tbuckley/cabot-search huggingface dataset:
Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals
Authors: Katrine B. Andersen, Anushree Krishnamurthy, Mie Kristine Just, Nathalie Van Den Berge, Casper Skjærbæk, Jacob Horsager, Karoline Knudsen, Jacob W. Vogel, Jon B. Toledo, Johannes Attems, Tuomo Polvikoski, Yuko Saito, Shigeo Murayama, Per Borghammer
Journal: Nature Neuroscience (2025)

Abstract Recent studies suggest the existence of brain-first and body-first subtypes within the Lewy body disorder (LBD) spectrum, including Parkinson’s disease. These studies primarily focused on α-synuclein propagation through the parasympathetic vagal and olfactory bulb routes, leaving the possibility of a sympathetic nervous system spreading route unexplored. In the present study, we analyzed two postmortem datasets, which included 173 and 129 cases positive for Lewy pathology. We observed a clear distinction between brain-first and body-first subtypes in early prediagnostic cases with mild Lewy pathology. Brain-first cases displayed minimal peripheral organ pathology in prediagnostic phases, contrasting with marked autonomic involvement in prediagnostic body-first cases. Utilizing the SuStaIn machine learning algorithm, we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions. Our study supports the existence of three prediagnostic LBD subtypes and highlights the sympathetic nervous system alongside the parasympathetic system in LBD onset and progression.
Multihit <scp><i>TP53</i></scp> Mutations in Myeloproliferative Neoplasms and Acute Myeloid Leukemia: Comparative Analysis of Survival and Risk Factors in 142 Informative Cases
Authors: Saubia Fathima, Maymona Abdelmagid, Ali Alsugair, Kebede H. Begna, Aref Al‐Kali, Abhishek A. Mangaonkar, Animesh D. Pardanani, Mrinal M. Patnaik, Cinthya J. Zepeda Mendoza, Rong He, Kaaren K. Reichard, Talha Badar, James M. Foran, Jeanne Palmer, Giuseppe G. Loscocco, Paola Guglielmelli, Alessandro M. Vannucchi, Attilio Orazi, Daniel A. Arber, Devendra Hiwase, Mithun V. Shah, Naseema Gangat, Ayalew Tefferi
Journal: American Journal of Hematology (2025)

ABSTRACT A total of 142 patients with myeloproliferative neoplasms (MPNs) or acute myeloid leukemia (AML) associated with multihit TP53 mutations (m TP53 MUT ) were accessed from the Mayo Clinic database and included (i) chronic phase MPN (MPN‐CP; N = 19), (ii) accelerated phase MPN (MPN‐AP; N = 14), (iii) blast phase MPN (MPN‐BP; N = 28), and (iv) AML ( N = 81). Concurrent ASXL1 MUT , EZH2 MUT , IDH1 , MUT and IDH2 MUT were more common in MPN‐ MUT BP‐mTP53 compared to AML‐m TP53 MUT . At median of 11.6 months follow‐up, 124 (87%) deaths and 19 (13%) allogeneic stem cell transplantations (ASCT) were documented. Overall survival (OS), calculated from the time of m TP53 MUT detection, was similar between MPN‐BP‐m TP53 MUT (median 4.6 months) and MPN‐AP‐m TP53 MUT (5.6 months; p = 0.5) but both were inferior to MPN‐CP‐m TP53 MUT (11.6 months, p &lt; 0.01). OS in MPN‐CP‐m TP53 MUT was similar to that of AML‐m TP53 MUT (median 7.4 months, p = 0.07). In multivariable analysis, OS was favorably affected by ASCT (HR 0.4, p = 0.03) and disease stage (i.e., chronic phase disease) or achieving response to pre‐transplant chemotherapy (HR 0.2, p &lt; 0.01) and unfavorably by the presence of concurrent TET2 MUT or DNMT3A MUT (HR 2.7, p &lt; 0.01). Based on these risk factors, a 3‐tiered risk model was constructed: low (no risk factors; N = 18; median OS 23.8 months); intermediate (one risk factor; N = 44; 11.1 months); and high (two or more risk factors; N = 80; 4 months; p &lt; 0.01). The current study highlights the equally detrimental impact of m TP53 MUT on long‐term survival in MPN and AML and identifies predictors of short‐term survival.
Interleukin-12 signaling drives Alzheimer’s disease pathology through disrupting neuronal and oligodendrocyte homeostasis
Authors: Shirin Schneeberger, Seung Joon Kim, Maria N. Geesdorf, Ekaterina Friebel, Pascale Eede, Marina Jendrach, Anastasiya Boltengagen, Caroline Braeuning, Torben Ruhwedel, Andreas J. Hülsmeier, Niclas Gimber, Marlene Foerster, Juliane Obst, Myrto Andreadou, Sarah Mundt, Jan Schmoranzer, Stefan Prokop, Wiebke Kessler, Tanja Kuhlmann, Wiebke Möbius, Klaus-Armin Nave, Thorsten Hornemann, Burkhard Becher, Julia M. Edgar, Nikos Karaiskos, Christine Kocks, Nikolaus Rajewsky, Frank L. Heppner
Journal: Nature Aging (2025)

