tbuckley/cabot-search huggingface dataset:
In vivo base editing of a pathogenic Eif2b5 variant improves vanishing white matter phenotypes in mice
Authors: Desirée Böck, Ilma M. Revers, Anastasia S.J. Bomhof, Anne E.J. Hillen, Claire Boeijink, Lucas Kissling, Sabina Egli, Miguel A. Moreno-Mateos, Marjo S. van der Knaap, Niek P. van Til, Gerald Schwank
Journal: Molecular Therapy (2024)

Vanishing white matter (VWM) is a fatal leukodystrophy caused by recessive mutations in subunits of the eukaryotic translation initiation factor 2B. Currently, there are no effective therapies for VWM. Here, we assessed the potential of adenine base editing to correct human pathogenic VWM variants in mouse models. Using adeno-associated viral vectors, we delivered intein-split adenine base editors into the cerebral ventricles of newborn VWM mice, resulting in 45.9±5.9% correction of the Eif2b5R191H variant in the cortex. Treatment slightly increased mature astrocyte populations and partially recovered the integrated stress response (ISR) in female VWM animals. This led to notable improvements in bodyweight and grip strength in females, however, locomotor disabilities were not rescued. Further molecular analyses suggest that more precise editing (i.e. lower rates of bystander editing) as well as more efficient delivery of the base editors to deep brain regions and oligodendrocytes would have been required for a broader phenotypic rescue. Our study emphasizes the potential, but also identifies limitations, of current in vivo base editing approaches for the treatment of VWM or other leukodystrophies.
Tislelizumab Plus Platinum and Etoposide Versus Placebo Plus Platinum and Etoposide as First-Line Treatment for Extensive-Stage SCLC (RATIONALE-312): A Multicenter, Double-Blind, Placebo-Controlled, Randomized, Phase 3 Clinical Trial
Authors: Ying Cheng, Yun Fan, Yanqiu Zhao, Dingzhi Huang, Xingya Li, Peng Zhang, Mafei Kang, Nong Yang, Diansheng Zhong, Zhen Wang, Yan Yu, Yu Zhang, Jun Zhao, Tai Qin, Chenqi Chen, Shiangjiin Leaw, Wenjuan Zheng, Yong Song
Journal: Journal of Thoracic Oncology (2024)
Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke
Authors: Jia Nong, Patrick M. Glassman, Vladimir V. Shuvaev, Sahily Reyes-Esteves, Helene C. Descamps, Raisa Y. Kiseleva, Tyler E. Papp, Mohamad-Gabriel Alameh, Ying K. Tam, Barbara L. Mui, Serena Omo-Lamai, Marco E. Zamora, Tea Shuvaeva, Evguenia Arguiri, Xijing Gong, Taylor V. Brysgel, Ai Wen Tan, Ashley G. Woolfork, Aalim Weljie, Christoph A. Thaiss, Jacob W. Myerson, Drew Weissman, Scott E. Kasner, Hamideh Parhiz, Vladimir R. Muzykantov, Jacob S. Brenner, Oscar A. Marcos-Contreras
Journal: Molecular Therapy (2024)
Autologous gene therapy for hemoglobinopathies: From bench to patient’s bedside
Authors: Franco Locatelli, Marina Cavazzana, Haydar Frangoul, Josu de la Fuente, Mattia Algeri, Roland Meisel
Journal: Molecular Therapy (2024)

In recent years, a growing number of clinical trials have been initiated to evaluate gene therapy approaches for the treatment of patients with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD). Therapeutic modalities being assessed in these trials utilize different molecular techniques, including lentiviral vectors to add functional copies of the gene encoding the hemoglobin β subunit in defective cells and CRISPR/Cas9, TALE nuclease (TALEN), and zinc finger nuclease (ZFN) gene editing strategies to either directly address the underlying genetic cause of disease or induce fetal hemoglobin production by gene disruption. Here, we review the mechanisms of action of these various gene addition and gene editing approaches and describe the status of clinical trials designed to evaluate the potentially for these approaches to provide one-time functional cures to patients with TDT and SCD.
Opioids for Acute Musculoskeletal Pain: A Systematic Review with Meta-Analysis
Authors: Caitlin M P Jones, Aili Langford, Chris G Maher, Christina Abdel Shaheed, Richard Day, Chung-Wei Christine Lin
Journal: Drugs (2024)

