tbuckley/cabot-search huggingface dataset:
Novel metabolomic predictors of incident colorectal cancer in men and women
Authors: Jonathan M Downie, Amit D Joshi, Connor M Geraghty, Brendan J Guercio, Oana A Zeleznik, Mingyang Song, Alaina M Bever, David A Drew, Fred K Tabung, Xuehong Zhang, Lina Jin, A Heather Eliassen, Walter C Willett, Kana Wu, Peter Kraft, Rulla Tamimi, Clary Clish, Charles S Fuchs, Edward Giovannucci, Jeffrey A Meyerhardt, Andrew T Chan
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Metabolomic profiles may influence colorectal cancer (CRC) development. Few studies have performed prediagnostic metabolome-wide analyses with CRC risk. Methods We conducted a nested case-control study among women (Nurses’ Health Study) and men (Health Professionals Follow-Up Study) who provided blood between 1989 and 1995. Over 22.9 years, 684 (409 Nurses’ Health Study, 275 Health Professionals Follow-Up Study) individuals developed CRC and were matched 1:1 to unaffected participants. Liquid chromatography-mass spectrometry identified 255 plasma metabolites after quality control. Cohort-specific and combined metabolite association analyses were performed using conditional logistic regression. Metabolite set enrichment analysis was used to identify differential abundance in metabolite classes. The R Weighted Correlation Network Analysis package provided modules of covarying metabolites, which were tested for CRC association. Results Metabolite set enrichment analysis identified specific acylcarnitines associated with higher CRC risk and triacylglycerols with lower CRC risk among women and men. Further, phosphatidylcholines were associated with a higher risk of CRC among men. In an analysis restricted to CRC diagnosed 2 years after blood draw, myristoleic acid (odds ratio = 1.37 [95% CI = 1.15 to 1.62]; false discovery rate = 0.072) and C60:12 triacylglycerol (odds ratio = 0.75 [95% CI = 0.64 to 0.88]; false discovery rate = 0.072) were associated with CRC risk in women. Weighted correlation network analysis identified amino acids associated with CRC in men, fatty acid esters (carnitines) with distal CRC in men, and triradylcglycerols inversely associated with CRC in women. Conclusions We identified prediagnostic CRC-associated metabolites with distinct sex-specific profiles. These results provide insight into CRC etiopathogenesis and have implications for risk prediction strategies.
Regulatory mechanism of cysteine-dependent methionine biosynthesis in <i>Bifidobacterium longum</i> : insights into sulfur metabolism in gut microbiota
Authors: You-Tae Kim, Joon-Gi Kwon, Daniel J. O’Sullivan, Ju-Hoon Lee
Journal: Gut Microbes (2024)

Sulfur, a critical element for bacterial growth, is not directly utilized by bifidobacteria, rendering the sulfur-containing amino acid biosynthesis pathway, particularly for cysteine and methionine, poorly understood. This research identifies six genes involved in this pathway through re-annotation of the
Cognitive Representations of Social Relationships and their Developmental Origins
Authors: Ashley J Thomas
Journal: Behavioral and Brain Sciences (2024)

Abstract In the human mind, what is a social relationship, and what are the developmental origins of this representation? I consider findings from infant psychology and propose that our representations of social relationships are intuitive theories built on core knowledge. I propose three central components of this intuitive theory. The purpose of the first component is to recognize whether a relationship exists, the purpose of the second is to characterize the relationship by categorizing it into a model and to compute its strength (i.e., intensity, pull, or thickness), and the purpose of the third is to understand how to change relationships through explicit or implicit communication. I propose that infants possess core knowledge on which this intuitive theory is built. This paper focuses on the second component and considers evidence that infants characterize relationships. Following Relational Models Theory (A. P. Fiske, 1992, 2004) I propose that from infancy humans recognize relationships that belong to three models: communal sharing (where people are ‘one’), authority ranking (where people are ranked), and equality matching (where people are separate, but evenly balanced). I further propose that humans, and potentially infants, recognize a relationship's strength which can be thought of as a continuous representation of obligations (the extent to which certain actions are expected), and commitment (the likelihood that people will continue the relationship). These representations and the assumption that others share them allow us to form, maintain, and change social relationships throughout our lives by informing how we interpret and evaluate the actions of others and plan our own.
Fecal microbial marker panel for aiding diagnosis of autism spectrum disorders
Authors: Yating Wan, Oscar W.H. Wong, Hein M Tun, Qi Su, Zhilu Xu, Whitney Tang, Suk Ling Ma, Sandra Chan, Francis K L Chan, Siew C Ng
Journal: Gut Microbes (2024)