Abstract Neuroinflammation including interleukin (IL)-12/IL-23-signaling is central to Alzheimer’s disease (AD) pathology. Inhibition of p40, a subunit of IL-12/IL-23, attenuates pathology in AD-like mice; however, its signaling mechanism and expression pattern remained elusive. Here we show that IL-12 receptors are predominantly expressed in neurons and oligodendrocytes in AD-like APPPS1 mice and in patients with AD, whereas IL-23 receptor transcripts are barely detectable. Consistently, deletion of the IL-12 receptor in neuroectodermal cells ameliorated AD pathology in APPPS1 mice, whereas removal of IL-23 receptors had no effect. Genetic ablation of IL-12 signaling alone reverted the loss of mature oligodendrocytes, restored myelin homeostasis, rescued the amyloid-β-dependent reduction of parvalbumin-positive interneurons and restored phagocytosis-related changes in microglia of APPPS1 mice. Furthermore, IL-12 protein expression was increased in human AD brains compared to healthy age-matched controls, and human oligodendrocyte-like cells responded profoundly to IL-12 stimulation. We conclude that oligodendroglial and neuronal IL-12 signaling, but not IL-23 signaling, are key in orchestrating AD-related neuroimmune crosstalk and that IL-12 represents an attractive therapeutic target in AD.
The conceptual structure of human relationships across modern and historical cultures
Authors: Xi Cheng, Haroon Popal, Huanqing Wang, Renfen Hu, Yinyin Zang, Mingzhe Zhang, Mark A. Thornton, Yina Ma, Huajian Cai, Yanchao Bi, Jamie Reilly, Ingrid R. Olson, Yin Wang
Journal: Nature Human Behaviour (2025)
The Access Of Oncological Patients To Medical Care Amid The Rigid Social Restriction Context Related To The Covid-19 Pandemic
Authors: Bruno Michelassi Bernardes De Oliveira, Cintia Kelly Bittar, Henrique Chiarini Batistella, Bruna Granin Valente, Aline Cremasco Rocha, Silvia Raquel Fricke Matte, Luciano Augusto Reganin
Journal: Journal of Clinical Oncology (2025)