To evaluate the efficacy of opioids for people with acute musculoskeletal pain against placebo. Systematic review and meta-analyses of randomised, placebo-controlled trials of opioid analgesics for acute musculoskeletal pain in any setting. The primary outcomes were pain and disability at the immediate timepoint (< 24 h). Multiple databases were searched from their inception to February 22nd, 2023. Continuous outcomes were converted to a 0–100 scale. Dichotomous outcomes were presented as risk differences. Risk of bias and certainty of evidence was assessed. We located 17 trials (1 intravenous and 16 oral route of administration). For adults, high certainty evidence from 11 comparisons shows that oral opioids provide small benefits relative to placebo in the immediate term for pain (mean difference [MD] − 8.8 95% confidence interval [CI] − 12.0 to − 5.6). For disability, the difference is uncertain (MD − 6.2, 95% CI − 17.8 to 5.4). Opioid groups were at higher risk of adverse events (MD 14.3%, 95% CI 8.3–20.4%, very low certainty). There was moderate certainty evidence of a large effect of IV morphine on sciatica pain (MD −42.5, 95% CI − 49.9 to − 35.1, n = 197, 1 study). In paediatric populations, moderate certainty evidence from 3 trials shows that oral opioids probably do not provide benefit beyond that of placebo for pain (MD 6.1, 95% CI − 1.7 to 12.8) and there was no evidence for disability. There was low certainty evidence that there may be no difference in adverse events (MD 10.4%, 95% CI − 0.6 to 21.4%). Intravenous morphine likely offers benefits, but oral opioids may not provide clinically meaningful benefits. CRD42021249346.
Regulation of HOX gene expression in AML
Authors: Irum Khan, Mohammed A Amin, Elizabeth A Eklund, Andrei L Gartel
Journal: Blood Cancer Journal (2024)

As key developmental regulators, HOX cluster genes have varied and context-specific roles in normal and malignant hematopoiesis. A complex interaction of transcription factors, epigenetic regulators, long non-coding RNAs and chromatin structural changes orchestrate HOX expression in leukemia cells. In this review we summarize molecular mechanisms underlying HOX regulation in clinical subsets of AML, with a focus on NPM1 mutated (NPM1
Generative AI and large language models in health care: pathways to implementation
Authors: Marium M. Raza, Kaushik P. Venkatesh, Joseph C. Kvedar
Journal: npj Digital Medicine (2024)

Generative AI is designed to create new content from trained parameters. Learning from large amounts of data, many of these models aim to simulate human conversation. Generative AI is being applied to many different sectors. Within healthcare there has been innovation specifically towards generative AI models trained on electronic medical record data. A recent review characterizes these models, their strengths, and weaknesses. Inspired by that work, we present our evaluation checklist for generative AI models applied to electronic medical records.
Epigenetic regulation of tumor-immune symbiosis in glioma
Authors: Yang Liu, Heba Ali, Fatima Khan, Lizhi Pang, Peiwen Chen
Journal: Trends in Molecular Medicine (2024)

Glioma is a type of aggressive and incurable brain tumor. Patients with glioma are highly resistant to all types of therapies, including immunotherapies. Epigenetic reprogramming is a key molecular hallmark in tumors across cancer types, including glioma. Mounting evidence highlights a pivotal role of epigenetic regulation in shaping tumor biology and therapeutic responses through mechanisms involving both glioma cells and immune cells, as well as their symbiotic interactions in the tumor microenvironment (TME). In this review, we discuss the molecular mechanisms of epigenetic regulation that impacts glioma cell biology and tumor immunity in both a cell-autonomous and non-cell-autonomous manner. Moreover, we provide an overview of potential therapeutic approaches that can disrupt epigenetic-regulated tumor-immune symbiosis in the glioma TME.
M1-polarized macrophage-derived cellular nanovesicle-coated lipid nanoparticles for enhanced cancer treatment through hybridization of gene therapy and cancer immunotherapy
Authors: Ha Eun Shin, Jun-Hyeok Han, Seungyong Shin, Ga-Hyun Bae, Boram Son, Tae-Hyung Kim, Hee Ho Park, Chun Gwon Park, Wooram Park
Journal: Acta Pharmaceutica Sinica B (2024)

Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy. Lipid nanoparticles (LNPs), considered a prospective vehicle for nucleic acid delivery, have demonstrated efficacy in human use during the COVID-19 pandemic. This study introduces a novel biomaterial-based platform, M1-polarized macrophage-derived cellular nanovesicle-coated LNPs (M1-C-LNPs), specifically engineered for a combined gene-immunotherapy approach against solid tumor. The dual-function system of M1-C-LNPs encapsulates Bcl2-targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles (M1-NVs), effectively facilitating apoptosis in cancer cells without impacting T and NK cells, which activate the intratumoral immune response to promote granule-mediating killing for solid tumor eradication. Enhanced retention within tumor was observed upon intratumoral administration of M1-C-LNPs, owing to the presence of adhesion molecules on M1-NVs, thereby contributing to superior tumor growth inhibition. These findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy, with significant implications for advancing biomaterial use in cancer therapeutics.
The extracellular cyclophilin A-integrin β2 complex as a therapeutic target of viral pneumonia
Authors: Xiaoyuan Bai, Wenxian Yang, Yuna Zhao, Tongtong Cao, Runshan Lin, Pengtao Jiao, Heqiao Li, Huizi Li, Jie Min, Xiaoxiao Jia, He Zhang, Wenhui Fan, Xiaojuan Jia, Yuhai Bi, Wenjun Liu, Lei Sun
Journal: Molecular Therapy (2024)

The acute respiratory virus infection can induce uncontrolled inflammatory responses, such as cytokine storm and viral pneumonia, which are the major causes of death in clinical cases. Cyclophilin A (CypA) is mainly distributed in the cytoplasm of resting cells and released into the extracellular space in response to inflammatory stimuli. Extracellular CypA (eCypA) is upregulated and promotes inflammatory response in severe COVID-19 patients. However, how eCypA promotes virus-induced inflammatory response remains elusive. Here, we observe that eCypA is induced by influenza A and B viruses and SARS-CoV-2 in cells, mice, or patients. Anti-CypA mAb reduces pro-inflammatory cytokines production, leukocytes infiltration, and lung injury in virus-infected mice. Mechanistically, eCypA binding to integrin β2 triggers integrin activation, thereby facilitating leukocyte trafficking and cytokines production via the focal adhesion kinase (FAK)/GTPase and FAK/ERK/P65 pathways, respectively. These functions are suppressed by the anti-CypA mAb that specifically blocks eCypA-integrin β2 interaction. Overall, our findings reveal that eCypA-integrin β2 signaling mediates virus-induced inflammatory response, indicating that eCypA is a potential target for antibody therapy against viral pneumonia.
Reducing and controlling metabolic active tumor volume prior to CAR T-cell infusion can improve survival outcomes in patients with large B-cell lymphoma
Authors: Kylie Keijzer, Janneke W de Boer, Jaap A van Doesum, Walter Noordzij, Gerwin A Huls, Lisanne V van Dijk, Tom van Meerten, Anne G H Niezink
Journal: Blood Cancer Journal (2024)

Abstract Bridging therapy before CD19-directed chimeric antigen receptor (CAR) T-cell infusion is frequently applied in patients with relapsed or refractory Large B-cell lymphoma (r/r LBCL). This study aimed to assess the influence of quantified MATV and MATV-dynamics, between pre-apheresis (baseline) and pre-lymphodepleting chemotherapy (pre-LD) MATV, on CAR T-cell outcomes and toxicities in patients with r/r LBCL. MATVs were calculated semi-automatically at baseline ( n = 74) and pre-LD ( n = 68) in patients with r/r LBCL who received axicabtagene ciloleucel. At baseline, patients with a low MATV (&lt; 190 cc) had a better time to progression (TTP) and overall survival (OS) compared to high MATV patients ( p &lt; 0.001). High MATV patients who remained stable or reduced upon bridging therapy showed a significant improvement in TTP ( p = 0.041) and OS ( p = 0.015), compared to patients with a high pre-LD MATV (&gt; 480 cc). Furthermore, high MATV baseline was associated with severe cytokine release syndrome (CRS, p = 0.001). In conclusion, patients with low baseline MATV had the best TTP/OS and effective reduction or controlling MATV during bridging improved survival outcomes in patients with a high baseline MATV, providing rationale for the use of more aggressive bridging regimens.
2024 update on allogeneic hematopoietic stem cell transplant for myelofibrosis: A review of current data and applications on risk stratification and management
Authors: Haris Ali, Andrea Bacigalupo
Journal: American Journal of Hematology (2024)

