tbuckley/cabot-search huggingface dataset:
Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours without Thrombectomy
Authors: Yunyun Xiong, Bruce C V Campbell, Lee H Schwamm, Xia Meng, Aoming Jin, Mark W Parsons, Marc Fisher, Yong Jiang, Fengyuan Che, Lihua Wang, Li Zhou, Hongguo Dai, Xintong Liu, Yuesong Pan, Chunmiao Duan, Yuming Xu, Anding Xu, Lixia Zong, Zefeng Tan, Wanxing Ye, Hao Wang, Ziran Wang, Manjun Hao, Zhixin Cao, Liyuan Wang, Shuangzhe Wu, Hao Li, Zixiao Li, Xingquan Zhao, Yongjun Wang
Journal: New England Journal of Medicine (2024)

Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited.
Reteplase versus Alteplase for Acute Ischemic Stroke
Authors: Shuya Li, Hong-Qiu Gu, Hao Li, Xuechun Wang, Aoming Jin, Shuming Guo, Guozhi Lu, Fengyuan Che, Weiwei Wang, Yan Wei, Yilong Wang, Zixiao Li, Xia Meng, Xingquan Zhao, Liping Liu, Yongjun Wang
Journal: New England Journal of Medicine (2024)

Alteplase is the standard agent used in early reperfusion therapy, but alternative thrombolytic agents are needed. The efficacy and safety of reteplase as compared with alteplase in patients with acute ischemic stroke are unclear.
LncRNA DYNLRB2-AS1 promotes gemcitabine resistance of nasopharyngeal carcinoma by inhibiting the ubiquitination degradation of DHX9 protein
Authors: Kai-Lin Chen, Sai-Wei Huang, Ji-Jin Yao, Shi-Wei He, Sha Gong, Xi-Rong Tan, Ye-Lin Liang, Jun-Yan Li, Sheng-Yan Huang, Ying-Qin Li, Yin Zhao, Han Qiao, Sha Xu, Shengbing Zang, Jun Ma, Na Liu
Journal: Drug Resistance Updates (2024)
The state of cancer-focused community outreach and engagement (COE): reflections of Black COE directors
Authors: Hayley S Thompson, Kimlin Tam Ashing, Nadine J Barrett, Monica L Baskin, Lisa Carter-Bawa, Timiya S Nolan, Folakemi T Odedina, Kim F Rhoads, Vanessa B Sheppard, Charnita Zeigler-Johnson
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract The requirement of community outreach and engagement (COE) as a major component of the National Cancer Institute (NCI) Cancer Center Support Grant has had an enormous impact on the way NCI-designated cancer centers identify, investigate, and address the needs of their catchment area (CA) communities. Given the wide-ranging diversity of our nation, COE’s scope of work (SOW) is extremely demanding and complex. Yet, COE is often marginalized and viewed as void of scientific methods when, in fact, it requires specialized scientific knowledge and a broad range of proficiencies. Black COE scientific directors may be particularly attuned to this marginalization as they have often confronted workplace inequities that resemble the health inequities observed within their cancer center’s CA. Thus, Black COE leaders are uniquely positioned to offer insight on the past, present, and future of COE. Key areas discussed include the low involvement of minoritized group members and those with appropriate expertise in national COE leadership; the lack of established, consistent criteria for evaluation of COE components and qualifications of evaluators; the need for substantial financial investment in COE; potential misalignment of community priorities and cancer center objectives; professional development and growth of COE staff and leaders; the expanding scope of COE across their respective cancer centers and CAs; and the need for center-wide involvement in COE and an “all-hands-on-deck” approach. These areas warrant thoughtful dialogue as COE evolves, for the benefit and success of all COE leaders. However, this dialogue must include diverse voices representing similarly diverse stakeholders at every level.
Injectable butyrate-prodrug micelles induce long-acting immune modulation and prevent autoimmune arthritis in mice
Authors: Shijie Cao, Erica Budina, Ruyi Wang, Matthew Sabados, Anish Mukherjee, Ani Solanki, Mindy Nguyen, Kevin Hultgren, Arjun Dhar, Jeffrey A. Hubbell
Journal: Journal of Controlled Release (2024)
EULAR recommendations for the involvement of patient research partners in rheumatology research: 2023 update
Authors: Maarten de Wit, Krystel Aouad, Muriel Elhai, Diego Benavent, Heidi Bertheussen, Steven Blackburn, Peter Böhm, Catia Duarte, Marie Falahee, Susanne Karlfeldt, Uta Kiltz, Elsa F Mateus, Dawn P Richards, Javier Rodríguez-Carrio, Joachim Sagen, Russka Shumnalieva, Simon R Stones, Sander W Tas, William Tillett, Ana Vieira, Tanita-Christina Wilhelmer, Condruta Zabalan, Jette Primdahl, Paul Studenic, Laure Gossec
Journal: Annals of the Rheumatic Diseases (2024)