Accumulating evidence suggests that gut microbiota alterations influence brain function and could serve as diagnostic biomarkers and therapeutic targets. The potential of using fecal microbiota signatures to aid autism spectrum disorder (ASD) detection is still not fully explored. Here, we assessed the potential of different levels of microbial markers (taxonomy and genome) in distinguishing children with ASD from age and gender-matched typically developing peers (
The case for microbial intervention at weaning
Authors: Julia N. Flores, Jean-Bernard Lubin, Michael A. Silverman
Journal: Gut Microbes (2024)

Weaning, the transition from a milk-based diet to solid food, coincides with the most significant shift in gut microbiome composition in the lifetime of most mammals. Notably, this period also marks a "window of opportunity" where key components of the immune system develop, and host-microbe interactions shape long-term immune homeostasis thereby influencing the risk of autoimmune and inflammatory diseases. This review provides a comprehensive analysis of the changes in nutrition, microbiota, and host physiology that occur during weaning. We explore how these weaning-associated processes differ across species, lifestyles, and regions of the intestine. Using prinicples of microbial ecology, we propose that the weaning transition is an optimal period for microbiome-targeted therapeutic interventions. Additionally, we suggest that replicating features of the weaning microbiome in adults could promote the successful engraftment of probiotics. Finally, we highlight key research areas that could deepen our understanding of the complex relationships between diet, commensal microbes, and the host, informing the development of more effective microbial therapies.
Wearable Multifunctional Hydrogel for Oral Microenvironment Visualized Sensing Coupled with Sonodynamic Bacterial Elimination and Tooth Whitening
Authors: Chaobo Dai, Zhenghan Shi, Yi Xu, Lingkai Su, Xin Li, Peixue Deng, Hao Wen, Jiahao Wang, Qing Ye, Ray P.S. Han, Qingjun Liu
Journal: Advanced Healthcare Materials (2024)

Abstract Bacterial‐driven dental caries and tooth discoloration are growing concerns as the most common oral health problems. Current diagnostic methods and treatment strategies hardly allow simultaneous early detection and non‐invasive treatment of these oral diseases. Herein, a wearable multifunctional double network hydrogel combined with polyaniline and barium titanate (PANI@BTO) nanoparticles is developed for oral microenvironment visualized sensing and sonodynamic therapy. Due to the colorimetric properties of polyaniline, the hydrogel displays a highly sensitive and selective response for visualized sensing of oral acidic microenvironment. Meanwhile, the barium titanate in the hydrogel efficiently generates reactive oxygen species (ROS) under ultrasound irradiation, realizing non‐invasive treatment in the oral cavity. Through bacterial elimination experiments and tooth whitening studies, the hydrogel can achieve the dual effect of effectively inhibiting the growth of cariogenic bacteria and degrading tooth surface pigments. Owing to the visualized sensing of the oral acidic microenvironment and efficient sonodynamic therapy function, the proposed hydrogel system offers a solution for the prevention of caries and tooth whitening, which is promising in developing the biomedical system targeting the simultaneous sensing and therapy for oral diseases.
Targeted NAD+ repletion via biomimetic nanoparticle enables simultaneous management of intimal hyperplasia and accelerated re-endothelialization: A proof-of-concept study toward next-generation of endothelium-protective, anti-restenotic therapy
Authors: Li Yin, Yao Tong, Ruosen Xie, Zhanpeng Zhang, Zain Husain Islam, Kaijie Zhang, Jacobus Burger, Nicholas Hoyt, Eric William Kent, William Aaron Marcum, Campbell Johnston, Rohan Kanchetty, Zoe Tetz, Sophia Stanisic, Yitao Huang, Lian-Wang Guo, Shaoqin Gong, Bowen Wang
Journal: Journal of Controlled Release (2024)
Melanoma arising from pre-existing naevus in carriers of a germline <i>CDKN2A</i> pathogenic variant
Authors: Daan J W Rauwerdink, Yann Hoogland, Anne M R Schrader, Thomas P Potjer, Ellen Kapiteijn, Jos A van der Hage, Remco van Doorn
Journal: British Journal of Dermatology (2024)

