tbuckley/cabot-search huggingface dataset:
Beclin 1 prevents ISG15-mediated cytokine storms to secure fetal hematopoiesis and survival
Authors: Wen Wei, Xueqin Gao, Jiawei Qian, Lei Li, Chen Zhao, Li Xu, Yanfei Zhu, Zhenzhen Liu, Nengrong Liu, Xueqing Wang, Zhicong Jin, Bowen Liu, Lan Xu, Jin Dong, Suping Zhang, Jiarong Wang, Yumu Zhang, Yao Yu, Zhanjun Yan, Yanjun Yang, Jie Lu, Yixuan Fang, Na Yuan, Jianrong Wang
Journal: Journal of Clinical Investigation (2024)

Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its evolutionarily conserved domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell-biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1-null hematopoietic lineage. The Becn1/STAT3/ISG15 axis remains functional in autophagy-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3/ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.
Endogenous antigens shape the transcriptome and TCR repertoire in an autoimmune arthritis model
Authors: Elizabeth E. McCarthy, Steven Yu, Noah Perlmutter, Yuka Nakao, Ryota Naito, Charles Lin, Vivienne Riekher, Joe DeRisi, Chun Jimmie Ye, Arthur Weiss, Judith F. Ashouri
Journal: Journal of Clinical Investigation (2024)

The development of pathogenic autoreactive CD4+ T cells, particularly in the context of impaired signaling, remains poorly understood. Unraveling how defective signaling pathways contribute to their activation and persistence is crucial for identifying new therapeutic targets. We profiled a highly arthritogenic subset of naïve CD4+ T cells using bulk and single-cell RNA and TCR sequencing from SKG mice, which develop CD4+ T cell mediated autoimmune arthritis driven by a hypomorphic mutation in Zap70—a key TCR signaling kinase. Despite impaired signaling, these cells exhibit heightened expression of T cell activation and cytokine signaling genes, but diminished expression of a subset of tolerogenic markers (Izumo1r, Tnfrsf9, Cd5, S100a11) compared to wild-type cells. The arthritogenic cells show an enrichment for TCR variable beta (Vβ) chains targeting superantigens from the endogenous mouse mammary tumor virus (MMTV) but exhibit diminished induction of tolerogenic markers following peripheral antigen encounter, contrasting with the robust induction of negative regulators seen in wild-type cells. In arthritic joints, cells expressing superantigen-reactive Vβs expand alongside detectable MMTV proviruses. Antiretroviral treatment and superantigen-reactive T cell depletion curtail SKG arthritis, suggesting that endogenous retroviruses disrupt peripheral tolerance and promote the activation and differentiation of self-reactive CD4+ T cells into pathogenic effector cells.
Ferumoxytol nanozymes effectively target chronic biofilm infections in apical periodontitis
Authors: Alaa Babeer, Yuan Liu, Zhi Ren, Zhenting Xiang, Min Jun Oh, Nil Kanatha Pandey, Aurea Simon-Soro, Ranran Huang, Bekir Karabucak, David P. Cormode, Chider Chen, Hyun Koo
Journal: Journal of Clinical Investigation (2024)

