tbuckley/cabot-search huggingface dataset:
Single-cell deconvolution reveals high lineage- and location-dependent heterogeneity in mesenchymal multivisceral stage 4 colorectal cancer
Authors: Christopher Berlin, Bernhard Mauerer, Pierre Cauchy, Jost Luenstedt, Roman Sankowski, Lisa Marx, Reinhild Feuerstein, Luisa Schaefer, Florian R. Greten, Marina Pesic, Olaf Groß, Marco Prinz, Naomi Ruehl, Laura Miketiuk, Dominik Jauch, Claudia Laessle, Andreas Jud, Esther A. Biesel, Hannes Neeff, Stefan Fichtner-Feigl, Philipp A. Holzner, Rebecca Kesselring
Journal: Journal of Clinical Investigation (2023)

Metastasized colorectal cancer (CRC) is associated with a poor prognosis and rapid disease progression. Besides hepatic metastasis, peritoneal carcinomatosis is the major cause of death in UICC (Union for International Cancer Control) stage IV CRC patients. Insights into differential site-specific reconstitution of tumour cells and the corresponding tumour microenvironment are still missing. Here, we analysed the transcriptome of single cells derived from murine multivisceral CRC and delineated the inter-metastatic cellular heterogeneity regarding tumour epithelium, stroma and immune cells. Interestingly, we found an intercellular site-specific network of cancer associated fibroblasts and tumour epithelium during peritoneal metastasis as well as an autologous feed-forward loop in cancer stem cells. We furthermore deciphered a metastatic dysfunctional adaptive immunity by a loss of B cell dependent antigen presentation and consecutive effector T cell exhaustion. Furthermore, we demonstrated major similarities of this murine metastatic CRC model with human disease and -based on the results of our analysis- provided an auspicious site-specific immune modulatory treatment approach for stage IV CRC by intraperitoneal checkpoint inhibition.
Combining high quality data with rigorous methods: emulation of a target trial using electronic health records and a nested case-control design
Authors: Bahareh Rasouli, Jessica Chubak, James S Floyd, Bruce M Psaty, Matthew Nguyen, Rod L Walker, Kerri L Wiggins, Roger W Logan, Goodarz Danaei
Journal: BMJ (2023)

Emulating a target trial reduces the potential for bias in observational comparative effectiveness research. Owing to feasibility constraints, large cohort studies often use electronic health records without validating key variables or collecting additional data. A case-control design allows researchers to validate, supplement, or collect additional data on key measurements in a much smaller sample compared with the entire cohort. In this article, Rasouli and colleagues describe methods to emulate a target trial using a nested case-control design, and provide a detailed guideline, an analytical program, and results of a clinical example.
Publisher Correction: Restoration of sensory feedback from the foot and reduction of phantom limb pain via closed-loop spinal cord stimulation
Authors: Ameya C Nanivadekar, Rohit Bose, Bailey A Petersen, Elizaveta V Okorokova, Devapratim Sarma, Tyler J Madonna, Beatrice Barra, Juhi Farooqui, Ashley N Dalrymple, Isaiah Levy, Eric R Helm, Vincent J Miele, Michael L Boninger, Marco Capogrosso, Sliman J Bensmaia, Douglas J Weber, Lee E Fisher
Journal: Nature Biomedical Engineering (2023)
Post–COVID-19 Condition in Children 6 and 12 Months After Infection
Authors: Frederick Dun-Dery, Jianling Xie, Kathleen Winston, Brett Burstein, Jocelyn Gravel, Jason Emsley, Vikram Sabhaney, Roger Zemek, Simon Berthelot, Darcy Beer, April Kam, Gabrielle Freire, Ahmed Mater, Robert Porter, Naveen Poonai, Anne Moffatt, Andrew Dixon, Marina I. Salvadori, Stephen B. Freedman, Bruce Wright, Tyrus Crawford, Waleed Alqurashi, Samina Ali
Journal: JAMA Network Open (2023)

