tbuckley/cabot-search huggingface dataset:
SERSomes for metabolic phenotyping and prostate cancer diagnosis
Authors: Xinyuan Bi, Jiayi Wang, Bingsen Xue, Chang He, Fugang Liu, Haoran Chen, Linley Li Lin, Baijun Dong, Butang Li, Cheng Jin, Jiahua Pan, Wei Xue, Jian Ye
Journal: Cell Reports Medicine (2024)

Molecular phenotypic variations in metabolites offer the promise of rapid profiling of physiological and pathological states for diagnosis, monitoring, and prognosis. Since present methods are expensive, time-consuming, and still not sensitive enough, there is an urgent need for approaches that can interrogate complex biological fluids at a system-wide level. Here, we introduce hyperspectral surface-enhanced Raman spectroscopy (SERS) to profile microliters of biofluidic metabolite extraction in 15 min with a spectral set, SERSome, that can be used to describe the structures and functions of various molecules produced in the biofluid at a specific time via SERS characteristics. The metabolite differences of various biofluids, including cell culture medium and human serum, are successfully profiled, showing a diagnosis accuracy of 80.8% on the internal test set and 73% on the external validation set for prostate cancer, discovering potential biomarkers, and predicting the tissue-level pathological aggressiveness. SERSomes offer a promising methodology for metabolic phenotyping.
The CD8+ T cell tolerance checkpoint triggers a distinct differentiation state defined by protein translation defects
Authors: Willem Van Der Byl, Simone Nüssing, Timothy J. Peters, Antonio Ahn, Hanjie Li, Guy Ledergor, Eyal David, Andrew S. Koh, Mayura V. Wagle, Christian Deo T. Deguit, Maria N. de Menezes, Avraham Travers, Shienny Sampurno, Kelly M. Ramsbottom, Rui Li, Axel Kallies, Paul A. Beavis, Ralf Jungmann, Maartje M.C. Bastings, Gabrielle T. Belz, Shom Goel, Joseph A. Trapani, Gerald R. Crabtree, Howard Y. Chang, Ido Amit, Chris C. Goodnow, Fabio Luciani, Ian A. Parish
Journal: Immunity (2024)
Pharmacodynamic changes in tumor and immune cells drive iberdomide’s clinical mechanisms of activity in relapsed and refractory multiple myeloma
Authors: Michael Amatangelo, Erin Flynt, Nicholas Stong, Pradipta Ray, Oliver Van Oekelen, Maria Wang, Maria Ortiz, Paulo Maciag, Teresa Peluso, Samir Parekh, Niels W.C.J. van de Donk, Sagar Lonial, Anjan Thakurta
Journal: Cell Reports Medicine (2024)

Iberdomide is a next-generation cereblon (CRBN)-modulating agent in the clinical development in multiple myeloma (MM). The analysis of biomarker samples from relapsed/refractory patients enrolled in CC-220-MM-001 (ClinicalTrials.gov: NCT02773030), a phase 1/2 study, shows that iberdomide treatment induces significant target substrate degradation in tumors, including in immunomodulatory agent (IMiD)-refractory patients or those with low CRBN levels. Additionally, some patients with CRBN genetic dysregulation who responded to iberdomide have a similar median progression-free survival (PFS) (10.9 months) and duration of response (DOR) (9.5 months) to those without CRBN dysregulation (11.2 month PFS, 9.4 month DOR). Iberdomide treatment promotes a cyclical pattern of immune stimulation without causing exhaustion, inducing a functional shift in T cells toward an activated/effector memory phenotype, including in triple-class refractory patients and those receiving IMiDs as a last line of therapy. This analysis demonstrates that iberdomide's clinical mechanisms of action are driven by both its cell-autonomous effects overcoming CRBN dysregulation in MM cells, and potent immune stimulation that augments anti-tumor immunity.
Radiotherapy and immunology
Authors: Liangliang Wang, Connor Lynch, Sean P. Pitroda, András Piffkó, Kaiting Yang, Amy K. Huser, Hua Laura Liang, Ralph R. Weichselbaum
Journal: The Journal of Experimental Medicine (2024)

