tbuckley/cabot-search huggingface dataset:
The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young
Authors: Megan J. Puckelwartz, Lorenzo L. Pesce, Edgar J. Hernandez, Gregory Webster, Lisa M. Dellefave-Castillo, Mark W. Russell, Sarah S. Geisler, Samuel D. Kearns, Felix Karthik, Susan P. Etheridge, Tanner O. Monroe, Tess D. Pottinger, Prince J. Kannankeril, M. Benjamin Shoemaker, Darlene Fountain, Dan M. Roden, Meghan Faulkner, Heather M. MacLeod, Kristin M. Burns, Mark Yandell, Martin Tristani-Firouzi, Alfred L. George, Elizabeth M. McNally
Journal: Genome Medicine (2024)

Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing.
Airway Tree Caliber and Susceptibility to Pollution-associated Emphysema: MESA Air and Lung Studies
Authors: Coralynn Sack, Meng Wang, Victoria Knutson, Amanda Gassett, Eric A. Hoffman, Lianne Sheppard, R. Graham Barr, Joel D. Kaufman, Benjamin Smith
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Rationale: Airway tree morphology varies in the general population and may modify the distribution and uptake of inhaled pollutants. Objectives: We hypothesized that smaller airway caliber would be associated with emphysema progression and would increase susceptibility to air pollutant-associated emphysema progression. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) is a general population cohort of adults 45-84 years old from six U.S. communities. Airway tree caliber was quantified as the mean of airway lumen diameters measured from baseline cardiac computed tomography (CT) (2000-02). Percent emphysema, defined as percentage of lung pixels below −950 Hounsfield units, was assessed up to 5 times per participant via cardiac CT scan (2000-07) and equivalent regions on lung CT scan (2010-18). Long-term outdoor air pollutant concentrations (PM2.5, NOx, O3) were estimated at residential address with validated spatio-temporal models. Linear mixed models estimated the association between airway tree caliber and emphysema progression; modification of pollutant-associated emphysema progression was assessed using multiplicative interaction terms. Main Results: Among 6,793 participants (mean±SD age: 62±10 years), baseline airway tree caliber was 3.95±1.1 mm and median (interquartile range) of percent emphysema was 2.88 (1.21-5.68). In adjusted analyses, 10-year emphysema progression rate was 0.75 percentage points (95%CI 0.54-0.96%) higher in the smallest compared to largest airway tree caliber quartile. Airway tree caliber also modified air pollutant-associated emphysema progression. Conclusions: Smaller airway tree caliber was associated with accelerated emphysema progression and modified air pollutant-associated emphysema progression. A better understanding of mechanisms of airway-alveolar homeostasis and air pollutant deposition are needed.
Generative artificial intelligence can have a role in combating vaccine hesitancy
Authors: Heidi J Larson, Leesa Lin
Journal: BMJ (2024)

Given the sluggish pace of traditional scientific approaches, artificial intelligence (AI), particularly generative AI, has emerged as a significant opportunity to tackle complex health challenges, including those in public health. 1 Against this backdrop, interest has focused on whether AI has a role in bolstering public trust in vaccines and helping to minimise vaccine hesitancy, which the World Health Organization named as one of the top 10 global health threats.
Using social media to build confidence in vaccines: lessons from community engagement and social science research in Africa
Authors: Sara Cooper, Muktar A Gadanya, David Kaawa-Mafigiri, Patrick D M C Katoto, Evanson Z Sambala, Elvis Temfack, Charles S Wiysonge
Journal: BMJ (2024)

