tbuckley/cabot-search huggingface dataset:
Mitochondrial Venus is more likely to have a lower birthweight
Authors: Elina Aleksejeva, Masoud Zamani Esteki, Andres Salumets
Journal: Trends in Endocrinology and Metabolism (2024)

Assisted reproductive technologies (ART) are associated with a moderately higher risk of preterm birth and low birthweight, but the causes are unknown. A recent study by Mertens et al. reveals a link between being born through ART, ovarian stimulation, and an increased incidence of mitochondrial heteroplasmic variants that correlate with lower birthweight.
RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives
Authors: Dana Alawieh, Leila Cysique-Foinlan, Christophe Willekens, Aline Renneville
Journal: Blood Cancer Journal (2024)

NRAS and KRAS activating point mutations are present in 10-30% of myeloid malignancies and are often associated with a proliferative phenotype. RAS mutations harbor allele-specific structural and biochemical properties depending on the hotspot mutation, contributing to variable biological consequences. Given their subclonal nature in most myeloid malignancies, their clonal architecture, and patterns of cooperativity with other driver genetic alterations may potentially have a direct, causal influence on the prognosis and treatment of myeloid malignancies. RAS mutations overall tend to be associated with poor clinical outcome in both chronic and acute myeloid malignancies. Several recent prognostic scoring systems have incorporated RAS mutational status. While RAS mutations do not always act as independent prognostic factors, they significantly influence disease progression and survival. However, their clinical significance depends on the type of mutation, disease context, and treatment administered. Recent evidence also indicates that RAS mutations drive resistance to targeted therapies, particularly FLT3, IDH1/2, or JAK2 inhibitors, as well as the venetoclax-azacitidine combination. The investigation of novel therapeutic strategies and combinations that target multiple axes within the RAS pathway, encompassing both upstream and downstream components, is an active field of research. The success of direct RAS inhibitors in patients with solid tumors has brought renewed optimism that this progress will be translated to patients with hematologic malignancies. In this review, we highlight key insights on RAS mutations across myeloid malignancies from the past decade, including their prevalence and distribution, cooperative genetic events, clonal architecture and dynamics, prognostic implications, and therapeutic targeting.
Dupilumab in Chronic Actinic Dermatitis: a retrospective case series
Authors: Marese O’Reilly, Alexandra Paolino, Pirunthan Pathmarajah, John Ferguson, Catherine H Smith, Robert Sarkany, Robert S Dawe, Amr Salam, Andrew E Pink, Hiva Fassihi, Sally Ibbotson
Journal: British Journal of Dermatology (2024)

We report a retrospective case series from two UK photobiology units of 12 patients with concomitant atopic dermatitis (AD) and chronic actinic dermatitis (CAD) treated with dupilumab as a systemic monotherapy. While dupilumab is an effective therapy for moderate-to-severe AD, our results suggest that it may be less effective for the photosensitivity of CAD. In 11 of 12 patients with CAD, dupilumab was associated with improvement in dermatitis, but only half the patients noted improvement in photosensitivity.
Hypothalamic neuronal activation in non-human primates drives naturalistic goal-directed eating behavior
Authors: Leslie Jaesun Ha, Hyeon-Gu Yeo, Yu Gyeong Kim, Inhyeok Baek, Eunha Baeg, Young Hee Lee, Jinyoung Won, Yunkyo Jung, Junghyung Park, Chang-Yeop Jeon, Keonwoo Kim, Jisun Min, Youngkyu Song, Jeong-Heon Park, Kyung Rok Nam, Sangkyu Son, Seng Bum Michael Yoo, Sung-hyun Park, Won Seok Choi, Kyung Seob Lim, Jae Yong Choi, Jee-Hyun Cho, Youngjeon Lee, Hyung Jin Choi
Journal: Neuron (2024)