The main objective of this study is to prove that the social restriction and isolation measures used in Campinas during the SARS-CoV-2 virus pandemic limited drastically the access of oncological patients to medical care for a long period of time in this city, being enough time to risk worsening the prognosis for these patients mainly through the delay of diagnosis and treatments. The methods for this research involved a collection of data from the medical records eletronic system of the Pontifical Catholic University of Campinas’s (PUCCAMP) hospital and ambulatory clinics about oncological patients admitted during the period that social restriction measures were at use in Campinas, analazying the variation on the numbers of neoplasm diagnosis, neoplasm related surgeries, and of neoplasm patient admissions in these institutions throughout this period. Between march and december of 2020, there was 13 diagnosis of neoplasm, 17 surgeries, and 1209 admissions. Throughout 2021, there was 31 diagnosis of neoplasm, 25 surgeries, and 2172 admissions. Throughout 2022, there was 82 diagnosis of neoplasm, 49 surgeries, and 3104 admissions. According to the results obtained, the numbers of diagnosis, surgeries and admissions for oncological patients increased as the years passed and, therefore, as the social restriction measures became slowly less rigid throughout these years, implying a relation of cause and effect between the high rigidity of social restriction norms and the loss of accessibility to medical care by oncological patients. Keywords: Neoplasm. Pandemic. Diagnosis. Admissions. Surgery
March2 Alleviates Aortic Aneurysm/Dissection by Regulating PKM2 Polymerization
Authors: Yiran E. Li, Shuolin Liu, Litao Wang, Yuxin Du, Lin Wu, Haoran Chen, Tingfang Zhu, Jie Lin, Shengjun Xiong, Yayu Wang, Qijun Zheng, Rongjun Zou, Ling Lin, Zheyun Li, Lixin Wang, Junbo Ge, Jun Ren, Yingmei Zhang
Journal: Circulation Research (2025)

BACKGROUND: Aortic aneurysm/dissection (AAD) is a life-threatening disease lacking effective pharmacological treatment. Protein ubiquitination plays a pivotal role in cardiovascular diseases. However, the possible contribution of the E3 ubiquitin ligase March2 (membrane-associated RING finger protein 2) to the cause of AAD remains elusive. METHODS: Integrated single-cell RNA sequencing analysis was conducted in human AAD tissues. Based on the screening results, we generated a mouse line of smooth muscle cell–specific March2 knockout. β-Aminopropionitrile monofumarate was used to establish AAD. Cleavage under targets and tagmentation and cleavage under targets and tagmentation–quantitative polymerase chain reaction were performed to identify possible target genes for histone H3K18 lactylation. RESULTS: March2 expression was downregulated in aorta from patients with AAD or β-aminopropionitrile monofumarate–induced AAD mice. β-Aminopropionitrile monofumarate–induced AAD was significantly accentuated in March2 global (March2 –/– ) and vascular smooth muscle cell–specific deletion (March2 fl/fl ; Tagln Cre ) mice, whereas the AAD pathology was rescued by rAAV9-SM22α-March2 (recombinant adeno-associated virus serotype 9 expressing Flag-tagged March2 under SM22α promoter). March2 interacted with PKM2 (pyruvate kinase M2) to promote K33-linked polyubiquitination. Deficiency of March2 lessened PKM2 dimer-to-tetramer conversion in AAD and overtly exacerbated AAD-induced histone H3K18 lactylation in vascular smooth muscle cells by fostering glucose metabolism reprogramming, thereby promoting p53-driven apoptotic transcriptional response—a hallmark of AAD pathogenesis. TEPP-46, a PKM2-specific activator, pronouncedly alleviated March2 deficiency–deteriorated AAD pathology. CONCLUSIONS: Our findings demonstrated that March2 is a novel endogenous defender that prevents AAD by inhibiting vascular smooth muscle cell apoptosis, suggesting that March2 represents a potential therapeutic target for AAD.
Inorganic Nanomaterials Meet the Immune System: An Intricate Balance
Authors: Gloria Pizzoli, Marco Gargaro, Giuliana Drava, Valerio Voliani
Journal: Advanced Healthcare Materials (2025)