The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.
Influence of donor–recipient sex on engraftment of normal and leukemia stem cells in xenotransplantation
Authors: Syed A. Mian, Linda Ariza‐McNaughton, Fernando Anjos‐Afonso, Remisha Gurung, Sophie Jackson, Aytug Kizilors, John Gribben, Dominique Bonnet
Journal: HemaSphere (2024)

Abstract Immunodeficient mouse models are widely used for the assessment of human normal and leukemic stem cells. Despite the advancements over the years, reproducibility, as well as the differences in the engraftment of human cells in recipient mice remains to be fully resolved. Here, we used various immunodeficient mouse models to characterize the effect of donor–recipient sex on the engraftment of the human leukemic and healthy cells. Donor human cells and recipient immunodeficient mice demonstrate sex‐specific engraftment levels with significant differences observed in the lineage output of normal CD34 + hematopoietic stem and progenitor cells upon xenotransplantation. Intriguingly, human female donor cells display heightened sensitivity to the recipient mice's gender, influencing their proliferation and resulting in significantly increased engraftment in female recipient mice. Our study underscores the intricate interplay taking place between donor and recipient characteristics, shedding light on important considerations for future studies, particularly in the context of pre‐clinical research.
A DNA tetrahedron-based nanosuit for efficient delivery of amifostine and multi-organ radioprotection
Authors: Yuting Yang, Jinlong Yang, Jianwei Zhu, Xingyu Chen, Li Zhou, Wenjuan Ma, Yunfeng Lin
Journal: Bioactive Materials (2024)

Unnecessary exposure to ionizing radiation (IR) often causes acute and chronic oxidative damages to normal cells and organs, leading to serious physiological and even life-threatening consequences. Amifostine (AMF) is a validated radioprotectant extensively applied in radiation and chemotherapy medicine, but the short half-life limits its bioavailability and clinical applications, remaining as a great challenge to be addressed. DNA-assembled nanostructures especially the tetrahedral framework nucleic acids (tFNAs) are promising nanocarriers with preeminent biosafety, low biotoxicity, and high transport efficiency. The tFNAs also have a relative long-term maintenance for structural stability and excellent endocytosis capacity. We therefore synthesized a tFNA-based delivery system of AMF for multi-organ radioprotection (tFNAs@AMF, also termed nanosuit). By establishing the mice models of accidental total body irradiation (TBI) and radiotherapy model of Lewis lung cancer, we demonstrated that the nanosuit could shield normal cells from IR-induced DNA damage by regulating the molecular biomarkers of anti-apoptosis and anti-oxidative stress. In the accidental total body irradiation (TBI) mice model, the nanosuit pretreated mice exhibited satisfactory alteration of superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents, and functional recovery of hematopoietic system, reducing IR-induced pathological damages of multi-organ and safeguarding mice from lethal radiation. More importantly, the nanosuit showed a selective radioprotection of the normal organs without interferences of tumor control in the radiotherapy model of Lewis lung cancer. Based on a conveniently available DNA tetrahedron-based nanocarrier, this work presents a high-efficiency delivery system of AMF with the prolonged half-life and enhanced radioprotection for multi-organs. Such nanosuit pioneers a promising strategy with great clinical translation potential for radioactivity protection.
Getting curiouser and curiouser about creativity: The search for a nuanced model
Authors: C. Blaine Horton, Malia F. Mason
Journal: Behavioral and Brain Sciences (2024)

Ivancovsky et al. propose a novelty-seeking model linking curiosity to creativity. This commentary suggests integrating their work with a stage-based creativity model for additional insights. It also encourages readers to address knowledge gaps identified by the authors, including factors that trigger the pursuit of creative solutions. We aim to refine theory and direct future research to clarify the complex curiosity-creativity relationship.
Bioconjugated Antibody‐Trojan Immune Converter Enhance Cancer Immunotherapy with Minimized Toxicity by Programmed Two‐step Immunomodulation of Myeloid Cells
Authors: Soyoung Park, Seung Mo Jin, Suhyeon Kim, Ju Hee Cho, JungHyub Hong, Yong‐Soo Bae, Yong Taik Lim
Journal: Advanced Healthcare Materials (2024)