Background Since the publication of the 2011 European Alliance of Associations for Rheumatology (EULAR) recommendations for patient research partner (PRP) involvement in rheumatology research, the role of PRPs has evolved considerably. Therefore, an update of the 2011 recommendations was deemed necessary. Methods In accordance with the EULAR Standardised Operational Procedures, a task force comprising 13 researchers, 2 health professionals and 10 PRPs was convened. The process included an online task force meeting, a systematic literature review and an in-person second task force meeting to formulate overarching principles (OAPs) and recommendations. The level of agreement of task force members was assessed anonymously (0–10 scale). Results The task force developed five new OAPs, updated seven existing recommendations and formulated three new recommendations. The OAPs address the definition of a PRP, the contribution of PRPs, the role of informal caregivers, the added value of PRPs and the importance of trust and communication in collaborative research efforts. The recommendations address the research type and phases of PRP involvement, the recommended number of PRPs per project, the support necessary for PRPs, training of PRPs and acknowledgement of PRP contributions. New recommendations concern the benefits of support and guidance for researchers, the need for regular evaluation of the patient–researcher collaboration and the role of a designated coordinator to facilitate collaboration. Agreements within the task force were high and ranged between 9.16 and 9.96. Conclusion The updated EULAR recommendations for PRP involvement are more substantially based on evidence. Together with added OAPs, they should serve as a guide for researchers and PRPs and will ultimately strengthen the involvement of PRPs in rheumatology research.
Penicillin V versus amoxicillin for pneumonia in children – a Swedish nationwide emulated target trial
Authors: Samuel Rhedin, Beatrice Kvist, Emma Caffrey Osvald, Gale Karte, Awad I. Smew, Pontus Nauclér, Cecilia Lundholm, Catarina Almqvist
Journal: Clinical Microbiology and Infection (2024)

While most countries recommend amoxicillin for pediatric pneumonia, there is a long tradition of treatment with penicillin V (PcV) in Sweden, thus not empirically covering Haemophilus influenzae. There are, however, large regional differences in treatment practice. The aim was to compare clinical outcomes (treatment failure and severe complications), in children aged 1 to 59 months treated with PcV versus amoxicillin for pneumonia. This population-based emulated target trial included all children born in Sweden between 2001-2021, utilizing national health, sociodemographic, and population registers. All pneumonia cases from hospitals and pediatric outpatient clinics in children aged 1 to 59 months treated as outpatients with PcV or amoxicillin between July 2005-December 2021, were identified. Adjusted odds ratios (aOR)s and 95% confidence intervals (CI)s for treatment failure (new dispensed antibiotic prescription or pneumonia associated hospitalization day 1-14) and severe complications (lung complications, invasive bacterial disease, admission to intensive care unit or death day 1-28) were calculated with logistic regression analysis. PcV was prescribed in 14,766 cases, and amoxicillin in 10,566. Treatment failure occurred in 7.7% with PcV versus 4.7% with amoxicillin, aOR 1.76 (95% CI: 1.54-2.00). Severe complications were rare, with no significant difference between PcV and amoxicillin (0.3% vs. 0.2%, aOR 0.96, 95% CI: 0.53-1.73). Sensitivity and interaction analyses showed consistent results. PcV treatment compared to amoxicillin, was associated with an increased risk for treatment failure but not for severe complications. The absolute risks for adverse outcomes were low in both groups suggesting a minor role of H. influenzae in pediatric pneumonia.
Novel formylpeptide receptor 1/2 agonist limits hypertension-induced cardiovascular damage
Authors: Jaideep Singh, Kristy L Jackson, Haoyun Fang, Audrey Gumanti, Bethany Claridge, Feng Shii Tang, Helen Kiriazis, Ekaterina Salimova, Alex M Parker, Cameron Nowell, Owen L Woodman, David W Greening, Rebecca H Ritchie, Geoffrey A Head, Cheng Xue Qin
Journal: Cardiovascular Research (2024)