Abstract The immune system provides defense against foreign agents that are considered harmful for the organism. Inorganic nanomaterials can be recognized by the immune system as antigens, inducing an immune reaction dependent on the patient's immunological anamnesis and from several factors including size, shape, and the chemical nature of the nanoparticles. Furthermore, nanomaterials‐driven immunomodulation might be exploited for therapeutic purposes, opening new horizons in oncology and beyond. In this scenario, we present a critical review of the state of the art regarding the preclinical evaluation of the effects of the most promising metals for biomedical applications (gold, silver, and copper) on the immune system. Because exploiting the interactions between the immune system and inorganic nanomaterials may result in a game changer for the management of (non)communicable diseases, within this review we encounter the need to summarize and organize the plethora of sometimes inconsistent information, analyzing the challenges and providing the expected perspectives. The field is still in its infancy, and our work emphasizes that a deep understanding on the influence of the features of metal nanomaterials on the immune system in both cultured cells and animal models is pivotal for the safe translation of nanotherapeutics to the clinical practice.
Direct-to-Consumer Genetic Testing for Cardiovascular Disease: A Scientific Statement From the American Heart Association
Authors: Leland E. Hull, Aaron W. Aday, Quan M. Bui, Jasmine A. Luzum, James M. Muchira, Hannah Wand, C. Anwar A. Chahal, Mina K. Chung, Anne E. Kwitek, Silvana Molossi, Pradeep Natarajan
Journal: Circulation (2025)

Despite insufficient evidence to support direct-to-consumer genetic testing in routine clinical care, cardiovascular clinicians increasingly face questions about its utility and interpretation because individuals can purchase these tests directly from laboratories. A burgeoning marketplace offers an expanding array of testing options. In many cases, direct-to-consumer genetic testing advertises information that could inform one’s risk of heritable disease, including insight into having a genetic predisposition to cardiovascular disease or data about gene-drug interactions that could affect response to cardiovascular medications. Navigating clinical questions about direct-to-consumer genetic testing involves understanding the evolution and oversight of the marketplace; the scope of direct-to-consumer genetic testing offerings; and the risks, benefits, and limitations of said testing. In this American Heart Association scientific statement, we summarize the state of the direct-to-consumer genetic testing industry, review types of cardiovascular genetic information that may be included in direct-to-consumer genetic testing, describe approaches to evaluate test quality, and provide resources for clinicians navigating questions about direct-to-consumer genetic testing. If direct-to-consumer genetic test information is used in clinical care, care should be taken to assess the limitations of the test, to contextualize the information specifically to the patient, and to corroborate potentially actionable monogenic findings.
Injectable Nanocomposite Hydrogels for Intervertebral Disc Degeneration: Combating Oxidative Stress, Mitochondrial Dysfunction, and Ferroptosis
Authors: Zhenyu Guo, Xinzhou Wang, Jing Sun, QiZhu Chen, Linjie Chen, Ouqiang Wu, Yuxin Jin, Taidong Lyu, Jones Morgan, Yan Michael Li, Hao Zhou, Yongcheng Chen, Xiuling You, Yunlong Zhou, Yu Chen, Qiuping Qian, Aimin Wu
Journal: Advanced Healthcare Materials (2025)