Abstract Current immune checkpoint blockade therapy (ICBT) predominantly targets T cells to harness the antitumor effects of adaptive immune system. However, the effectiveness of ICBT is reduced by immunosuppressive innate myeloid cells in tumor microenvironments (TMEs). Toll‐like receptor 7/8 agonists (TLR7/8a) are often used to address this problem because they can reprogram myeloid‐derived suppressor cells (MDSCs) and tumor‐associated M2 macrophages, and boost dendritic cell (DC)‐based T‐cell generation; however, the systemic toxicity of TLR7/8a limits its clinical translation. Here, to address this limitation and utilize the effectiveness of TLR7/8a, this work suggests a programmed two‐step activation strategy via Antibody‐Trojan Immune Converter Conjugates (ATICC) that specifically targets myeloid cells by anti‐SIRPα followed by reactivation of transiently inactivated Trojan TLR7/8a after antibody‐mediated endocytosis. ATICC blocks the CD47‐SIRPα (“don't eat me” signal), enhances phagocytosis, reprograms M2 macrophages and MDSCs, and increases cross‐presentation by DCs, resulting in antigen‐specific CD8 + T‐cell generation in tumor‐draining lymph nodes and TME while minimizing systemic toxicity. The local or systemic administration of ATICC improves ICBT responsiveness through reprogramming of the immunosuppressive TME, increased infiltration of antigen‐specific CD8 + T cells, and antibody‐dependent cellular phagocytosis. These results highlight the programmed and target immunomodulation via ATICC could enhance cancer immunotherapy with minimized systemic toxicities.
Curiosity is more than novelty seeking
Authors: Yana Litovsky, Samantha Horn, Christopher Y. Olivola
Journal: Behavioral and Brain Sciences (2024)

The novelty-seeking model (NSM) does not offer a compelling unifying framework for understanding creativity and curiosity. It fails to explain important manifestations and features of curiosity. Moreover, the arguments offered to support a curiosity-creativity link - a shared association with a common core process and various superficial associations between them - are neither convincing nor do they yield useful predictions.
Routine colonoscopy in patients with high risk of non-occlusive mesenteric ischemia
Authors: Alexander Supady, Hannes Neeff, Tobias Wengenmayer, Dominik Bettinger
Journal: Intensive Care Medicine (2024)

We thank Acosta et al. [1] for their critical comment on our retrospective study [2] and important clarifications regarding the nomenclature of acute mesenteric ischemia (AMI).Most importantly, the authors point out the difference between intensive care unit (ICU) patients and non-ICU inpatients or outpatients with AMI.In our cohort, over 80% of the patients have been treated in the ICU when AMI was suspected, and more than 50% were supported with vasopressors [2, 3].Clinical signs and symptoms for AMI such as abdominal pain are unspecific and occur late in many patients [4].Critically ill patients in the ICU frequently receive analgesics, or they are even comatose, seriously complicating clinical assessment.Due to hemodynamic instability or even cardiocirculatory arrest resulting in intestinal hypoperfusion, these patients are particularly susceptible to non-occlusive mesenteric ischemia (NOMI).Diagnostic difficulties mean that NOMI is often overlooked and only diagnosed post-mortem by autopsy [5].The small intestine is mainly affected in patients with acute occlusion of the superior mesenteric artery (SMA).In these cases, AMI can be reliably diagnosed by clinical assessment and computed tomography angiography (CTA) in many cases.In contrast, NOMI often affects the right hemicolon [5].Therefore, we recommend developing screening protocols for colonoscopy in critically ill patients in the ICU with a high risk of NOMI for timely detection of colon ischemia.We argue that patients
Glycolytic enzyme PFKL governs lipolysis by promoting lipid droplet–mitochondria tethering to enhance β-oxidation and tumor cell proliferation
Authors: Ying Meng, Dong Guo, Liming Lin, Hong Zhao, Weiting Xu, Shudi Luo, Xiaoming Jiang, Shan Li, Xuxiao He, Rongxuan Zhu, Rongkai Shi, Liwei Xiao, Qingang Wu, Haiyan He, Jingjing Tao, Hongfei Jiang, Zheng Wang, Pengbo Yao, Daqian Xu, Zhimin Lu
Journal: Nature Metabolism (2024)
Orexin neurons track temporal features of blood glucose in behaving mice
Authors: Paulius Viskaitis, Alexander L. Tesmer, Ziyu Liu, Mahesh M. Karnani, Myrtha Arnold, Dane Donegan, Eva Bracey, Nikola Grujic, Tommaso Patriarchi, Daria Peleg-Raibstein, Denis Burdakov
Journal: Nature Neuroscience (2024)