In this study we used total body photography (TBP) to determine whether melanoma emerges from a preexisting naevi or normal-appearing skin in individuals with pathogenic CDKN2a variant. In total, 60 melanoma cases occurred in 44 CDKN2a germline carriers. In addition, we observed that 78% of the 60 included melanoma cases developed from preexisting naevi, significantly higher than the 30% reported for sporadic melanoma. This high incidence may be due to the numerous atypical naevi and early bi-allelic loss of CDKN2A. Our findings underscore the importance of routine TBP in these patients for early detection of melanoma. More than previously appreciated, the surgical removal of melanocytic naevi in these high-risk patients may prevent melanoma development.
Biologics in congenital ichthyosis: are they effective?
Authors: Juliette Mazereeuw-Hautier, Céline Granier Tournier, Angela Hernandez-Martin, Sarah Milesi, Hélène Texier, Maëlla Severino-Freire, Nathalia Bellon, Christine Bodemer, Robert Gruber, Emmanuel Mahé, Fanny Morice Picard, Katariina Hannula-Jouppi, Jenny E Murase, Sébastien Barbarot, Eran Cohen-Barak, Maurico Torres-Pradilla, Anna Bruckner, Moise Levy, Mark J A Koh, Marie Masson Regnault, Vanya Rossel, Christine Chiaverini, Lisa M Arkin, Hagen Ott, Cristina Has, Kira Süβmuth, Antoni Gostynski, Jason Shourick, Amy S Paller
Journal: British Journal of Dermatology (2024)

Abstract Background Congenital ichthyoses comprise a heterogeneous group of genetic diseases that require lifelong treatment and have a major impact on patients’ quality of life. Conventional treatments reduce scaling and skin discomfort; however, they usually have little or no effect on erythema and pruritus. The identification of cytokine alterations in congenital ichthyoses has raised the possibility of repurposing currently available biologics. Several case reports have reported success with different biologics. Objectives To report the real-life effects of biologics on congenital ichthyoses. Methods This was a retrospective observational international multicentric study of patients with congenital ichthyoses treated with at least one biologic for a minimum of 3 months. The effect of the biologics was evaluated using an Investigator Global Assessment for change (IGA-C) scale. A comprehensive literature search was performed in parallel. Results Ninety-eight patients were included [mean (SD) age of 19.7 years, 50 female patients]. Patients with Netherton syndrome (NS) or congenital ichthyosiform erythroderma (CIE) represented the majority of patients (30% and 21%, respectively). Most patients (85%) had a severe or very severe form of congenital ichthyoses. The most frequently used biologics were inhibitors targeting interleukin (IL)-17, IL-12/IL-23 or the IL-4 receptor (IL-4R). The mean (SD) duration of treatment was 22.1 (20.1) months. There were 45 responders (46%), including 18 (18%) who were good responders; all had a subset of erythrodermic congenital ichthyoses and received one of the three main biologics. In patients with NS and CIE, IL-12/IL-23 and IL-4R inhibitors tended to be most effective. The literature review revealed a shorter mean (SD) duration of biologic treatment [11.5 (8.5) months] and higher percentage of responders (86%), suggesting reporter bias. Conclusions This series identified subsets of congenital ichthyoses that may respond to biologics and will help with the design of future clinical trials of biologics for congenital ichthyoses.
EVA1-Antibody Drug Conjugate is a new therapeutic strategy for eliminating glioblastoma-initiating cells
Authors: Jiahui Hou, Tamami Uejima, Miho Tanaka, You Lee Son, Kazuharu Hanada, Mutsuko Kukimoto-Niino, Shigeru Yamaguchi, Shigeru Hashimoto, Shigeyuki Yokoyama, Toshitada Takemori, Takashi Saito, Mikako Shirouzu, Toru Kondo
Journal: Neuro-Oncology (2024)