Highlights•The role of LHAGABA neurons on macaque's naturalistic eating behavior was investigated•Chemogenetic activation increased goal-directed behaviors, mainly for palatable food•PET and MRS functionally validated chemogenetic activation•Rs-fMRI revealed increased LHA-frontal FC, with decreased FC within frontal corticesSummaryMaladaptive feeding behavior is the primary cause of modern obesity. While the causal influence of the lateral hypothalamic area (LHA) on eating behavior has been established in rodents, there is currently no primate-based evidence available on naturalistic eating behaviors. We investigated the role of LHA GABAergic (LHAGABA) neurons in eating using chemogenetics in three macaques. LHAGABA neuron activation significantly increased naturalistic goal-directed behaviors and food motivation, predominantly for palatable food. Positron emission tomography and magnetic resonance spectroscopy validated chemogenetic activation. Resting-state functional magnetic resonance imaging revealed that the functional connectivity (FC) between the LHA and frontal areas was increased, while the FC between the frontal cortices was decreased after LHAGABA neuron activation. Thus, our study elucidates the role of LHAGABA neurons in eating and obesity therapeutics for primates and humans.Graphical abstract
Inhibiting Eph/ephrin signaling reduces vascular leak and endothelial cell dysfunction in mice with sepsis
Authors: Nemat Khan, Vinod Kumar, Pengcheng Li, Luregn J. Schlapbach, Andrew W. Boyd, Mark G. Coulthard, Trent M. Woodruff, Luregn J. Schlapbach, Sainath Raman, Natalie Sharp, Natalie Phillips, Adam Irwin, Shane George, Keith Grimwood, Peter Snelling, Arjun Chavan, Allison Hempenstall, Kristen Gibbons, Renate Le Marsney, Antje Blumenthal, Devika Ganesamoorthy, Lachlan Coin
Journal: Science Translational Medicine (2024)

Sepsis is a life-threatening disease caused by a dysregulated host response to infection, resulting in 11 million deaths globally each year. Vascular endothelial cell dysfunction results in the loss of endothelial barrier integrity, which contributes to sepsis-induced multiple organ failure and mortality. Erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their ephrin ligands play a key role in vascular endothelial barrier disruption but are currently not a therapeutic target in sepsis. Using a cecal ligation and puncture (CLP) mouse model of sepsis, we showed that prophylactic or therapeutic treatment of mice with EphA4-Fc, a decoy receptor and pan-ephrin inhibitor, resulted in improved survival and a reduction in vascular leak, lung injury, and endothelial cell dysfunction. EphA2 −/− mice also exhibited reduced mortality and pathology after CLP compared with wild-type mice. Proteomics of plasma samples from mice with sepsis after CLP revealed dysregulation of a number of Eph/ephrins, including EphA2/ephrin A1. Administration of EphA4-Fc to cultured human endothelial cells pretreated with TNF-α or ephrin-A1 prevented loss of endothelial junction proteins, specifically VE-cadherin, with maintenance of endothelial barrier integrity. In children admitted to hospital with fever and suspected infection, we observed that changes in EphA2/ephrin A1 in serum samples correlated with endothelial and organ dysfunction. Targeting Eph/ephrin signaling may be a potential therapeutic strategy to reduce sepsis-induced endothelial dysfunction and mortality.
Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of antiviral pharmacodynamic studies: an individual patient data meta-analysis of a randomised, controlled, adaptive platform study (PLATCOV)
Authors: Phrutsamon Wongnak, William H K Schilling, Podjanee Jittamala, Simon Boyd, Viravarn Luvira, Tanaya Siripoon, Thundon Ngamprasertchai, Elizabeth M Batty, Shivani Singh, Jindarat Kouhathong, Watcharee Pagornrat, Patpannee Khanthagan, Borimas Hanboonkunupakarn, Kittiyod Poovorawan, Mayfong Mayxay, Kesinee Chotivanich, Mallika Imwong, Sasithon Pukrittayakamee, Elizabeth A Ashley, Arjen M Dondorp, Nicholas P J Day, Mauro M Teixeira, Watcharapong Piyaphanee, Weerapong Phumratanaprapin, Nicholas J White, James A Watson
Journal: The Lancet Infectious Diseases (2024)

Effective antiviral drugs prevent hospitalisation and death from COVID-19. Antiviral efficacy can be efficiently assessed in vivo by measuring rates of SARS-CoV-2 clearance estimated from serial viral genome densities quantitated in nasopharyngeal or oropharyngeal swab eluates. We conducted an individual patient data meta-analysis of unblinded arms in the PLATCOV platform trial to characterise changes in viral clearance kinetics and infer optimal design and interpretation of antiviral pharmacometric evaluations.
Regulation of metabolic microenvironment with a nanocomposite hydrogel for improved bone fracture healing
Authors: Kangkang Zha, Meijun Tan, Yiqiang Hu, Weixian Hu, Shengming Zhang, Yanzhi Zhao, Ze Lin, Wenqian Zhang, Hang Xue, Bobin Mi, Wu Zhou, Qian Feng, Faqi Cao, Guohui Liu
Journal: Bioactive Materials (2024)