There is a need to understand the long-term outcomes among children infected with SARS-CoV-2.
Mesenchymal Stem Cells for Prophylaxis of Chronic Graft-vs-Host Disease After Haploidentical Hematopoietic Stem Cell Transplant
Authors: Ruihao Huang, Ting Chen, Sanbin Wang, Jishi Wang, Yi Su, Jing Liu, Yanqi Zhang, Xiangyu Ma, Qin Wen, Peiyan Kong, Cheng Zhang, Lei Gao, Jiang F. Zhong, Li Gao, Xi Zhang
Journal: JAMA Oncology (2023)

Chronic graft-vs-host disease (GVHD) limits the long-term benefit of haploidentical hematopoietic stem cell transplant (HSCT). This clinical trial evaluated repeated infusions of umbilical cord mesenchymal stem cells (MSCs) during the early stage (45 days and 100 days) after haplo-HSCT to prevent chronic GVHD.
The Potential of Genetics in Identifying Women at Lower Risk of Breast Cancer
Authors: Alexandre Bolze, Elizabeth T. Cirulli, Catherine Hajek, Jamie M. Schnell Blitstein, Joseph J. Grzymski
Journal: JAMA Oncology (2023)

Genetic information is not being used to identify women at lower risk of breast cancer or other diseases in clinical practice. With the new US Preventive Services Task Force guidelines lowering the age for mammogram screening for all, there is a potential benefit in identifying women at lower risk of disease who may defer the start of mammographic screening. This genetic risk-based approach would help mitigate overscreening, associated costs, and anxiety.
NHE7 upregulation potentiates the uptake of small extracellular vesicles by enhancing maturation of macropinosomes in hepatocellular carcinoma
Authors: Yue Yao, Yi Xu, Liang Yu, Ting‐Mao Xue, Zhi‐Jie Xiao, Pui‐Chi Tin, Hiu‐Ling Fung, Hoi‐Tang Ma, Jing‐Ping Yun, Judy Wai Ping Yam
Journal: Cancer Communications (2023)

Abstract Background Small extracellular vesicles (sEVs) mediate intercellular communication that contributes to hepatocellular carcinoma (HCC) progression via multifaceted pathways. The success of cell entry determines the effect of sEV on recipient cells. Here, we aimed to delineate the mechanisms underlying the uptake of sEV in HCC. Methods Macropinocytosis was examined by the ability of cells to internalize dextran and sEV. Macropinocytosis was analyzed in Na(+)/H(+) exchanger 7 ( NHE7 )‐knockdown and ‐overexpressing cells. The properties of cells were studied using functional assays. pH biosensor was used to evaluate the intracellular and endosomal pH. The expression of NHE7 in patients’ liver tissues was examined by immunofluorescent staining. Inducible silencing of NHE7 in established tumors was performed to reveal the therapeutic potential of targeting NHE7. Results The data revealed that macropinocytosis controlled the internalization of sEVs and their oncogenic effect on recipient cells. It was found that metastatic HCC cells exhibited the highest efficiency of sEV uptake relative to normal liver cells and non‐metastatic HCC cells. Attenuation of macropinocytic activity by 5‐(N‐ethyl‐N‐isopropyl)‐amiloride (EIPA) limited the entry of sEVs and compromised cell aggressiveness. Mechanistically, we delineated that high level of NHE7, a sodium‐hydrogen exchanger, alkalized intracellular pH and acidized endosomal pH, leading to the maturation of macropinosomes. Inducible inhibition of NHE7 in established tumors developed in mice delayed tumor development and suppressed lung metastasis. Clinically, NHE7 expression was upregulated and linked to dismal prognosis of HCC. Conclusions This study advances the understanding that NHE7 enhances sEV uptake by macropinocytosis to promote the malignant properties of HCC cells. Inhibition of sEV uptake via macropinocytosis can be exploited as a treatment alone or in combination with conventional therapeutic approaches for HCC.
Artificial intelligence methods for improved detection of undiagnosed heart failure with preserved ejection fraction
Authors: Jack Wu, Dhruva Biswas, Matthew Ryan, Brett S. Bernstein, Maleeha Rizvi, Natalie Fairhurst, George Kaye, Ranu Baral, Tom Searle, Narbeh Melikian, Daniel Sado, Thomas F. Lüscher, Richard Grocott‐Mason, Gerald Carr‐White, James Teo, Richard Dobson, Daniel I. Bromage, Theresa A. McDonagh, Ajay M. Shah, Kevin O'Gallagher
Journal: European Journal of Heart Failure (2023)