Abstract Does the brain track how fast our blood glucose is changing? Knowing such a rate of change would enable the prediction of an upcoming state and a timelier response to this new state. Hypothalamic arousal-orchestrating hypocretin/orexin neurons (HONs) have been proposed to be glucose sensors, yet whether they track glucose concentration (proportional tracking) or rate of change (derivative tracking) is unknown. Using simultaneous recordings of HONs and blood glucose in behaving male mice, we found that maximal HON responses occur in considerable temporal anticipation (minutes) of glucose peaks due to derivative tracking. Analysis of &gt;900 individual HONs revealed glucose tracking in most HONs (98%), with derivative and proportional trackers working in parallel, and many (65%) HONs multiplexed glucose and locomotion information. Finally, we found that HON activity is important for glucose-evoked locomotor suppression. These findings reveal a temporal dimension of brain glucose sensing and link neurobiological and algorithmic views of blood glucose perception in the brain’s arousal orchestrators.
LINE-1 retrotransposons contribute to mouse PV interneuron development
Authors: Gabriela O Bodea, Juan M Botto, Maria E Ferreiro, Francisco J Sanchez-Luque, Jose de Los Rios Barreda, Jay Rasmussen, Muhammed A Rahman, Laura R Fenlon, Natasha Jansz, Carolina Gubert, Patricia Gerdes, Liviu-Gabriel Bodea, Prabha Ajjikuttira, Darwin J Da Costa Guevara, Linda Cumner, Charles C Bell, Peter Kozulin, Victor Billon, Santiago Morell, Marie-Jeanne H C Kempen, Chloe J Love, Karabi Saha, Lucy M Palmer, Adam D Ewing, Dhanisha J Jhaveri, Sandra R Richardson, Anthony J Hannan, Geoffrey J Faulkner
Journal: Nature Neuroscience (2024)

Abstract Retrotransposons are mobile DNA sequences duplicated via transcription and reverse transcription of an RNA intermediate. Cis -regulatory elements encoded by retrotransposons can also promote the transcription of adjacent genes. Somatic LINE-1 (L1) retrotransposon insertions have been detected in mammalian neurons. It is, however, unclear whether L1 sequences are mobile in only some neuronal lineages or therein promote neurodevelopmental gene expression. Here we report programmed L1 activation by SOX6, a transcription factor critical for parvalbumin (PV) interneuron development. Mouse PV interneurons permit L1 mobilization in vitro and in vivo, harbor unmethylated L1 promoters and express full-length L1 mRNAs and proteins. Using nanopore long-read sequencing, we identify unmethylated L1s proximal to PV interneuron genes, including a novel L1 promoter-driven Caps2 transcript isoform that enhances neuron morphological complexity in vitro. These data highlight the contribution made by L1 cis -regulatory elements to PV interneuron development and transcriptome diversity, uncovered due to L1 mobility in this milieu.
Corrigendum to “Comparison of baseline patient characteristics in Italian oncology drug monitoring registries and clinical trials: a real-world cross-sectional study” [The Lancet Regional Health – Europe 41 (2024) 100912]
Authors: Maria Lucia Iacovino, Simone Celant, Luca Tomassini, Laura Arenare, Andrea Caglio, Andrea Canciello, Flavio Salerno, Pier Paolo Olimpieri, Susanna Di Segni, Antonella Sferrazza, Maria Carmela Piccirillo, Giordano Domenico Beretta, Carmine Pinto, Livio Blasi, Saverio Cinieri, Luigi Cavanna, Massimo Di Maio, Pierluigi Russo, Francesco Perrone
Journal: The Lancet Regional Health - Europe (2024)
Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms
Authors: Hima Priyanka Nadimpalli, Georgia Katsioudi, Enes Salih Arpa, Lies Chikhaoui, Alaaddin Bulak Arpat, Angelica Liechti, Gaël Palais, Claudia Tessmer, Ilse Hofmann, Bruno Galy, David Gatfield
Journal: Genome biology (2024)