Bone nonunion poses an urgent clinical challenge that needs to be addressed. Recent studies have revealed that the metabolic microenvironment plays a vital role in fracture healing. Macrophages and bone marrow-derived mesenchymal stromal cells (BMSCs) are important targets for therapeutic interventions in bone fractures. Itaconate is a TCA cycle metabolite that has emerged as a potent macrophage immunomodulator that limits the inflammatory response. During osteogenic differentiation, BMSCs tend to undergo aerobic glycolysis and metabolize glucose to lactate. Copper ion (Cu2+) is an essential trace element that participates in glucose metabolism and may stimulate glycolysis in BMSCs and promote osteogenesis. In this study, we develop a 4-octyl itaconate (4-OI)@Cu@Gel nanocomposite hydrogel that can effectively deliver and release 4-OI and Cu2+ to modulate the metabolic microenvironment and improve the functions of cells involved in the fracture healing process. The findings reveal that burst release of 4-OI reduces the inflammatory response, promotes M2 macrophage polarization, and alleviates oxidative stress, while sustained release of Cu2+ stimulates BMSC glycolysis and osteogenic differentiation and enhances endothelial cell angiogenesis. Consequently, the 4-OI@Cu@Gel system achieves rapid fracture healing in mice. Thus, this study proposes a promising regenerative strategy to expedite bone fracture healing through metabolic reprogramming of macrophages and BMSCs.
Membrane Fusion Liposomes Deliver Antifibrotic and Chemotherapeutic Drugs Sequentially to Enhance Tumor Treatment Efficacy by Reshaping Tumor Microenvironment
Authors: Nan Jia, Qi Wang, Wenpan Li, Dawei Chen, Haiyang Hu
Journal: Advanced Healthcare Materials (2024)

The intricate tumor microenvironment in triple-negative breast cancer (TNBC) hampers chemotherapy and immunotherapy efficacy due to dense extracellular matrix (ECM) by tumor-associated fibroblasts (TAFs). Nanoparticle-based therapies, especially "all-in-one" nanoparticles, have shown great potential in combined drug delivery strategies to reshape the tumor microenvironment and enhance therapeutic efficiency. However, these "all-in-one" nanoparticles suffer from limitations in targeting different target cells, uncontrollable dosing ratio, and disregarding the impact of delivery schedules. This study prepared cell membrane fusion liposomes (TAFsomes and CCMsomes) to load FDA-approved antifibrotic drug pirfenidone (PFD/TAFsomes) and antitumor drug doxorubicin (DOX/CCMsomes). These liposomes can specifically target TAFs cells and tumor cells, and combined administration can effectively inhibit TAFs activity, reshape the tumor microenvironment (TME), and significantly enhance the tumor chemotherapy efficacy. Combined drug delivery defeats "all-in-one" liposomes (DOX/PFD/Liposomes, DOX/PFD/TAFsomes, and DOX/PFD/CCMsomes) by flexibly adjusting the drug delivery ratio. Moreover, an asynchronous delivery strategy that optimizes the administration schedule not only further improves the therapeutic effect, but also amplifies the effectiveness of α-PD-L1 immunotherapy by modulating the tumor immune microenvironment. This delivery strategy provides a personalized treatment approach with clinical translation potential, providing new ideas for enhancing the therapeutic effect against solid tumors such as TNBC.
An electroencephalogram microdisplay to visualize neuronal activity on the brain surface
Authors: Youngbin Tchoe, Tianhai Wu, Hoi Sang U, David M. Roth, Dongwoo Kim, Jihwan Lee, Daniel R. Cleary, Patricia Pizarro, Karen J. Tonsfeldt, Keundong Lee, Po Chun Chen, Andrew M. Bourhis, Ian Galton, Brian Coughlin, Jimmy C. Yang, Angelique C. Paulk, Eric Halgren, Sydney S. Cash, Shadi A. Dayeh
Journal: Science Translational Medicine (2024)

