, our analysis of Y 1 R evolutionary dynamics suggests that this sub‐pocket has undergone functional adaptive evolution across different species. Collectively, our findings shed light on the molecular underpinnings of neuropeptide recognition and receptor activation, and they present a promising avenue for the design of selective drugs targeting the NPY receptor family.
Spatial sequencing reveals transcriptional variation between amelanotic and pigmented acral melanoma
Authors: Martin McMahon, Dekker C Deacon
Journal: British Journal of Dermatology (2024)

Journal Article Accepted manuscript Spatial sequencing reveals transcriptional variation between amelanotic and pigmented acral melanoma Get access Martin McMahon, Martin McMahon Department of Dermatology, University of Utah, Salt Lake City, Utah, USAHuntsman Cancer Institute, Salt Lake City, Utah, USADepartment of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah, USA https://orcid.org/0000-0003-2812-1042 Search for other works by this author on: Oxford Academic Google Scholar Dekker C Deacon Dekker C Deacon Department of Dermatology, University of Utah, Salt Lake City, Utah, USAHuntsman Cancer Institute, Salt Lake City, Utah, USA Correspondence: Dekker Deacon, Email:dekker.deacon@hsc.utah.edu https://orcid.org/0000-0002-4160-5730 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae253, https://doi.org/10.1093/bjd/ljae253 Published: 15 June 2024 Article history Received: 07 June 2024 Accepted: 13 June 2024 Published: 15 June 2024
Sustained release hypoxia-activated prodrug-loaded BSA nanoparticles enhance transarterial chemoembolization against hepatocellular carcinoma
Authors: Yinghong Hao, Wenzhi Zhu, Jie Li, Ruirui Lin, Wenting Huang, Qurat Ul Ain, Kaicai Liu, Ning Wei, Delei Cheng, Yi Wu, Weifu Lv
Journal: Journal of Controlled Release (2024)
Corrigendum to “Peptide conjugation enhances the cellular co-localization, but not endosomal escape, of modular poly (acrylamide-co-methacrylic acid) nanogels” [Journal of Controlled Release, 329, 1162–1171]
Authors: John R. Clegg, Jessie A. Sun, Joann Gu, Abhijeet K. Venkataraman, Nicholas A. Peppas
Journal: Journal of Controlled Release (2024)
Randomized Trial of a Vascular Care Team vs Education for Patients With Peripheral Artery Disease
Authors: Connie N. Hess, Ashley Daffron, Mark R. Nehler, Justin T. Morrison, Cullen E. Buchanan, Michael Szarek, Victoria E. Anderson, Christopher P. Cannon, Judith Hsia, Joseph J. Saseen, Marc P. Bonaca
Journal: Journal of the American College of Cardiology (2024)
Osteogenic Induction and Anti‐Inflammatory Effects of Calcium‐Chlorogenic Acid Nanoparticles Remodel the Osteoimmunology Microenvironment for Accelerating Bone Repair
Authors: Qi Liu, Shuo Zhang, Lusen Shi, Jiapei Shi, Chunhui Sun, Jingang Wang, Weijia Zhou, Hengxing Zhou, Fengjuan Shan, Hongli Wang, Jie Wang, Na Ren, Shiqing Feng, Hong Liu, Shuping Wang
Journal: Advanced Healthcare Materials (2024)

Successful bone regeneration requires close cooperation between bone marrow mesenchymal stem cells (BMSCs) and macrophages, but the low osteogenic differentiation efficiency of stem cells and the excessive inflammatory response of immune cells hinder the development of bone repair. It is necessary to develop a strategy that simultaneously regulates the osteogenic differentiation of BMSCs and the anti-inflammatory polarization of macrophages for accelerating the bone regeneration. Herein, calcium-chlorogenic acid nanoparticles (Ca-CGA NPs) are synthesized by combining the small molecules of chlorogenic acid (CGA) with Ca
Addressing the Global Burden of Cardiovascular Disease in Women
Authors: Dominique Vervoort, Ruoting Wang, Guowei Li, Lynaea Filbey, Omosivie Maduka, LaPrincess C. Brewer, Mamas A. Mamas, Maria Cecilia Bahit, Sofia B. Ahmed, Harriette G.C. Van Spall
Journal: Journal of the American College of Cardiology (2024)
Timing of P2Y12 Inhibitor Administration in Patients With STEMI Undergoing Primary PCI
Authors: Manuel Almendro-Delia, Begoña Hernández-Meneses, Gloria Padilla-Rodríguez, Emilia Blanco-Ponce, Jose Andres Arboleda-Sánchez, Juan Carlos Rodríguez-Yáñez, José Manuel Soto-Blanco, Isabel Fernández-García, José M. Castillo-Caballero, Juan C. García-Rubira, Rafael Hidalgo-Urbano
Journal: Journal of the American College of Cardiology (2024)