Bacterial biofilms are pervasive and recalcitrant to current antimicrobials, causing numerous infections. Iron oxide nanozymes, including an FDA-approved formulation, ferumoxytol (FMX), show potential against biofilm infections via catalytic activation of hydrogen peroxide (H2O2). However, clinical evidence regarding the efficacy and therapeutic mechanisms of FMX is lacking. Here, we investigate whether FMX nanozymes can treat chronic biofilm infections and compare their bioactivity to that of the gold standard sodium hypochlorite (NaOCl), a potent but caustic disinfectant. Clinical performance was assessed in patients with apical periodontitis, an intractable endodontic infection affecting half of the global adult population. Data show robust antibiofilm activity by a single application of FMX with H2O2 achieving results comparable to those seen with NaOCl without adverse effects. FMX binds efficiently to the bacterial pathogens Enterococcus faecalis and Fusobacterium nucleatum and remains catalytically active without being affected by dental tissues. This allows for effective eradication of endodontic biofilms via on-site free radical generation without inducing cytotoxicity. Unexpectedly, FMX promotes growth of stem cells of the apical papilla (SCAPs), with transcriptomic analyses revealing upregulation of proliferation-associated pathways and downregulation of cell cycle suppressor genes. Notably, FMX activates SCAP pluripotency and WNT/NOTCH signaling that induces its osteogenic capacity. Together, these results show that FMX nanozymes are clinically effective against severe chronic biofilm infection with pathogen targeting and unique stem cell-stimulatory properties, offering a regenerative approach to antimicrobial therapy.
Author Correction: PNPO–PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity
Authors: Hiroki Sekine, Haruna Takeda, Norihiko Takeda, Akihiro Kishino, Hayato Anzawa, Takayuki Isagawa, Nao Ohta, Shohei Murakami, Hideya Iwaki, Nobufumi Kato, Shu Kimura, Zun Liu, Koichiro Kato, Fumiki Katsuoka, Masayuki Yamamoto, Fumihito Miura, Takashi Ito, Masatomo Takahashi, Yoshihiro Izumi, Hiroyuki Fujita, Hitoshi Yamagata, Takeshi Bamba, Takaaki Akaike, Norio Suzuki, Kengo Kinoshita, Hozumi Motohashi
Journal: Nature Metabolism (2024)
Efficacy and safety of SQ house dust mite sublingual immunotherapy-tablet (12 SQ-HDM) in children with allergic rhinitis/rhinoconjunctivitis with or without asthma (MT-12): a randomised, double-blind, placebo-controlled, phase III trial
Authors: Antje Schuster, Davide Caimmi, Hendrik Nolte, Silviya Novakova, Jan Mikler, Majken Hougaard Foss-Skiftesvik, Anne Sofie Østerdal, Andrzej Emeryk, Remi Gagnon, Oliver Pfaar
Journal: The Lancet Regional Health - Europe (2024)
Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance
Authors: Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Rosario Rizzuto, Jerome N Feige, Cristina Mammucari, Umberto De Marchi
Journal: Cell Metabolism (2024)
Macrophages are activated toward phagocytic lymphoma cell clearance by pentose phosphate pathway inhibition
Authors: Anna C Beielstein, Elena Izquierdo, Stuart Blakemore, Nadine Nickel, Michael Michalik, Samruddhi Chawan, Reinhild Brinker, Hans-Henrik Bartel, Daniela Vorholt, Lukas Albert, Janica L Nolte, Rebecca Linke, Carolina Raíssa Costa Picossi, Jorge Sáiz, Felix Picard, Alexandra Florin, Jörn Meinel, Reinhard Büttner, Paul Diefenhardt, Sebastian Brähler, Alma Villaseñor, Holger Winkels, Michael Hallek, Marcus Krüger, Coral Barbas, Christian P Pallasch
Journal: Cell Reports Medicine (2024)
Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling
Authors: Masato Ogishi, Koji Kitaoka, Kim L Good-Jacobson, Darawan Rinchai, Baihao Zhang, Jun Wang, Vincent Gies, Geetha Rao, Tina Nguyen, Danielle T Avery, Taushif Khan, Megan E Smithmyer, Joseph Mackie, Rui Yang, Andrés Augusto Arias, Takaki Asano, Khoren Ponsin, Matthieu Chaldebas, Peng Zhang, Jessica N Peel, Jonathan Bohlen, Romain Lévy, Simon J Pelham, Wei-Te Lei, Ji Eun Han, Iris Fagniez, Maya Chrabieh, Candice Laine, David Langlais, Conor Gruber, Fatima Al Ali, Mahbuba Rahman, Caner Aytekin, Basilin Benson, Matthew J Dufort, Clara Domingo-Vila, Kunihiko Moriya, Mark Shlomchik, Gulbu Uzel, Paul E Gray, Daniel Suan, Kahn Preece, Ignatius Chua, Satoshi Okada, Shunsuke Chikuma, Hiroshi Kiyonari, Timothy I Tree, Dusan Bogunovic, Philippe Gros, Nico Marr, Cate Speake, Richard A Oram, Vivien Béziat, Jacinta Bustamante, Laurent Abel, Bertrand Boisson, Anne-Sophie Korganow, Cindy S Ma, Matthew B Johnson, Kenji Chamoto, Stéphanie Boisson-Dupuis, Tasuku Honjo, Jean-Laurent Casanova, Stuart G Tangye
Journal: Immunity (2024)
Prenatal antibiotics reduce breast milk IgA and induce dysbiosis in mouse offspring, increasing neonatal susceptibility to bacterial sepsis
Authors: Carlo Pietrasanta, Carolina Carlosama, Michela Lizier, Giulia Fornasa, Tanja Rezzonico Jost, Sara Carloni, Silvia Giugliano, Alessandra Silvestri, Paola Brescia, Benedetta De Ponte Conti, Daniele Braga, Martin Mihula, Lavinia Morosi, Alessandro Bernardinello, Andrea Ronchi, Giuseppe Martano, Fabio Mosca, Giuseppe Penna, Fabio Grassi, Lorenza Pugni, Maria Rescigno
Journal: Cell Host & Microbe (2024)
Framework for the Pathology Workup of Metastatic Castration-Resistant Prostate Cancer Biopsies
Authors: Michael C. Haffner, Michael J. Morris, Chien-Kuang C. Ding, Erolcan Sayar, Rohit Mehra, Brian Robinson, Lawrence D. True, Martin Gleave, Tamara L. Lotan, Rahul Aggarwal, Jiaoti Huang, Massimo Loda, Peter S. Nelson, Mark A. Rubin, Himisha Beltran
Journal: Clinical Cancer Research (2024)