<b>Sara Cooper and colleagues</b> argue that a better understanding of the complex sociopolitical drivers of distrust in vaccination will increase the potential of social media to rebuild vaccine confidence
Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes
Authors: Jonathan P. Bradfield, Rachel L. Kember, Anna Ulrich, Zhanna Balkhiyarova, Akram Alyass, Izzuddin M. Aris, Joshua A. Bell, K. Alaine Broadaway, Zhanghua Chen, Jin-Fang Chai, Neil M. Davies, Dietmar Fernandez-Orth, Mariona Bustamante, Ruby Fore, Amitavo Ganguli, Anni Heiskala, Jouke-Jan Hottenga, Carmen Íñiguez, Sayuko Kobes, Jaakko Leinonen, Estelle Lowry, Leo-Pekka Lyytikainen, Anubha Mahajan, Niina Pitkänen, Theresia M. Schnurr, Christian Theil Have, David P. Strachan, Elisabeth Thiering, Suzanne Vogelezang, Kaitlin H. Wade, Carol A. Wang, Andrew Wong, Louise Aas Holm, Alessandra Chesi, Catherine Choong, Miguel Cruz, Paul Elliott, Steve Franks, Christine Frithioff-Bøjsøe, W. James Gauderman, Joseph T. Glessner, Vicente Gilsanz, Kendra Griesman, Robert L. Hanson, Marika Kaakinen, Heidi Kalkwarf, Andrea Kelly, Joseph Kindler, Mika Kähönen, Carla Lanca, Joan Lappe, Nanette R. Lee, Shana McCormack, Frank D. Mentch, Jonathan A. Mitchell, Nina Mononen, Harri Niinikoski, Emily Oken, Katja Pahkala, Xueling Sim, Yik-Ying Teo, Leslie J. Baier, Toos van Beijsterveldt, Linda S. Adair, Dorret I. Boomsma, Eco de Geus, Mònica Guxens, Johan G. Eriksson, Janine F. Felix, Frank D. Gilliland, Penn Medicine Biobank, Torben Hansen, Rebecca Hardy, Marie-France Hivert, Jens-Christian Holm, Vincent W. V. Jaddoe, Marjo-Riitta Järvelin, Terho Lehtimäki, David A. Mackey, David Meyre, Karen L. Mohlke, Juha Mykkänen, Sharon Oberfield, Craig E. Pennell, John R. B. Perry, Olli Raitakari, Fernando Rivadeneira, Seang-Mei Saw, Sylvain Sebert, John A. Shepherd, Marie Standl, Thorkild I. A. Sørensen, Nicholas J. Timpson, Maties Torrent, Gonneke Willemsen, Elina Hypponen, Chris Power, Mark I. McCarthy, Rachel M. Freathy, Elisabeth Widén, Hakon Hakonarson, Inga Prokopenko, Benjamin F. Voight, Babette S. Zemel, Struan F. A. Grant, Diana L. Cousminer
Journal: Genome biology (2024)

Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.
Brain clearance of protein aggregates: a close-up on astrocytes
Authors: Veronica Giusti, Gurkirat Kaur, Elena Giusto, Laura Civiero
Journal: Molecular Neurodegeneration (2024)

Abstract Protein misfolding and accumulation defines a prevailing feature of many neurodegenerative disorders, finally resulting in the formation of toxic intra- and extracellular aggregates. Intracellular aggregates can enter the extracellular space and be subsequently transferred among different cell types, thus spreading between connected brain districts. Although microglia perform a predominant role in the removal of extracellular aggregated proteins, mounting evidence suggests that astrocytes actively contribute to the clearing process. However, the molecular mechanisms used by astrocytes to remove misfolded proteins are still largely unknown. Here we first provide a brief overview of the progressive transition from soluble monomers to insoluble fibrils that characterizes amyloid proteins, referring to α-Synuclein and Tau as archetypical examples. We then highlight the mechanisms at the basis of astrocyte-mediated clearance with a focus on their potential ability to recognize, collect, internalize and digest extracellular protein aggregates. Finally, we explore the potential of targeting astrocyte-mediated clearance as a future therapeutic approach for the treatment of neurodegenerative disorders characterized by protein misfolding and accumulation.
Prognostic impact of CEBPA mutational subgroups in adult AML
Authors: Julia-Annabell Georgi, Sebastian Stasik, Michael Kramer, Manja Meggendorfer, Christoph Röllig, Torsten Haferlach, Peter Valk, David Linch, Tobias Herold, Nicolas Duployez, Franziska Taube, Jan Moritz Middeke, Uwe Platzbecker, Hubert Serve, Claudia D. Baldus, Carsten Muller-Tidow, Claudia Haferlach, Sarah Koch, Wolfgang E. Berdel, Bernhard J. Woermann, Utz Krug, Jan Braess, Wolfgang Hiddemann, Karsten Spiekermann, Emma L. Boertjes, Robert K. Hills, Alan Burnett, Gerhard Ehninger, Klaus Metzeler, Maja Rothenberg-Thurley, Annika Dufour, Hervé Dombret, Cecile Pautas, Claude Preudhomme, Laurene Fenwarth, Martin Bornhäuser, Rosemary Gale, Christian Thiede
Journal: Leukemia (2024)