Functional mapping during brain surgery is applied to define brain areas that control critical functions and cannot be removed. Currently, these procedures rely on verbal interactions between the neurosurgeon and electrophysiologist, which can be time-consuming. In addition, the electrode grids that are used to measure brain activity and to identify the boundaries of pathological versus functional brain regions have low resolution and limited conformity to the brain surface. Here, we present the development of an intracranial electroencephalogram (iEEG)–microdisplay that consists of freestanding arrays of 2048 GaN light-emitting diodes laminated on the back of micro-electrocorticography electrode grids. With a series of proof-of-concept experiments in rats and pigs, we demonstrate that these iEEG-microdisplays allowed us to perform real-time iEEG recordings and display cortical activities by spatially corresponding light patterns on the surface of the brain in the surgical field. Furthermore, iEEG-microdisplays allowed us to identify and display cortical landmarks and pathological activities from rat and pig models. Using a dual-color iEEG-microdisplay, we demonstrated coregistration of the functional cortical boundaries with one color and displayed the evolution of electrical potentials associated with epileptiform activity with another color. The iEEG-microdisplay holds promise to facilitate monitoring of pathological brain activity in clinical settings.
Artificial Intelligence‐Driven Platform: Unveiling Critical Hepatic Molecular Alterations in Hepatocellular Carcinoma Development
Authors: Miao Jiang, Pengyun Wu, Yuwei Zhang, Mengling Wang, Mingjie Zhang, Zhaoxiang Ye, Xuejun Zhang, Cai Zhang
Journal: Advanced Healthcare Materials (2024)

Since most Hepatocellular Carcinoma (HCC) typically arises as a consequence of long-term liver damage, the hepatic molecular characteristics are closely related to the occurrence of HCC. Gaining comprehensive information about the location, morphology, and hepatic molecular alterations related to HCC is essential for accurate diagnosis. However, there is a dearth of technological advancements capable of concurrently providing precise HCC diagnosis and discerning the accompanying hepatic molecular alterations. In this study, an integrated information system is developed for the pathological-level diagnosis of HCC and the revelation of critical molecular alterations in the liver. This system utilizes computed tomography/Surface-enhanced Raman scattering combined with an artificial intelligence strategy to establish connections between the occurrence of HCC and alterations in hepatic biomolecules. Employing artificial intelligence techniques, the SERS spectra from both healthy and HCC groups are successfully classified into two distinct categories with a remarkable accuracy rate of 91.38%. Based on molecular profiling, it is identified that the nucleotide-to-lipid signal ratio holds significant potential as a reliable indicator for the occurrence of HCC, thereby serving as a promising tool for prevention and therapeutic surveillance.
Single-Cell and Spatial Transcriptome Profiling Identifies the Transcription Factor BHLHE40 as a Driver of EMT in Metastatic Colorectal Cancer
Authors: Sheng Yang, Dongsheng Zhang, Qingyang Sun, Hongxu Nie, Yue Zhang, Xiaowei Wang, Yuanjian Huang, Yueming Sun
Journal: Cancer Research (2024)

Colorectal cancer is one of the most common malignant tumors in humans, with liver metastasis being the primary cause of mortality. The epithelial-mesenchymal transition (EMT) process endows cancer cells with enhanced metastatic potential. To elucidate the cellular mechanisms driving EMT in colorectal cancer, we analyzed single-cell RNA sequencing data from 11 nonmetastatic primary tumors (TnM) and 11 metastatic primary tumors (TM) from colorectal cancer patients. Compared with the TnM group, the TM samples showed elevated numbers of malignant epithelial cell and cancer-associated fibroblast (CAF) subsets that displayed enrichments of EMT, angiogenesis, and TGFβ signaling pathways. One specific TM-enriched subgroup of malignant epithelial cells underwent EMT to transdifferentiate into CXCL1+ CAFs that subsequently differentiated into SFRP2+ CAFs, which was validated by spatial transcriptomic and pseudotime trajectory analyses. Furthermore, cell-cell communication analysis identified BHLHE40 as a probable key transcription factor driving EMT that was associated with poor prognosis. Finally, in vitro and in vivo experiments functionally substantiated that BHLHE40 promoted the proliferation, invasion, migration, EMT, and liver metastasis of colorectal cancer cells. In summary, this study identified BHLHE40 as a key transcription factor regulating EMT that promotes liver metastasis in colorectal cancer. Significance: Integrated analysis of single-cell RNA sequencing and spatial transcriptomics in metastatic colorectal cancer provides insights into the mechanisms underlying EMT and cancer-associated fibroblast differentiation, which could help improve patient diagnosis and treatment.
ACSM1 and ACSM3 Regulate Fatty Acid Metabolism to Support Prostate Cancer Growth and Constrain Ferroptosis
Authors: Raj K. Shrestha, Zeyad D. Nassar, Adrienne R. Hanson, Richard Iggo, Scott L. Townley, Jonas Dehairs, Chui Y. Mah, Madison Helm, Mohammadreza Alizadeh-Ghodsi, Marie Pickering, Bart Ghesquière, Matthew J. Watt, Lake-Ee Quek, Andrew J. Hoy, Wayne D. Tilley, Johannes V. Swinnen, Lisa M. Butler, Luke A. Selth
Journal: Cancer Research (2024)