Formylpeptide receptors (FPRs) play a critical role in the regulation of inflammation, an important driver of hypertension-induced end-organ damage. We have previously reported that the biased FPR small-molecule agonist, compound17b (Cmpd17b), is cardioprotective against acute, severe inflammatory insults. Here, we reveal the first compelling evidence of the therapeutic potential of this novel FPR agonist against a longer-term, sustained inflammatory insult, i.e. hypertension-induced end-organ damage. The parallels between the murine and human hypertensive proteome were also investigated.
Targeting the secretory program of 3q-amplified lung cancers
Authors: Luis Pardo, Jim C. Norman
Journal: Journal of Clinical Investigation (2024)

Designing strategies to target cell proliferation has been a priority of cancer researchers for decades. However, targeting the secretory programs of transformed cells can influence other cancer features such as cell survival, migration, and communication with the tumor stroma. In this issue of the JCI, Tan and colleagues describe functional cooperativity between the Golgi-resident proteins Golgi integral membrane protein 4 (GOLIM4) and ATPase secretory pathway Ca2+ transporting 1 (ATP2C1) in the coordination of a secretory program in 3q-amplified cancers. Targeting these tumors with manganese (Mn2+) promoted GOLIM4 degradation and imposed a secretory blockade that impaired tumor progression and stromal cell recruitment in mice. These findings highlight the secretory program as a therapeutic target in 3q-amplified malignancies and provide a promising strategy to treat tumor progression.
CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes
Authors: Nunziata Maio, Rotem Orbach, Irina T. Zaharieva, Ana Töpf, Sandra Donkervoort, Pinki Munot, Juliane Mueller, Tracey Willis, Sumit Verma, Stojan Peric, Deepa Krishnakumar, Sniya Sudhakar, A. Reghan Foley, Sarah Silverstein, Ganka Douglas, Lynn Pais, Stephanie DiTroia, Christopher Grunseich, Ying Hu, Caroline Sewry, Anna Sarkozy, Volker Straub, Francesco Muntoni, Tracey A. Rouault, Carsten G. Bönnemann
Journal: Journal of Clinical Investigation (2024)

Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.
Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia
Authors: Baskar Ramdas, Neetu Dayal, Ruchi Pandey, Elizabeth Larocque, Rahul Kanumuri, Santhosh Kumar Pasupuleti, Sheng Liu, Chrysi Kanellopoulou, Elizabeth Fei Yin Chu, Rodrigo Mohallem, Saniya Virani, Gaurav Chopra, Uma K. Aryal, Rena Lapidus, Jun Wan, Ashkan Emadi, Laura S. Haneline, Frederick W. Holtsberg, M. Javad Aman, Herman O. Sintim, Reuben Kapur
Journal: Journal of Clinical Investigation (2024)

Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.
Autoimmunity to stromal-derived autoantigens in rheumatoid ectopic germinal centers exacerbates arthritis and affects clinical response
Authors: Elisa Corsiero, Mattia Caliste, Lucas Jagemann, Liliane Fossati-Jimack, Katriona Goldmann, Cankut Cubuk, Giulia M. Ghirardi, Edoardo Prediletto, Felice Rivellese, Cristiano Alessandri, Mark Hopkinson, Behzad Javaheri, Andrew A. Pitsillides, Myles J. Lewis, Costantino Pitzalis, Michele Bombardieri
Journal: Journal of Clinical Investigation (2024)