Abstract Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC) occurs in up to 15-20% of patients with castration-resistant prostate cancer (CRPC) as mechanism of treatment resistance and is associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of neuroendocrine (NE) lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions making clinical trial design challenging. Here we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors based on histomorphology (adenocarcinoma, small cell carcinoma, poorly differentiated carcinoma, other morphologic variant, or mixed morphology) and immunohistochemical markers with a priority for AR, NKX3.1, INSM1, synaptophysin and cell proliferation based on Ki-67 positivity, with additional markers to be considered based on the clinical context. Ultimately, a unified workup of metastatic CRPC biopsies can improve clinical trial design and eventually practice.
A nucleoside signal generated by a fungal endophyte regulates host cell death and promotes root colonization
Authors: Nick Dunken, Heidi Widmer, Gerd U Balcke, Henryk Straube, Gregor Langen, Nyasha M Charura, Pia Saake, Concetta De Quattro, Jonas Schön, Hanna Rövenich, Stephan Wawra, Mamoona Khan, Armin Djamei, Matias D Zurbriggen, Alain Tissier, Claus-Peter Witte, Alga Zuccaro
Journal: Cell Host & Microbe (2024)
Redefining Acute Virtual Care for Overburdened Health Systems
Authors: Michael J. Maniaci, Richard D. Rothman, Jessica A. Hohman
Journal: JAMA Network Open (2024)