Solid tumors are highly reliant on lipids for energy, growth, and survival. In prostate cancer, the activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes. Here, we identified acyl-CoA synthetase medium chain family members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 were upregulated in prostate tumors compared with nonmalignant tissues and other cancer types. Both enzymes enhanced proliferation and protected prostate cancer cells from death in vitro, whereas silencing ACSM3 led to reduced tumor growth in an orthotopic xenograft model. ACSM1 and ACSM3 were major regulators of the prostate cancer lipidome and enhanced energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation, and cell death by ferroptosis. Conversely, elevated ACSM1/3 activity enabled prostate cancer cells to survive toxic levels of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, this study reveals a tumor-promoting function of medium chain acyl-CoA synthetases and positions ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance. Significance: Androgen receptor-induced ACSM1 and ACSM3 mediate a metabolic pathway in prostate cancer that enables the utilization of medium chain fatty acids for energy production, blocks ferroptosis, and drives resistance to clinically approved antiandrogens.
Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease
Authors: Po Hu, Jack Rychik, Juanjuan Zhao, Huajun Bai, Aidan Bauer, Wenbao Yu, Elizabeth B. Rand, Kathryn M. Dodds, David J. Goldberg, Kai Tan, Benjamin J. Wilkins, Liming Pei
Journal: Science Translational Medicine (2024)

The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type-specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first "responder" in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A's transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.
Efficacy of CAR T-cell therapy is not impaired by previous bispecific antibody treatment in large B-cell lymphoma
Authors: Gilles Crochet, Gloria Iacoboni, Audrey Couturier, Emmanuel Bachy, Josu Iraola-Truchuelo, Thomas Gastinne, Guillaume Cartron, Tom Fradon, Bastien Lesne, Mi Kwon, Romain Gounot, Nuria Martínez-Cibrian, Cristina Castilla-Llorente, Pau Abrisqueta, Manuel Guerreiro, Clémentine Sarkozy, Jose María Aspa-Cilleruelo, Vincent Camus, Stéphanie Guidez, Adrien Chauchet, Eric Deconinck, Krimo Bouabdallah, Francesc Bosch, Pere Barba, Franck Morschhauser, Roch Houot
Journal: Blood (2024)
Delivery of miRNAs Using Porous Silicon Nanoparticles Incorporated into 3D Hydrogels Enhances MSC Osteogenesis by Modulation of Fatty Acid Signalling and Silicon Degradation
Authors: Surakshya Shrestha, Terence Tieu, Marcin Wojnilowicz, Nicolas H. Voelcker, John S. Forsythe, Jessica E. Frith
Journal: Advanced Healthcare Materials (2024)

Abstract Strategies incorporating mesenchymal stromal cells (MSC), hydrogels and osteoinductive signals offer promise for bone repair. Osteoinductive signals such as growth factors face challenges in clinical translation due to their high cost, low stability and immunogenicity leading to interest in microRNAs as a simple, inexpensive and powerful alternative. The selection of appropriate miRNA candidates and their efficient delivery must be optimised to make this a reality. This study evaluated pro‐osteogenic miRNAs and used porous silicon nanoparticles modified with polyamidoamine dendrimers (PAMAM‐pSiNP) to deliver these to MSC encapsulated within gelatin‐PEG hydrogels. miR‐29b‐3p, miR‐101‐3p and miR‐125b‐5p are strongly pro‐osteogenic and are shown to target FASN and ELOVL4 in the fatty acid biosynthesis pathway to modulate MSC osteogenesis. Hydrogel delivery of miRNA:PAMAM‐pSiNP complexes enhanced transfection compared to 2D. The osteogenic potential of hBMSC in hydrogels with miR125b:PAMAM‐pSiNP complexes is evaluated. Importantly, a dual‐effect on osteogenesis occurred, with miRNAs increasing expression of alkaline phosphatase (ALP) and Runt‐related transcription factor 2 (RUNX2) whilst the pSiNPs enhanced mineralisation, likely via degradation into silicic acid. Overall, this work presents insights into the role of miRNAs and fatty acid signalling in osteogenesis, providing future targets to improve bone formation and a promising system to enhance bone tissue engineering.