Abstract Intervertebral disc degeneration (IVDD) is a major cause of low back pain, where oxidative stress and mitochondrial dysfunction are key contributors. Additionally, ferroptosis, an iron‐dependent form of cell death, is identified as a critical mechanism in IVDD pathogenesis. Herein, the therapeutic potential of gallic acid (GA)‐derived PGA‐Cu nanoparticles, enhanced with functional octapeptide (Cys‐Lys‐His‐Gly‐ d ‐Arg‐ d ‐Tyr‐Lys‐Phe, SS08) to build the mitochondria‐targeted nanoparticles (PGA‐Cu@SS08), and embedded within a hydrogel matrix to form a nanocomposite hydrogel, is explored. The nanoparticles show targeted localization within mitochondria, effectively scavenging reactive oxygen species and preserving mitochondrial function. The abundant phenolic hydroxyl groups present on the nanoparticle surface, along with the histidine residue of the SS08 peptide, endow these entities with the capacity to chelate iron. Through RNA sequencing analysis, it is discovered that PGA‐Cu@SS08 activates the NRF2 signaling pathway, mitigating ferroptosis. It also reduces iron overload by inhibiting the autophagy of iron storage proteins. Additionally, the nanocomposite hydrogels exhibit excellent biocompatibility and biodegradability, along with enhanced mechanical properties that improve intervertebral disc (IVD) performance. PGA‐Cu@SS08 is continuously released from these hydrogels, restoring IVD height and maintaining tissue hydration levels, thus facilitating future applications for alleviating IVDD.
Cascade‐Responsive Nanoprodrug Disrupts Immune‐Fibroblast Communications for Potentiated Cancer Mechanoimmunotherapy
Authors: Xin Guan, Yuting Shen, Chongke Zhao, Xiao Li, Xiaolong Li, Dan Lu, Lifan Wang, Linna Liu, Shengbo Wu, Bin Huang, Lehang Guo, Huixiong Xu
Journal: Advanced Healthcare Materials (2025)

Abstract The abnormal tumor mechanical microenvironment due to specific cancer‐associated fibroblasts (CAFs) subset and low tumor immunogenicity caused by inefficient conversion of active chemotherapeutic agents are two key obstacles that impede patients with desmoplastic tumors from achieving stable and complete immune responses. Herein, it is demonstrated that FAP‐α + CAFs‐induced stromal stiffness accelerated tumor progression by precluding cytotoxic T lymphocytes. Subsequently, a cascade‐responsive nanoprodrug capable of re‐educating FAP‐α + CAFs and amplifying tumor immunogenicity for potentiated cancer mechanoimmunotherapy is ingeniously designed. Benefiting from the active targeted release of angiotensin II receptor antagonist (losartan) guided by FAP‐α cleavable peptide and the efficient conversion of topoisomerase I inhibitor (7‐Ethyl‐10‐hydroxycamptothecin) prodrug under high glutathione/esterase within tumor cells, this regimen created an immune‐activated landscape that retarded primary tumor growth and counteracted resistance to immune checkpoint inhibitor in mice with triple‐negative breast cancer. This nanoprodrug‐assisted mechanoimmunotherapy can serve as a universal strategy for conferring efficient tumoricidal immunity in “immune excluded” desmoplastic tumor interventions.
Corrigendum to "Cyanobacteria-based self-oxygenated photodynamic therapy for anaerobic infection treatment and tissue repair" [Bioactive Materials 12 (2022) 314–326]
Authors: Bailiang Wang, Liyang Zhou, Yishun Guo, Hanwen Guo, Yiming Zhong, Xiaomin Huang, Yifan Ge, Qingying Wang, Xiaoying Chu, Yingying Jin, Kaiyue Lan, Mei Yang, Jia Qu
Journal: Bioactive Materials (2025)
ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma
Authors: Dhana Sekhar Reddy Bandi, Ganji Purnachandra Nagaraju, Sujith Sarvesh, Julienne L. Carstens, Jeremy B. Foote, Emily C. Graff, Yu-Hua D Fang, Adam B. Keeton, Xi Chen, Jacob Valiyaveettil, Kristy L. Berry, Sejong Bae, Mehmet Akce, Greg Gorman, Karina J. Yoon, Upender Manne, Michael R. Boyd, Donald J. Buchsbaum, Asfar S. Azmi, Yulia Y. Maxuitenko, Gary A. Piazza, Bassel F. El-Rayes
Journal: Molecular Cancer (2025)