Josh Banerjee, MD, MPH, MS; Christopher Lynch, MD; Hugh Gordon, MD; Charles E. Coffey Jr, MD, MS; Catherine P. Canamar, PhD; Soodtida Tangpraphaphorn, MPH; Karla Gonzalez, MD, MPH; Neha Mahajan, MD; Jan Shoenberger, MD; Michael Menchine, MD; Andrew Oh, MD, MBA; Emily Johnson, MD, MPH; Molly Grassini, MD; Rachel Baden, MD; Paul Holtom, MD; Douglass Hutcheon, MD; Brandon M. Wiley, MD; Kusha Davar, MD, MBA, MS; Sheila Mallet-Smith, DNP, RN; Margaret Sanfratello, RN; Brenda Gallardo, MSN, RN, RNC-NIC, NE-BC; Meixine Song, RN; Nikole Swain, RN, MSN; Maria Lydia Solis, RN; Jenny Silva, RN; Charmaine Pablico, RN; Eduardo Aceves, RN; Erica Bonilla, RN; Ria Ashley Legaspi, RN; Deisy M. Guevara, RN; Karissa Lee, PharmD, BCACP; Christina Martinez, RN; Michelle Banh, MD; Dana Russell, MD; Lissette Cervantes, MD; Jacqueline Cervantes, MD; Cesar Gonzalez, MD; Phillip Sheth, MD; Shadi Dowlatshahi, MD, MSc; Alex Rosenberg, MD; Pruthul Patel, MD; Wei-An Lee, DO; Tanzim Khan, DPM; Tze-Woei Tan, MD, MPH; Michael Fong, MD; Samuel S. Gordon, MD; Brandi Clark, BA; Victor Pena, MBA; Steven Dohi, PharmD; Beatrisa Bannister, PharmD; Roman Villalta, BS; Priya Induru, BA; Pauline Vuong, BA; David Lwe, BA; Karen Stoffel, BSN, RN CI-BC; Sam Oh, BS; Christian Voyageur, BA; Andrew Cool, BA; Yong Lee, BA; Stephen Lenh, BA; Janet Luong, BA; Gary Hanna, BA; Jason N. Doctor, PhD; Bryan Munoz, MHA; Concepcion Castro, BA; Edgar Solis, RN; Nancy Blake, PhD; Roza Sakzalyan, BA; Christopher J. Rodriguez, BA; Christina Ghaly, MD; Jorge Orozco, PT; Hal F. Yee Jr, MD, PhD; Brad Spellberg, MD
Active trans-corneal drug delivery with ocular adhesive micelles for efficient glaucoma therapy
Authors: Qiuyu Wei, Chenchen Zhu, Guiping Yuan, Jiahui Jin, Jing Zhang, Wufa Fan, Ying Piao, Shiqun Shao, Sen Lin, Jiajia Xiang, Youqing Shen
Journal: Journal of Controlled Release (2024)
Biocompatible DNA hydrogel composed of minimized Takumi-shaped DNA nanostructure exhibits sustained retention after in vivo administration
Authors: Jian Jin, Kosuke Kusamori, Takumi Tanifuji, Yoshifumi Yamagata, Shoko Itakura, Makiya Nishikawa
Journal: Journal of Controlled Release (2024)

Our previous studies showed that DNA hydrogels containing unmethylated CpG motifs effectively induced antigen-specific immune responses when combined with the appropriate antigens. A potential drawback of existing DNA hydrogels for further applications is the need for many oligodeoxynucleotide (ODN) types. Therefore, in this study, we attempted to optimize and minimize the nanostructured DNA units for DNA hydrogels to reduce the preparation cost, design difficulty, and possible risk of sequence-dependent off-target effects, and prepare DNA hydrogels with sustained retention ability. A Takumi-shaped unit with a stem and four flanking cohesive parts was constructed using one type of ODN with a palindromic sequence. A DNA hydrogel was prepared by mixing two Takumi-shaped units with complementary cohesive parts. The required length of the cohesive part was first examined using ODNs with 14 or 18 bases of stem length. Electrophoresis, melting temperature measurements, and viscoelastic analysis showed that the properties of the cohesive part determined the hydrogel properties. ODNs with a cohesive part consisting of GC-rich 5'-ccgcaagacg-3' efficiently formed a hydrogel with sustained retention in mice after administration. Several ODNs with optimized cohesive sequences and different stem lengths and sequences were designed. Analyses showed that a stem of 10 bases or longer was required for efficient hydrogel formation, and ODNs with a 12-base stem part exhibited the most prolonged retention after subcutaneous injection into mice. Thus, the present study demonstrated the requirements of minimal DNA units for preparing DNA hydrogels with sustained retention ability.
Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis
Authors: Arja Ray, Kenneth H. Hu, Kelly Kersten, Tristan Courau, Nicholas F. Kuhn, Itzia Zaleta-Linares, Bushra Samad, Alexis J. Combes, Matthew F. Krummel
Journal: The Journal of Experimental Medicine (2024)

CD206 is a common marker of a putative immunosuppressive “M2” state in tumor-associated macrophages (TAMs). We made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ TAMs. Early depletion of CD206+ macrophages and monocytes (Mono/Macs) led to the indirect loss of conventional type I dendritic cells (cDC1), CD8 T cells, and NK cells in tumors. CD206+ TAMs robustly expressed CXCL9, contrasting with stress-responsive Spp1-expressing TAMs and immature monocytes, which became prominent with early depletion. CD206+ TAMs differentially attracted activated CD8 T cells, and the NK and CD8 T cells in CD206-depleted tumors were deficient in Cxcr3 and cDC1-supportive Xcl1 and Flt3l expressions. Disrupting this key antitumor axis decreased tumor control by antigen-specific T cells in mice. In human cancers, a CD206Replete, but not a CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, cDC1, and NK signatures and was associated with better survival. These findings negate the unqualified classification of CD206+ “M2-like” macrophages as immunosuppressive.
Guidelines at a Crossroad: Comparing European and ACC/AHA Guidelines regarding the Use of Imaging in Peripheral Vascular Arterial Disease and Aortic Disease
Authors: Riccardo Liga, Aurelien Hostalrich, Alessia Gimelli, Jean-Baptiste Ricco
Journal:  (2024)