Heart failure with preserved ejection fraction (HFpEF) remains under-diagnosed in clinical practice despite accounting for nearly half of all heart failure (HF) cases. Accurate and timely diagnosis of HFpEF is crucial for proper patient management and treatment. In this study, we explored the potential of natural language processing (NLP) to improve the detection and diagnosis of HFpEF according to the European Society of Cardiology (ESC) diagnostic criteria.
Letter regarding the article ‘<scp>Head‐to‐head</scp> comparison between recommendations by the <scp>ESC</scp> and <scp>ACC</scp>/<scp>AHA</scp>/<scp>HFSA</scp> heart failure guidelines’
Authors: Laiba Amini, Samia Kazmi, Muhammad Junaid Patel
Journal: European Journal of Heart Failure (2023)
Persistent Sweet syndrome post‐hematopoietic stem cell transplantation heralding molecular relapse of myelofibrosis
Authors: David H. Xiang, Mohammadreza Pakyari, John Koreth, Connie R. Shi
Journal: American Journal of Hematology (2023)

Persistent Sweet syndrome in a patient with history of myelofibrosis thought to be in remission post-hematopoietic stem cell transplantation leads to diagnosis of molecular relapse of myelofibrosis. The authors declare no conflicts of interest.
Arterial Thromboembolism in Patients With Atrial Fibrillation and CHA <sub>2</sub> DS <sub>2</sub> -VASc Score 1: A Nationwide Study
Authors: Lauge Østergaard, Jonas Bjerring Olesen, Jeppe Kofoed Petersen, Lukas Schak Nielsen, Søren Lund Kristensen, Morten Schou, Lars Køber, Emil Fosbøl
Journal: Circulation (2023)