Abstract Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA -mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIP InDel ), frameshift InDel or nonsense mutations inducing translational stop (bZIP STOP ) or single base-pair missense alterations (bZIP ms ), and transcription activation domain (TAD) mutations) and the allelic state (single (sm CEBPA ) vs. double mutant (dm CEBPA )). Only bZIP InDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA- mutant subgroups. Moreover, co-mutations in bZIP InDel patients (e.g. GATA2 , FLT3 , WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIP InDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIP InDel mutations to be the major independent determinant of outcome in CEBPA -mutant AML, thereby refining current classifications according to WHO (including all dm CEBPA and sm CEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIP ms ).
Ligand‐Selective Targeting of Macrophage Hydrogel Elicits Bone Immune‐Stem Cell Endogenous Self‐Healing Program to Promote Bone Regeneration
Authors: Jiahao Wang, Liang Zhang, Lingjun Wang, Jincheng Tang, Wei Wang, Yichang Xu, Ziang Li, Zhouye Ding, Xinzhao Jiang, Kun Xi, Liang Chen, Yong Gu
Journal: Advanced Healthcare Materials (2024)

Targeting macrophages can facilitate the site-specific repair of critical bone defects. Herein, a composite hydrogel, gelatin-Bletilla striata polysaccharide-mesoporous bioactive glass hydrogel (GBMgel), is constructed via the self-assembly of mesoporous bioactive glass on polysaccharide structures, through the Schiff base reaction. GBMgel can efficiently capture macrophages and drive the recruitment of seed stem cells and vascular budding required for regeneration in the early stages of bone injury, and the observed sustained release of inorganic silicon ions further enhances bone matrix deposition, mineralization, and vascular maturation. Moreover, the use of macrophage-depleted rat calvarial defect models further confirms that GBMgel, with ligand-selective macrophage targeting, increases the bone regeneration area and the proportion of mature bone. Mechanistic studies reveal that GBMgel upregulates the TLR4/NF-κB and MAPK macrophage pathways in the early stages and the JAK/STAT3 pathway in the later stages; thus initiating macrophage polarization at different time points. In conclusion, this study is based on the endogenous self-healing properties of bone macrophages, which enhances stem cell homing, and provides a research and theoretical basis upon which bone tissue can be reshaped and regenerated using the body's immune power, providing a new strategy for the treatment of critical bone defects.
Correspondence to “Short‐course subcutaneous treatment with <scp>PQ</scp> Grass strongly improves symptom and medication scores in grass allergy<sup>1</sup>”
Authors: I‐Han Cheng, Chin‐Yuan Yii, Liang‐Chun Shih, Su‐Boon Yong
Journal: Allergy (2024)