Ectopic lymphoid structures (ELSs) in the rheumatoid synovial joints sustain autoreactivity against locally expressed autoantigens. We recently identified recombinant monoclonal antibodies (RA-rmAbs) derived from single, locally differentiated rheumatoid arthritis (RA) synovial B cells, which specifically recognize fibroblast-like synoviocytes (FLSs). Here, we aimed to identify the specificity of FLS-derived autoantigens fueling local autoimmunity and the functional role of anti-FLS antibodies in promoting chronic inflammation. A subset of anti-FLS RA-rmAbs reacting with a 60 kDa band from FLS extracts demonstrated specificity for HSP60 and partial cross-reactivity to other stromal autoantigens (i.e., calreticulin/vimentin) but not to citrullinated fibrinogen. Anti-FLS RA-rmAbs, but not anti–neutrophil extracellular traps rmAbs, exhibited pathogenic properties in a mouse model of collagen-induced arthritis. In patients, anti-HSP60 antibodies were preferentially detected in RA versus osteoarthritis (OA) synovial fluid. Synovial HSPD1 and CALR gene expression analyzed using bulk RNA-Seq and GeoMx-DSP closely correlated with the lympho-myeloid RA pathotype, and HSP60 protein expression was predominantly observed around ELS. Moreover, we observed a significant reduction in synovial HSP60 gene expression followed B cell depletion with rituximab that was strongly associated with the treatment response. Overall, we report that synovial stromal-derived autoantigens are targeted by pathogenic autoantibodies and are associated with specific RA pathotypes, with potential value for patient stratification and as predictors of the response to B cell–depleting therapies.
Epigenetic regulation of tumor immunity
Authors: Lizhi Pang, Fei Zhou, Yang Liu, Heba Ali, Fatima Khan, Amy B. Heimberger, Peiwen Chen
Journal: Journal of Clinical Investigation (2024)

Although cancer has long been considered a genetic disease, increasing evidence shows that epigenetic aberrations play a crucial role in affecting tumor biology and therapeutic response. The dysregulated epigenome in cancer cells reprograms the immune landscape within the tumor microenvironment, thereby hindering antitumor immunity, promoting tumor progression, and inducing immunotherapy resistance. Targeting epigenetically mediated tumor-immune crosstalk is an emerging strategy to inhibit tumor progression and circumvent the limitations of current immunotherapies, including immune checkpoint inhibitors. In this Review, we discuss the mechanisms by which epigenetic aberrations regulate tumor-immune interactions and how epigenetically targeted therapies inhibit tumor progression and synergize with immunotherapy.
Targeting senescent cells to boost bone fracture healing
Authors: Lorenz C. Hofbauer, Ulrike Baschant, Christine Hofbauer
Journal: Journal of Clinical Investigation (2024)

Bone fracture healing is a complex process with distinct phases: the inflammatory phase, the soft and hard callus formation, and the remodeling phase. In older individuals, bone healing can be delayed or disturbed, leading to non-union fractures at worst. The initial healing phases require communication between immune cells and osteoprogenitor cells. However, senescence in these cell types impedes fracture healing by unknown mechanisms. In this issue of the JCI, Saul et al. showed that two distinct senescent p21-expressing cell populations, an osteochondroprogenitor cell and a neutrophil subpopulation, intrinsically impair fracture healing in mice irrespective of age. Genetic ablation of p21-positive cells accelerated fracture healing, while removal of a different senescent cell population, p16-positive cells, made no difference. Conceptually, this view of senescence in fracture healing with a spotlight on osteoimmune cross-talk provides a promising rationale for therapies to boost bone repair at all ages.
Evolutionary Dynamics of Accelerated Antiviral Resistance Development in Hypermutator Herpesvirus
Authors: Thomas Höfler, Mariana Mara Nascimento, Michaela Zeitlow, Ji Yoon Kim, Jakob Trimpert
Journal: Molecular Biology and Evolution (2024)