BACKGROUND: Oral anticoagulation is suggested in patients with atrial fibrillation and a CHA 2 DS 2 -VASc score ≥1 (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke, vascular disease, age 65–74 years, and sex score). To assess granular differences within CHA 2 DS 2 -VASc 1, the incidence of arterial thromboembolism according to CHA 2 DS 2 -VASc 1 subgroups was examined. METHODS: The Danish National Patient Registry and the Danish Prescription Registry were linked on a nationwide level to identify patients with atrial fibrillation from 2000 to 2021 without oral anticoagulation and categorized according to CHA 2 DS 2 -VASc score: CHA 2 DS 2 -VASc 0 (male and female subjects); CHA 2 DS 2 -VASc 1 (hypertension, heart failure, diabetes, vascular disease, and age 65–74 years); or CHA 2 DS 2 -VASc 2 (age ≥75 years without other risk factors). Female sex was not considered a risk factor in any risk group. The outcome was arterial thromboembolism (ischemic stroke, embolism of extremity, or transient cerebral ischemia). Study groups were compared using Cox regression analysis. RESULTS: We included 26 701 patients with a CHA 2 DS 2 -VASc 0 score; 22 915 with CHA 2 DS 2 -VASc 1 (1483 patients with heart failure, 9066 with hypertension, 843 with diabetes, 770 with vascular disease, and 10 753 who were 65 to 74 years of age); and 14 525 patients with CHA 2 DS 2 -VASc 2 (≥75 years of age without other risk factors). With a median of 1 year of observation time, the cumulative incidence of arterial thromboembolism was 0.6% (n=154 [95% CI, 0.6%–0.8%]), 1.4% (n=16 [95% CI, 0.8%–2.2%]), 1.9% (n=141 [95% CI, 1.6%–2.2%]), 1.7% (n=12 [95% CI, 0.9%–2.9%]), 2.0% (n=13 [95% CI, 1.1%–3.4%]), 2.3% (n=187 [95% CI, 2.0%–2.7%]), and 4.4% (n=533 [95% CI, 4.1%–4.8%]) for CHA 2 DS 2 -VASc 0, heart failure, hypertension, diabetes, vascular disease, age 65 to 74 years (CHA 2 DS 2 -VASc 1), and age ≥75 years (CHA 2 DS 2 -VASc 2), respectively. No statistically significant difference was identified among subgroups of CHA 2 DS 2 -VASc 1 ( P =0.15 for difference). CONCLUSIONS: For patients with atrial fibrillation, all subgroups of CHA 2 DS 2 -VASc 1 were associated with lower incidence of arterial thromboembolism compared with age ≥75 years without other risk factors (ie, CHA 2 DS 2 -VASc 2) and a higher incidence compared with CHA 2 DS 2 -VASc 0. No statistically significant difference was identified between the subgroups of CHA 2 DS 2 -VASc 1. These findings support current recommendations that patients within this intermediate risk group could be identified with a similar risk of arterial thromboembolism.
Proteogenomic Data Integration Reveals CXCL10 as a Potentially Downstream Causal Mediator for IL-6 Signaling on Atherosclerosis
Authors: Savvina Prapiadou, Luka Živković, Barbara Thorand, Marc J. George, Sander W. van der Laan, Rainer Malik, Christian Herder, Wolfgang Koenig, Thor Ueland, Ola Kleveland, Pål Aukrust, Lars Gullestad, Jürgen Bernhagen, Gerard Pasterkamp, Annette Peters, Aroon D. Hingorani, Jonathan Rosand, Martin Dichgans, Christopher D. Anderson, Marios K. Georgakis
Journal: Circulation (2023)

Genetic and experimental studies support a causal involvement of IL-6 (interleukin-6) signaling in atheroprogression. Although trials targeting IL-6 signaling are underway, any benefits must be balanced against an impaired host immune response. Dissecting the mechanisms that mediate the effects of IL-6 signaling on atherosclerosis could offer insights about novel drug targets with more specific effects.
Metabolic Communication by SGLT2 Inhibition
Authors: Anja M. Billing, Young Chul Kim, Søren Gullaksen, Benedikt Schrage, Janice Raabe, Arvid Hutzfeldt, Fatih Demir, Elina Kovalenko, Moritz Lassé, Aurelien Dugourd, Robin Fallegger, Birgit Klampe, Johannes Jaegers, Qing Li, Olha Kravtsova, Maria Crespo-Masip, Amelia Palermo, Robert A. Fenton, Elion Hoxha, Stefan Blankenberg, Paulus Kirchhof, Tobias B. Huber, Esben Laugesen, Tanja Zeller, Maria Chrysopoulou, Julio Saez-Rodriguez, Christina Magnussen, Thomas Eschenhagen, Alexander Staruschenko, Gary Siuzdak, Per L. Poulsen, Clarissa Schwab, Friederike Cuello, Volker Vallon, Markus M. Rinschen
Journal: Circulation (2023)

BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood. METHODS: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or are secondary to improvement by SGLT2i, we performed an in-depth proteomics, phosphoproteomics, and metabolomics analysis by integrating signatures from multiple metabolic organs and body fluids after 1 week of SGLT2i treatment of nondiabetic as well as diabetic mice with early and uncomplicated hyperglycemia. RESULTS: Kidneys of nondiabetic mice reacted most strongly to SGLT2i in terms of proteomic reconfiguration, including evidence for less early proximal tubule glucotoxicity and a broad downregulation of the apical uptake transport machinery (including sodium, glucose, urate, purine bases, and amino acids), supported by mouse and human SGLT2 interactome studies. SGLT2i affected heart and liver signaling, but more reactive organs included the white adipose tissue, showing more lipolysis, and, particularly, the gut microbiome, with a lower relative abundance of bacteria taxa capable of fermenting phenylalanine and tryptophan to cardiovascular uremic toxins, resulting in lower plasma levels of these compounds (including p-cresol sulfate). SGLT2i was detectable in murine stool samples and its addition to human stool microbiota fermentation recapitulated some murine microbiome findings, suggesting direct inhibition of fermentation of aromatic amino acids and tryptophan. In mice lacking SGLT2 and in patients with decompensated heart failure or diabetes, the SGLT2i likewise reduced circulating p-cresol sulfate, and p-cresol impaired contractility and rhythm in human induced pluripotent stem cell–derived engineered heart tissue. CONCLUSIONS: SGLT2i reduced microbiome formation of uremic toxins such as p-cresol sulfate and thereby their body exposure and need for renal detoxification, which, combined with direct kidney effects of SGLT2i, including less proximal tubule glucotoxicity and a broad downregulation of apical transporters (including sodium, amino acid, and urate uptake), provides a metabolic foundation for kidney and cardiovascular protection.
Cardiorespiratory fitness and risk of heart failure with preserved ejection fraction
Authors: Peter Kokkinos, Charles Faselis, Andreas Pittaras, Immanuel Babu Henry Samuel, Carl J. Lavie, Jose D. Vargas, Michael Lamonte, Barry Franklin, Themistocles L. Assimes, Rayelynn Murphy, Jiajia Zhang, Xuemei Sui, Jonathan Myers
Journal: European Journal of Heart Failure (2023)

Abstract Aims Preventive strategies for heart failure with preserved ejection fraction (HFpEF) include pharmacotherapies and lifestyle modifications. However, the association between cardiorespiratory fitness (CRF) assessed objectively by a standardized exercise treadmill test (ETT) and the risk of HFpEF has not been evaluated. Thus, we evaluated the association between CRF and HFpEF incidence. Methods and results We assessed CRF in US Veterans (624 551 men; mean age 61.2 ± 9.7 years and 43 179 women; mean age 55.0 ± 8.9 years) by a standardized ETT performed between 1999 and 2020 across US Veterans Affairs Medical Centers. All had no evidence of heart failure or myocardial infarction prior to completion of the ETT. We assigned participants to one of five age‐ and gender‐specific CRF categories (quintiles) based on peak metabolic equivalents (METs) achieved during the ETT and four categories based on CRF changes in those with two ETT evaluations ( n = 139 434) ≥1.0 year apart. During a median follow‐up of 10.1 years (interquartile range 6.0–14.3 years), providing 6 879 229 person‐years, there were 16 493 HFpEF events with an average annual rate of 2.4 events per 1000 person‐years. The adjusted risk of HFpEF decreased across CRF categories as CRF increased, independent of comorbidities. For fit individuals (≥10.5 METs) the hazard ratio (HR) was 0.48 (95% confidence interval [CI] 0.46–0.51) compared with least fit (≤4.9 METs; referent). Being unfit carried the highest risk (HR 2.88, 95% CI 2.67–3.11) of any other comorbidity. The risk of unfit individuals who became fit was 37% lower (HR 0.63, 95% CI 0.57–0.71), compared to those who remained unfit. Conclusions Higher CRF levels are independently associated with lower HFpEF in a dose–response manner. Changes in CRF reflected proportional changes in HFpEF risk, suggesting that the HFpEF risk was modulated by CRF.
INO80-Dependent Remodeling of Transcriptional Regulatory Network Underlies the Progression of Heart Failure
Authors: Zongna Ren, Wanqing Zhao, Dandan Li, Peng Yu, Lin Mao, Quanyi Zhao, Luyan Yao, Xuelin Zhang, Yandan Liu, Bingying Zhou, Li Wang
Journal: Circulation (2023)