Allogeneic hemopoietic stem cell transplantation (HSCT) currently remains the only curative treatment for patients with myelofibrosis (MF). Transplant related mortality (TRM) and relapse, remain two significant complications which need to be addressed.
Unraveling cradle-to-grave disease trajectories from multilayer comorbidity networks
Authors: Elma Dervić, Johannes Sorger, Liuhuaying Yang, Michael Leutner, Alexander Kautzky, Stefan Thurner, Alexandra Kautzky-Willer, Peter Klimek
Journal: npj Digital Medicine (2024)

Abstract We aim to comprehensively identify typical life-spanning trajectories and critical events that impact patients’ hospital utilization and mortality. We use a unique dataset containing 44 million records of almost all inpatient stays from 2003 to 2014 in Austria to investigate disease trajectories. We develop a new, multilayer disease network approach to quantitatively analyze how cooccurrences of two or more diagnoses form and evolve over the life course of patients. Nodes represent diagnoses in age groups of ten years; each age group makes up a layer of the comorbidity multilayer network. Inter-layer links encode a significant correlation between diagnoses ( p &lt; 0.001, relative risk &gt; 1.5), while intra-layers links encode correlations between diagnoses across different age groups. We use an unsupervised clustering algorithm for detecting typical disease trajectories as overlapping clusters in the multilayer comorbidity network. We identify critical events in a patient’s career as points where initially overlapping trajectories start to diverge towards different states. We identified 1260 distinct disease trajectories (618 for females, 642 for males) that on average contain 9 (IQR 2–6) different diagnoses that cover over up to 70 years (mean 23 years). We found 70 pairs of diverging trajectories that share some diagnoses at younger ages but develop into markedly different groups of diagnoses at older ages. The disease trajectory framework can help us to identify critical events as specific combinations of risk factors that put patients at high risk for different diagnoses decades later. Our findings enable a data-driven integration of personalized life-course perspectives into clinical decision-making.
Socioeconomic disparities in European cystic fibrosis outcomes: time to close the gap
Authors: Edward F. McKone
Journal: European Respiratory Journal (2024)

Cystic fibrosis (CF) is one of the most common autosomal recessive genetic conditions that causes progressive lung disease and premature death [1]. Median survival worldwide is estimated to be around 50 years, but there is variation between countries [2–4]. Reasons for this variation are complex, and include genetic factors such as cystic fibrosis transmembrane conductance regulator ( CFTR ) genetic mutations in the population [5], as well as non-genetic factors such as access to lung transplantation and socioeconomic status (SES) [4]. Disparities exist in CF across Europe. Time to close the gap! https://bit.ly/3OVQrkZ
Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial
Authors: Christine E Brown, Jonathan C Hibbard, Darya Alizadeh, M Suzette Blanchard, Heini M Natri, Dongrui Wang, Julie R Ostberg, Brenda Aguilar, Jamie R Wagner, Jinny A Paul, Renate Starr, Robyn A Wong, Wuyang Chen, Noah Shulkin, Maryam Aftabizadeh, Aleksandr Filippov, Ammar Chaudhry, Julie A Ressler, Julie Kilpatrick, Paige Myers-McNamara, Mike Chen, Leo D Wang, Russell C Rockne, Joseph Georges, Jana Portnow, Michael E Barish, Massimo D'Apuzzo, Nicholas E Banovich, Stephen J Forman, Behnam Badie
Journal: Nature Medicine (2024)

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 10
Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury
Authors: Caitlyn Vlasschaert, Cassianne Robinson-Cohen, Jianchun Chen, Elvis Akwo, Alyssa C. Parker, Samuel A. Silver, Pavan K. Bhatraju, Hannah Poisner, Shirong Cao, Ming Jiang, Yinqiu Wang, Aolei Niu, Edward Siew, Joseph C. Van Amburg, Holly J. Kramer, Anna Kottgen, Nora Franceschini, Bruce M. Psaty, Russell P. Tracy, Alvaro Alonso, Dan E. Arking, Josef Coresh, Christie M. Ballantyne, Eric Boerwinkle, Morgan Grams, Ming-Zhi Zhang, Bryan Kestenbaum, Matthew B. Lanktree, Michael J. Rauh, Raymond C. Harris, Alexander G. Bick
Journal: Nature Medicine (2024)