Oncogenic KRAS mutations occur in nearly, 90% of patients with pancreatic ductal adenocarcinoma (PDAC). Targeting KRAS has been complicated by mutational heterogeneity and rapid resistance. We developed a novel pan-RAS inhibitor, ADT-1004 (an oral prodrug of ADT-007) and evaluated antitumor activity in murine and human PDAC models. Murine PDAC cells with KRASG12D mutation (KPC-luc or 2838c3-luc) were orthotopically implanted into the pancreas of C57BL/6J mice, and four PDX PDAC tumors with KRAS mutations were implanted subcutaneously in NSG mice. To assess potential to overcome RAS inhibitor resistance, parental and resistant MIA PaCa-2 PDAC cells (KRASG12C mutation) were implanted subcutaneously. Subcutaneously implanted RASWT BxPC-3 cells were used to assess the selectivity of ADT-1004. ADT-1004 potently blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity with target engagement and reduced activated RAS and ERK phosphorylation. In addition, ADT-1004 suppressed tumor growth in PDX PDAC models with KRASG12D, KRASG12V, KRASG12C, or KRASG13Q mutations and increased CD4+ and CD8+ T cells in the TME consistent with exhaustion and increased MHCII+ M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models resistant to these KRASG12C inhibitors and MRTX1133 resistant KRASG12D mutant cells. As evidence of selectivity for tumors with mutant KRAS, ADT-1004 did not impact the growth of tumors from RASWT PDAC cells. ADT-1004 has strong antitumor activity in aggressive and clinically relevant PDAC models with unique selectivity to block RAS-mediated signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.
Administration of Porphyromonas gingivalis in pregnant mice enhances glycolysis and histone lactylation/ADAM17 leading to cleft palate in offspring
Authors: Xige Zhao, Xiaoyu Zheng, Yijia Wang, Jing Chen, Xiaotong Wang, Xia Peng, Dong Yuan, Ying Liu, Zhiwei Wang, Juan Du
Journal: International Journal of Oral Science (2025)

Abstract Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes. Cleft palate (CP), the most common congenital craniofacial defect, has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection. A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring. However, the precise relationship remains unclear. In this study, the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P. gingivalis injected intravenously and orally into pregnant mice. We investigated an obvious increasing CP (12.5%) in sonicated P. gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium. Then glycolysis and H4K12 lactylation (H4K12la) were detected to elevate in both mouse embryonic palatal mesenchyme (MEPM) cells and macrophages under P. gingivalis exposure which further promoted the transcription of metallopeptidase domain17 (ADAM17), subsequently mediated the shedding of transforming growth factor-beta receptor 1 (TGFBR1) in MEPM cells and mer tyrosine kinase (MerTK) in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate, eventually caused abnormalities in palate fusion and ossification. The abnormal efferocytosis also led to a predominance of M1 macrophages, which indirectly inhibited palatal osteogenesis via extracellular vesicles. Furthermore, pharmacological ADAM17 inhibition could ameliorate the abnormality of P. gingivalis -induced abnormal palate development. Therefore, our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.
Expert consensus on the clinical strategies for orthodontic treatment with clear aligners
Authors: Yan Wang, Hu Long, Zhihe Zhao, Ding Bai, Xianglong Han, Jun Wang, Bing Fang, Zuolin Jin, Hong He, Yuxin Bai, Weiran Li, Min Hu, Yanheng Zhou, Hong Ai, Yuehua Liu, Yang Cao, Jun Lin, Huang Li, Jie Guo, Wenli Lai
Journal: International Journal of Oral Science (2025)

Abstract Clear aligner treatment is a novel technique in current orthodontic practice. Distinct from traditional fixed orthodontic appliances, clear aligners have different material features and biomechanical characteristics and treatment efficiencies, presenting new clinical challenges. Therefore, a comprehensive and systematic description of the key clinical aspects of clear aligner treatment is essential to enhance treatment efficacy and facilitate the advancement and wide adoption of this new technique. This expert consensus discusses case selection and grading of treatment difficulty, principle of clear aligner therapy, clinical procedures and potential complications, which are crucial to the clinical success of clear aligner treatment.