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Connectivity-guided intermittent theta burst versus repetitive transcranial magnetic stimulation for treatment-resistant depression: a randomized controlled trial
Authors: Richard Morriss, Paul M. Briley, Lucy Webster, Mohamed Abdelghani, Shaun Barber, Peter Bates, Cassandra Brookes, Beth Hall, Luke Ingram, Micheal Kurkar, Sudheer Lankappa, Peter F. Liddle, R. Hamish McAllister-Williams, Alexander O’Neil-Kerr, Stefan Pszczolkowski, Ana Suazo Di Paola, Yvette Walters, Dorothee P. Auer
Journal: Nature Medicine (2024)

Abstract Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation. In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with ‘treatment-resistant depression’. Participants were randomly assigned to 20 sessions over 4–6 weeks of either cgiTBS ( n = 128) or rTMS ( n = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, −0.31, 95% confidence interval (CI) −1.87, 1.24, P = 0.689). Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks (trial registration no. ISRCTN19674644).
Correspondence to “Allergic bronchopulmonary aspergillosis with atopic, nonatopic, and sans asthma—Factor analysis”
Authors: Kai‐Yen Chang, Chi‐Tung Lu, Chin‐Yuan Yii, Su‐Boon Yong
Journal: Allergy (2024)

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
A humanized mouse model to study asthmatic airway remodeling and Muc‐5ac secretion via the human <scp>IL</scp>‐33
Authors: Dong Zhang, Jintao Zhang, Changjuan Xu, Qian Qi, Rong Zeng, Xiaofei Liu, Yun Pan, Jiawei Xu, Liang Dong
Journal: Allergy (2024)

These sequence data have been submitted to the GenBank databases under accession number PRJNA1048633. Materials and methods in this study were provided by Supplementary Data—Materials and Methods. The other data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1 Data S2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Addressing Structural Racism Through Public Policy Advocacy: A Policy Statement From the American Heart Association
Authors: Michelle A. Albert, Keith Churchwell, Nihar Desai, Janay C. Johnson, Michelle N. Johnson, Amit Khera, Jennifer H. Mieres, Fatima Rodriguez, Gladys Velarde, David R. Williams, Joseph C. Wu
Journal: Circulation (2024)

During the COVID-19 pandemic, the American Heart Association created a new 2024 Impact Goal with health equity at its core, in recognition of the increasing health disparities in our country and the overwhelming evidence of the damaging effect of structural racism on cardiovascular and stroke health. Concurrent with the announcement of the new Impact Goal was the release of an American Heart Association presidential advisory on structural racism, recognizing racism as a fundamental driver of health disparities and directing the American Heart Association to advance antiracist strategies regarding science, business operations, leadership, quality improvement, and advocacy. This policy statement builds on the call to action put forth in our presidential advisory, discussing specific opportunities to leverage public policy in promoting overall well-being and rectifying those long-standing structural barriers that impede the progress that we need and seek for the health of all communities. Although this policy statement discusses difficult aspects of our past, it is meant to provide a forward-looking blueprint that can be embraced by a broad spectrum of stakeholders who share the association’s commitment to addressing structural racism and realizing true health equity.
Patient-specific signaling signatures predict optimal therapeutic combinations for triple negative breast cancer
Authors: Heba Alkhatib, Jason Conage-Pough, Sangita Roy Chowdhury, Denen Shian, Deema Zaid, Ariel M. Rubinstein, Amir Sonnenblick, Tamar Peretz-Yablonsky, Avital Granit, Einat Carmon, Ishwar N. Kohale, Judy C. Boughey, Matthew P. Goetz, Liewei Wang, Forest M. White, Nataly Kravchenko-Balasha
Journal: Molecular Cancer (2024)