Abstract Background The discovery of glioblastoma (GBM)-initiating cells (GICs) has impacted GBM research. These cells are not only tumorigenic, but also exhibit resistance to radiotherapy and chemotherapy. Therefore, it is crucial to characterize GICs thoroughly and identify new therapeutic targets. In a previous study, we successfully identified Epithelial V-like antigen 1 (EVA1) as a novel functional factor specific to GICs. Methods Hybridoma cells were generated by immunizing BALB/c mice with EVA1-Fc fusion protein. The reactivity of the supernatant from these hybridoma cells was examined using EVA1-overexpressing cells and GICs. Candidate antibodies were further selected using Biacore surface plasmon resonance analysis and two cytotoxicity assays, antibody-dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Among the antibodies, the cytotoxicity of the B2E5-antibody drug conjugate (B2E5-ADC) was evaluated by both adding it to cultured GICs and injecting it into GIC tumor-bearing brains. Results B2E5 demonstrated a high affinity for human EVA1 and effectively killed both EVA1-expressing cell lines and GICs in culture through ADCC and CDC. B2E5-ADC also exhibited strong cytotoxicity to GICs in culture and prevented their tumorigenesis in the brain when administered intracranially to the tumor-bearing brain. Conclusion Our data indicate that B2E5-ADC is a new and promising therapeutic strategy for GBM.
Imaging PD-L1 in the brain—Journey from the lab to the clinic
Authors: Dawoud Dar, Magdalena Rodak, Chiara Da Pieve, Izabela Gorczewska, Gitanjali Sharma, Ewa Chmielik, Marcin Niedbala, Pawel Bzowski, Andrea d’Amico, Barbara Bobek-Billewicz, Elzbieta Nowicka, Rafal Tarnawski, Wojciech Kaspera, Gabriela Kramer-Marek
Journal: Neuro-Oncology (2024)

Abstract Background Immune checkpoint inhibitors (ICPIs) have proven to restore adaptive anti-tumor immunity in many cancers; however, no noteworthy therapeutic schedule has been established for patients with glioblastoma (GBM). High programmed death-ligand 1 (PD-L1) expression is associated with immunosuppressive and aggressive phenotypes in GBM. Presently, there is no standardized protocol for assessing PD-L1 expression levels to select patients and monitor their response to ICPI therapy. The aim of this study was to investigate the use of 89Zr-DFO-Atezolizumab to image the spatio-temporal distribution of PD-L1 in preclinical mouse models and in patients with newly diagnosed GBM treated with/without neoadjuvant Pembrolizumab. Methods The immunoreactivity, binding affinity, and specificity of 89Zr-DFO-Atezolizumab were confirmed in vitro. Mice-bearing orthotopic GBM tumors or patients with newly diagnosed GBM treated with/without Pembrolizumab were intravenously injected with 89Zr-DFO-Atezolizumab, and PET/CT images were acquired 24, 48, and 72 hours in mice and at 48 and 72 post-injection in patients. Radioconjugate uptake was quantified in the tumor and healthy tissues. Ex vivo immunohistochemistry (IHC) and immunophenotyping were performed on mouse tumor samples or resected human tumors. Results 89Zr-DFO-Atezolizumab was prepared with high radiochemical purity (RCP &amp;gt; 99%). In vitro cell-associated radioactivity of 89Zr-DFO-Atezolizumab corroborated cell line PD-L1 expression. PD-L1 in mouse GBM tumors was detected with high specificity using 89Zr-DFO-Atezolizumab and radioconjugate uptake correlated with IHC. Patients experienced no 89Zr-DFO-Atezolizumab-related side effects. High 89Zr-DFO-Atezolizumab uptake was observed in patient tumors at 48 hours post-injection, however, the uptake varied between patients treated with/without Pembrolizumab. Conclusions 89Zr-DFO-Atezolizumab can visualize distinct PD-L1 expression levels with high specificity in preclinical mouse models and in patients with GBM, whilst complementing ex vivo analysis.
Suppression of melanoma by mice lacking MHC-II: Mechanisms and implications for cancer immunotherapy
Authors: Hexin Shi, Dawson Medler, Jianhui Wang, Rachel Browning, Aijie Liu, Sara Schneider, Claudia Duran Bojorquez, Ashwani Kumar, Xiaohong Li, Jiexia Quan, Sara Ludwig, James J. Moresco, Chao Xing, Eva Marie Y. Moresco, Bruce Beutler
Journal: The Journal of Experimental Medicine (2024)

Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen in C57BL/6J mice, we discovered a mutation in host H2-Aa that caused strong immune-mediated resistance to mouse melanomas. H2-Aa encodes an MHC class II α chain, and its absence in C57BL/6J mice eliminates all MHC-II expression. H2-Aa deficiency, specifically in dendritic cells (DC), led to a quantitative increase in type 2 conventional DC (cDC2) and a decrease in cDC1. H2-Aa-deficient cDC2, but not cDC1, were essential for melanoma suppression and effectively cross-primed and recruited CD8 T cells into tumors. Lack of T regulatory cells, also observed in H2-Aa deficiency, contributed to melanoma suppression. Acute disruption of H2-Aa was therapeutic in melanoma-bearing mice, particularly when combined with checkpoint inhibition, which had no therapeutic effect by itself. Our findings suggest that inhibiting MHC-II may be an effective immunotherapeutic approach to enhance immune responses to cancer.
χ-Conotoxins are an evolutionary innovation of mollusk-hunting cone snails as a counter-adaptation to prey defense
Authors: Samuel Espino, Maren Watkins, Rodolfo Probst, Thomas Lund Koch, Kevin Chase, Julita Imperial, Samuel D Robinson, Paula Flórez Salcedo, Dylan Taylor, Joanna Gajewiak, Mark Yandell, Helena Safavi-Hemami, Baldomero M Olivera
Journal: Molecular Biology and Evolution (2024)

Abstract Mollusk-hunting (molluscivorous) cone snails belong to a monophyletic group in Conus, a genus of venomous marine snails. The molluscivorous lineage evolved from ancestral worm-hunting (vermivorous) snails ∼18 Ma. To enable the shift to a molluscivorous lifestyle, molluscivorous cone snails must solve biological problems encountered when hunting other gastropods, namely: (i) preventing prey escape and (ii) overcoming the formidable defense of the prey in the form of the molluscan shell, a problem unique to molluscivorous Conus. Here, we show that χ-conotoxins, peptides exclusively expressed in the venoms of molluscivorous Conus, provide solutions to the above problems. Injecting χ-conotoxins into the gastropod mollusk Aplysia californica results in impaired locomotion and uncoordinated hyperactivity. Impaired locomotion impedes escape, and a hyperactive snail will likely emerge from its shell, negating the protection the shell provides. Thus, χ-conotoxins are an evolutionary innovation that accompanied the emergence of molluscivory in Conus and provide solutions to problems posed by hunting other snails.
Comparative small molecule screening of primary human acute leukemias, engineered human leukemia and leukemia cell lines
Authors: Safia Safa-Tahar-Henni, Karla Páez Martinez, Verena Gress, Nayeli Esparza, Élodie Roques, Florence Bonnet-Magnaval, Mélanie Bilodeau, Valérie Gagné, Eva Bresson, Sophie Cardin, Nehme El-Hachem, Isabella Iasenza, Gabriel Alzial, Isabel Boivin, Naoto Nakamichi, Anne-Cécile Soufflet, Cristina Mirela Pascariu, Jean Duchaine, Simon Mathien, Éric Bonneil, Kolja Eppert, Anne Marinier, Guy Sauvageau, Geneviève Deblois, Pierre Thibault, Josée Hébert, Connie J. Eaves, Sonia Cellot, Frédéric Barabé, Brian T. Wilhelm
Journal: Leukemia (2024)

Targeted therapeutics for high-risk cancers remain an unmet medical need. Here we report the results of a large-scale screen of over 11,000 molecules for their ability to inhibit the survival and growth in vitro of human leukemic cells from multiple sources including patient samples, de novo generated human leukemia models, and established human leukemic cell lines. The responses of cells from de novo models were most similar to those of patient samples, both of which showed striking differences from the cell-line responses. Analysis of differences in subtype-specific therapeutic vulnerabilities made possible by the scale of this screen enabled the identification of new specific modulators of apoptosis, while also highlighting the complex polypharmacology of anti-leukemic small molecules such as shikonin. These findings introduce a new platform for uncovering new therapeutic options for high-risk human leukemia, in addition to reinforcing the importance of the test sample choice for effective drug discovery.
The Inflation Reduction Act and Patient Costs for Drugs to Treat Heart Failure
Authors: Erin Trish, Karen Van Nuys, Joanne Wu, Nihar R. Desai
Journal: JAMA Network Open (2024)

This cross-sectional study examines the pre–Inflation Reduction Act out-of-pocket burden on Medicare patients taking dapagliflozin, empagliflozin, and sacubitril/valsartan.
Parenthood and Paychecks—The Gender Pay Gap in Medicine
Authors: Kyung Mi Kim, Aditya Narayan, Nirav R. Shah, Arnold Milstein
Journal: JAMA (2024)

This Viewpoint examines recent evidence on the gender pay gap in US medical professions and its relationship with motherhood (the motherhood penalty ) and suggests opportunities for mitigating inequity that reflect the current health care environment, advance gender equity, and enhance medical practice.