Progressive remodeling of cardiac gene expression underlies decline in cardiac function, eventually leading to heart failure. However, the major determinants of transcriptional network switching from normal to failed hearts remain to be determined.
Gene Regulatory Network that Shaped the Evolution of Larval Apical Organ in Cnidaria
Authors: Eleanor Gilbert, Jamie Craggs, Vengamanaidu Modepalli
Journal: Molecular Biology and Evolution (2023)

Among non-bilaterian animals, a larval apical sensory organ with integrated neurons is only found in cnidarians. Within cnidarians, an apical organ with a ciliary tuft is mainly found in Actiniaria. Whether this apical tuft has evolved independently in Actiniaria or alternatively originated in the common ancestor of Cnidaria and Bilateria and was lost in specific groups is uncertain. To test this hypothesis, we generated transcriptomes of the apical domain during the planula stage of four species representing three key groups of cnidarians: Aurelia aurita (Scyphozoa), Nematostella vectensis (Actiniaria), and Acropora millepora and Acropora tenuis (Scleractinia). We showed that the canonical genes implicated in patterning the apical domain of N. vectensis are largely absent in A. aurita. In contrast, the apical domain of the scleractinian planula shares gene expression pattern with N. vectensis. By comparing the larval single-cell transcriptomes, we revealed the apical organ cell type of Scleractinia and confirmed its homology to Actiniaria. However, Fgfa2, a vital regulator of the regionalization of the N. vectensis apical organ, is absent in the scleractinian genome. Likewise, we found that FoxJ1 and 245 genes associated with cilia are exclusively expressed in the N. vectensis apical domain, which is in line with the presence of ciliary apical tuft in Actiniaria and its absence in Scleractinia and Scyphozoa. Our findings suggest that the common ancestor of cnidarians lacked a ciliary apical tuft, and it could have evolved independently in the Actiniaria.
The Impact of Recent Demography on Functional Genetic Variation in North African Human Groups
Authors: Marcel Lucas-Sánchez, Amine Abdeli, Asmahan Bekada, Francesc Calafell, Traki Benhassine, David Comas
Journal: Molecular Biology and Evolution (2023)

The strategic location of North Africa has made the region the core of a wide range of human demographic events, including migrations, bottlenecks, and admixture processes. This has led to a complex and heterogeneous genetic and cultural landscape, which remains poorly studied compared to other world regions. Whole-exome sequencing is particularly relevant to determine the effects of these demographic events on current-day North Africans' genomes, since it allows to focus on those parts of the genome that are more likely to have direct biomedical consequences. Whole-exome sequencing can also be used to assess the effect of recent demography in functional genetic variation and the efficacy of natural selection, a long-lasting debate. In the present work, we use newly generated whole-exome sequencing and genome-wide array genotypes to investigate the effect of demography in functional variation in 7 North African populations, considering both cultural and demographic differences and with a special focus on Amazigh (plur. Imazighen) groups. We detect genetic differences among populations related to their degree of isolation and the presence of bottlenecks in their recent history. We find differences in the functional part of the genome that suggest a relaxation of purifying selection in the more isolated groups, allowing for an increase of putatively damaging variation. Our results also show a shift in mutational load coinciding with major demographic events in the region and reveal differences within and between cultural and geographic groups.
Quantitative risk assessment of egg‐white, milk and wheat in infants
Authors: Kazuma Takada, Tatsuki Fukuie, Hiroya Ogita, Seiko Hirai, Kenji Toyokuni, Kiwako Yamamoto‐Hanada, Yukihiro Ohya
Journal: Allergy (2023)

The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.