Abstract Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI. In three population-based epidemiology cohorts, we found that CHIP was associated with a greater risk of incident AKI, which was more pronounced in patients with AKI requiring dialysis and in individuals with somatic mutations in genes other than DNMT3A , including mutations in TET2 and JAK2 . Mendelian randomization analyses supported a causal role for CHIP in promoting AKI. Non- DNMT3A -CHIP was also associated with a nonresolving pattern of injury in patients with AKI. To gain mechanistic insight, we evaluated the role of Tet2 -CHIP and Jak2 V617F -CHIP in two mouse models of AKI. In both models, CHIP was associated with more severe AKI, greater renal proinflammatory macrophage infiltration and greater post-AKI kidney fibrosis. In summary, this work establishes CHIP as a genetic mechanism conferring impaired kidney function recovery after AKI via an aberrant inflammatory response mediated by renal macrophages.
Status and Future Directions for Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Disease With and Without Pulmonary Hypertension: A Scientific Statement From the American Heart Association
Authors: Vikas Aggarwal, Jay Giri, Scott H. Visovatti, Ehtisham Mahmud, Hiromi Matsubara, Michael Madani, Frances Rogers, Deepa Gopalan, Kenneth Rosenfield, Vallerie V. McLaughlin
Journal: Circulation (2024)

Balloon pulmonary angioplasty continues to gain traction as a treatment option for patients with chronic thromboembolic pulmonary disease with and without pulmonary hypertension. Recent European Society of Cardiology guidelines on pulmonary hypertension now give balloon pulmonary angioplasty a Class 1 recommendation for inoperable and residual chronic thromboembolic pulmonary hypertension. Not surprisingly, chronic thromboembolic pulmonary hypertension centers are rapidly initiating balloon pulmonary angioplasty programs. However, we need a comprehensive, expert consensus document outlining critical concepts, including identifying necessary personnel and expertise, criteria for patient selection, and a standardized approach to preprocedural planning and establishing criteria for evaluating procedural efficacy and safety. Given this lack of standards, the balloon pulmonary angioplasty skill set is learned through peer-to-peer contact and training. This document is a state-of-the-art, comprehensive statement from key thought leaders to address this gap in the current clinical practice of balloon pulmonary angioplasty. We summarize the current status of the procedure and provide a consensus opinion on the role of balloon pulmonary angioplasty in the overall care of patients with chronic thromboembolic pulmonary disease with and without pulmonary hypertension. We also identify knowledge gaps, provide guidance for new centers interested in initiating balloon pulmonary angioplasty programs, and highlight future directions and research needs for this emerging therapy.
Diuretic use and outcomes in patients with heart failure with reduced ejection fraction: Insights from the <scp>VICTORIA</scp> trial
Authors: Justin Ezekowitz, Wendimagegn Alemayehu, Frank Edelmann, Piotr Ponikowski, Carolyn S.P. Lam, Christopher M. O'Connor, Javed Butler, Stefano Corda, Ciaran J. McMullan, Cynthia M. Westerhout, Adriaan A. Voors, Robert J. Mentz, Paul W. Armstrong
Journal: European Journal of Heart Failure (2024)
Some future directions for genome-wide association studies of preserved ratio impaired spirometry
Authors: Zhou Jin, Guangfa Wang
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>Future GWAS studies of PRISm could be more refined, especially considering the three state transitions of PRISm and the distinction between restricted and unrestricted from a genetic perspective</b>https://bit.ly/3SVMPlj
The receptor binding domain of SARS-CoV-2 Omicron subvariants targets Siglec-9 to decrease its immunogenicity by preventing macrophage phagocytosis
Authors: Xin He, Xiantao Zhang, Bolin Wu, Jieyi Deng, Yongli Zhang, Airu Zhu, Yaochang Yuan, Yingtong Lin, Achun Chen, Jinzhu Feng, Xiumei Wang, Shijian Wu, Yingying Liu, Jie Liu, Yalin Wang, Rong Li, Chaofeng Liang, Quyu Yuan, Yu Liang, Qiannan Fang, Zhihui Xi, Wenjie Li, Liting Liang, Zhenglai Zhang, Hui Tang, Yi Peng, Changwen Ke, Xiancai Ma, Weibin Cai, Ting Pan, Bingfeng Liu, Kai Deng, Jun Chen, Jincun Zhao, Xuepeng Wei, Ran Chen, Yiwen Zhang, Hui Zhang
Journal: Nature Immunology (2024)