Abstract Antiviral therapy is constantly challenged by the emergence of resistant pathogens. At the same time, experimental approaches to understand and predict resistance are limited by long periods required for evolutionary processes. Here, we present a herpes simplex virus 1 mutant with impaired proofreading capacity and consequently elevated mutation rates. Comparing this hypermutator to parental wild type virus, we study the evolution of antiviral drug resistance in vitro. We model resistance development and elucidate underlying genetic changes against three antiviral substances. Our analyzes reveal no principle difference in the evolutionary behavior of both viruses, adaptive processes are overall similar, however significantly accelerated for the hypermutator. We conclude that hypermutator viruses are useful for modeling adaptation to antiviral therapy. They offer the benefit of expedited adaptation without introducing apparent bias and can therefore serve as an accelerator to predict natural evolution.
Myasthenia gravis: the future is here
Authors: Henry J. Kaminski, Patricia Sikorski, S. Isabel Coronel, Linda L. Kusner
Journal: Journal of Clinical Investigation (2024)

Myasthenia gravis (MG) stands as a prototypical antibody-mediated autoimmune disease: it is dependent on T cells and characterized by the presence of autoantibodies targeting proteins located on the postsynaptic surface of skeletal muscle, known as the neuromuscular junction. Patients with MG exhibit a spectrum of weakness, ranging from limited ocular muscle involvement to life-threatening respiratory failure. Recent decades have witnessed substantial progress in understanding the underlying pathophysiology, leading to the delineation of distinct subcategories within MG, including MG linked to AChR or MuSK antibodies as well as age-based distinction, thymoma-associated, and immune checkpoint inhibitor–induced MG. This heightened understanding has paved the way for the development of more precise and targeted therapeutic interventions. Notably, the FDA has recently approved therapeutic inhibitors of complement and the IgG receptor FcRn, a testament to our improved comprehension of autoantibody effector mechanisms in MG. In this Review, we delve into the various subgroups of MG, stratified by age, autoantibody type, and histology of the thymus with neoplasms. Furthermore, we explore both current and potential emerging therapeutic strategies, shedding light on the evolving landscape of MG treatment.
RNA-binding protein PCBP2 regulates pancreatic β cell function and adaptation to glucose
Authors: Matthew W. Haemmerle, Andrea V. Scota, Mina Khosravifar, Matthew J. Varney, Sabyasachi Sen, Austin L. Good, Xiaodun Yang, Kristen L. Wells, Lori Sussel, Andrea V. Rozo, Nicolai M. Doliba, Louis R. Ghanem, Doris A. Stoffers
Journal: Journal of Clinical Investigation (2024)

Glucose plays a key role in shaping pancreatic β cell function. Thus, deciphering the mechanisms by which this nutrient stimulates β cells holds therapeutic promise for combating β cell failure in type 2 diabetes (T2D). β Cells respond to hyperglycemia in part by rewiring their mRNA metabolism, yet the mechanisms governing these changes remain poorly understood. Here, we identify a requirement for the RNA-binding protein PCBP2 in maintaining β cell function basally and during sustained hyperglycemic challenge. PCBP2 was induced in primary mouse islets incubated with elevated glucose and was required to adapt insulin secretion. Transcriptomic analysis of primary Pcbp2-deficient β cells revealed impacts on basal and glucose-regulated mRNAs encoding core components of the insulin secretory pathway. Accordingly, Pcbp2-deficient β cells exhibited defects in calcium flux, insulin granule ultrastructure and exocytosis, and the amplification pathway of insulin secretion. Further, PCBP2 was induced by glucose in primary human islets, was downregulated in islets from T2D donors, and impacted genes commonly altered in islets from donors with T2D and linked to single-nucleotide polymorphisms associated with T2D. Thus, these findings establish a paradigm for PCBP2 in governing basal and glucose-adaptive gene programs critical for shaping the functional state of β cells.