Abstract This review examines the differences and similarities between the European and American guidelines concerning the use of imaging in the diagnosis and management of peripheral arterial disease (PAD) and aortic disease. PAD and aortic conditions contribute significantly to global cardiovascular morbidity and mortality; yet, they are often underdiagnosed and undertreated. Imaging plays a critical role in addressing this gap, with the European Society of Cardiology and American Cardiac Society offering different approaches to diagnostic and interventional imaging modalities. The review highlights that while both guidelines endorse duplex ultrasound as the first-line imaging method for PAD, discrepancies arise in the use of advanced modalities such as computed tomography angiography and magnetic resonance angiography. The European guidelines adopts a more conservative approach, reserving these advanced techniques for specific clinical scenarios, whereas the American guidelines places a stronger emphasis on comprehensive imaging for all patients with suspected PAD. The review also compares the guidelines on aortic disease, noting consensus on the role of computed tomography angiography and magnetic resonance angiography for aortic aneurysm diagnosis, but with differences in the emphasis on transoesophageal echocardiography, which is more strongly recommended by the American guidelines for acute cases. The manuscript calls for harmonization of these guidelines to streamline clinical practice and improve patient outcomes.
Recommendations to Ensure Safety of AI in Real-World Clinical Care
Authors: Dean F. Sittig, Hardeep Singh
Journal: JAMA (2024)

This Viewpoint provides recommendations for health care organizations (HCOs) and clinicians to facilitate the use of artificial intelligence (AI)–enabled systems, including electronic health records with AI features, in routine clinical care and provides pragmatic guidance for HCOs and clinicians at all stages of AI implementation.
Corrections for Conversion of Laboratory Values and Units of Activity Levels
Authors: Zhongrong Miao
Journal: JAMA (2024)

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Prophylactic Drain Placement and Postoperative Invasive Procedures After Gastrectomy
Authors: Jacopo Weindelmayer, Valentina Mengardo, Filippo Ascari, Gian Luca Baiocchi, Riccardo Casadei, Giovanni Domenico De Palma, Stefano De Pascale, Ugo Elmore, Giovanni Carlo Ferrari, Massimo Framarini, Roberta Gelmini, Monica Gualtierotti, Federico Marchesi, Marco Milone, Lucia Puca, Rossella Reddavid, Riccardo Rosati, Leonardo Solaini, Lorena Torroni, Luigi Totaro, Alessandro Veltri, Giuseppe Verlato, Giovanni de Manzoni, Carlo Muzi, Mariella Alloggio, Mariagiulia Dal Cero, Federica Filippini, Maria Bencivenga, Simone Giacopuzzi, Maurizio Degiuli
Journal: JAMA Surgery (2024)

Evidence suggests that prophylactic abdominal drainage after gastrectomy for cancer may reduce postoperative morbidity and hospital stay but this evidence comes from small studies with a high risk of bias. Further research is needed to determine whether drains safely meet their primary purpose of identifying and managing postoperative intraperitoneal collections without the need for reoperation or additional percutaneous drainage.
Targeting CNS Metastases in Non–Small Cell Lung Cancer With Evolving Approaches Using Molecular Markers
Authors: Jyoti Malhotra, Isa Mambetsariev, Gregory Gilmore, Jeremy Fricke, Arin Nam, Natalie Gallego, Bihong T. Chen, Mike Chen, Arya Amini, Rimas V. Lukas, Ravi Salgia
Journal: JAMA Oncology (2024)

Central nervous system (CNS) metastases presenting as either brain parenchymal metastases or leptomeningeal metastases are diagnosed in up to 50% of patients with advanced non-small cell lung cancer during their disease course. While historically associated with a poor prognosis due to limited treatment options, the availability of an increasing number of targeted therapies with good CNS penetration has significantly improved clinical outcomes for these patients. This has occurred in parallel with a more nuanced understanding of prognostic factors.