Abstract Triple negative breast cancer (TNBC) is a heterogeneous group of tumors which lack estrogen receptor, progesterone receptor, and HER2 expression. Targeted therapies have limited success in treating TNBC, thus a strategy enabling effective targeted combinations is an unmet need. To tackle these challenges and discover individualized targeted combination therapies for TNBC, we integrated phosphoproteomic analysis of altered signaling networks with patient-specific signaling signature (PaSSS) analysis using an information-theoretic, thermodynamic-based approach. Using this method on a large number of TNBC patient-derived tumors (PDX), we were able to thoroughly characterize each PDX by computing a patient-specific set of unbalanced signaling processes and assigning a personalized therapy based on them. We discovered that each tumor has an average of two separate processes, and that, consistent with prior research, EGFR is a major core target in at least one of them in half of the tumors analyzed. However, anti-EGFR monotherapies were predicted to be ineffective, thus we developed personalized combination treatments based on PaSSS. These were predicted to induce anti-EGFR responses or to be used to develop an alternative therapy if EGFR was not present. In-vivo experimental validation of the predicted therapy showed that PaSSS predictions were more accurate than other therapies. Thus, we suggest that a detailed identification of molecular imbalances is necessary to tailor therapy for each TNBC. In summary, we propose a new strategy to design personalized therapy for TNBC using pY proteomics and PaSSS analysis. This method can be applied to different cancer types to improve response to the biomarker-based treatment.
Abstract B059: A novel pancreatic cancer mouse model with human immunity
Authors: Norio Miyamura, Kodai Suzuki, Richard A. Friedman, Aristidis Floratos, Yuki Kunisada, Kazuya Masuda, Andrew M. Lowy, Moriya Tsuji, Kazuki N. Sugahara
Journal: Cancer Research (2024)

Abstract The iRGD tumor-penetrating peptide delivers chemically linked drugs and even co-injected free drugs selectively to extravascular tumor tissue by targeting the αvβ5 integrin and neuropilin-1 (NRP1). A phase 1b clinical trial showed that iRGD appears to safely double the response rate of standard chemotherapy in patients with stage 4 pancreatic ductal adenocarcinoma (PDAC). We recently found that long-term iRGD treatment, even as a monotherapy, reduced regulatory T cells (Tregs) selectively in the PDAC tissue, which led to the expansion of CD8+ T cells and improved efficacy of immunotherapy in syngeneic PDAC mice. This finding led to the discovery of αvβ5 integrin being a novel targetable marker for tumor-resident Tregs in PDAC mice. Our recent data show that αvβ5 integrin+ Tregs are also present in human PDAC tissue. To study the significance of αvβ5 integrin+ human Tregs as a therapeutic target for iRGD, we developed a humanized PDAC (huPDAC) mouse model by transplanting human PDAC cells into human immune system (HIS) mice, which harbor fully matured human CD8+ and CD4+ T cells, natural killer T cells, B cells, and dendritic cells. The CD8+ T cells are human leukocyte antigen (HLA)-restricted and show a tumor antigen-specific response. We orthotopically implanted HLA-matched human PDAC cells into HLA-A2-positive HIS mice. Both an established human PDAC cell line (PANC-1) and patient-derived PDAC cells (0779E) successfully formed orthotopic tumors and liver metastases. The tumors were infiltrated by various human immune cells at a ratio similar to that found in patient-derived PDAC tissues. Of note, αvβ5 integrin+ human Tregs were also noted in the tumors but not in the spleen. iRGD monotherapy increased the ratio of CD8+ T cells per Tregs in the tumors, suggesting that iRGD will likely function as an immunomodulator in humans. The first patient was recently dosed in a new phase 1b/2a clinical trial (iLSTA Trial: ACTRN12623000223639), which assesses the safety and preliminary efficacy of iRGD in combination with standard-of-care chemotherapy and immunotherapy in locally advanced PDAC patients. Citation Format: Norio Miyamura, Kodai Suzuki, Richard A. Friedman, Aristidis Floratos, Yuki Kunisada, Kazuya Masuda, Andrew M. Lowy, Moriya Tsuji, Kazuki N. Sugahara. A novel pancreatic cancer mouse model with human immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B059.