Abstract Background Cellular iron homeostasis is regulated by iron regulatory proteins (IRP1 and IRP2) that sense iron levels (and other metabolic cues) and modulate mRNA translation or stability via interaction with iron regulatory elements (IREs). IRP2 is viewed as the primary regulator in the liver, yet our previous datasets showing diurnal rhythms for certain IRE-containing mRNAs suggest a nuanced temporal control mechanism. The purpose of this study is to gain insights into the daily regulatory dynamics across IRE-bearing mRNAs, specific IRP involvement, and underlying systemic and cellular rhythmicity cues in mouse liver. Results We uncover high-amplitude diurnal oscillations in the regulation of key IRE-containing transcripts in the liver, compatible with maximal IRP activity at the onset of the dark phase. Although IRP2 protein levels also exhibit some diurnal variations and peak at the light–dark transition, ribosome profiling in IRP2-deficient mice reveals that maximal repression of target mRNAs at this timepoint still occurs. We further find that diurnal regulation of IRE-containing mRNAs can continue in the absence of a functional circadian clock as long as feeding is rhythmic. Conclusions Our findings suggest temporally controlled redundancy in IRP activities, with IRP2 mediating regulation of IRE-containing transcripts in the light phase and redundancy, conceivably with IRP1, at dark onset. Moreover, we highlight the significance of feeding-associated signals in driving rhythmicity. Our work highlights the dynamic nature and regulatory complexity in a metabolic pathway that had previously been considered well-understood.
3D Imaging Reveals Complex Microvascular Remodeling in the Right Ventricle in Pulmonary Hypertension
Authors: Kenzo Ichimura, Mario Boehm, Adam M. Andruska, Fan Zhang, Katharina Schimmel, Spencer Bonham, Angela Kabiri, Vitaly O. Kheyfets, Shoko Ichimura, Sushma Reddy, Yuqiang Mao, Tianyi Zhang, Gordon X. Wang, Everton J. Santana, Xuefei Tian, Ilham Essafri, Ryan Vinh, Wen Tian, Mark R. Nicolls, Shin Yajima, Yasuhiro Shudo, John W. MacArthur, Y. Joseph Woo, Ross J. Metzger, Edda Spiekerkoetter
Journal: Circulation Research (2024)

BACKGROUND: Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure. METHODS: Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function. RESULTS: Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments. CONCLUSIONS: 3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction.
Phase 2 Trial of Deucravacitinib in Psoriatic Arthritis: Biomarkers Associated With Disease Activity, Pharmacodynamics, and Clinical Responses
Authors: Oliver FitzGerald, Dafna D. Gladman, Philip J. Mease, Christopher Ritchlin, Josef S. Smolen, Lu Gao, Yanhua Hu, Miroslawa Nowak, Subhashis Banerjee, Ian Catlett
Journal: Arthritis & Rheumatology (2024)

Our objective was to evaluate the association of serum biomarkers with baseline psoriatic arthritis (PsA) disease activity, pharmacodynamic effects of deucravacitinib on biomarker levels, and the relationship between biomarkers and clinical responses to deucravacitinib.