tbuckley/cabot-search huggingface dataset:
Overlooked poor-quality patient samples in sequencing data impair reproducibility of published clinically relevant datasets
Authors: Maximilian Sprang, Jannik Möllmann, Miguel A. Andrade-Navarro, Jean-Fred Fontaine
Journal: Genome biology (2024)

Abstract Background Reproducibility is a major concern in biomedical studies, and existing publication guidelines do not solve the problem. Batch effects and quality imbalances between groups of biological samples are major factors hampering reproducibility. Yet, the latter is rarely considered in the scientific literature. Results Our analysis uses 40 clinically relevant RNA-seq datasets to quantify the impact of quality imbalance between groups of samples on the reproducibility of gene expression studies. High-quality imbalance is frequent (14 datasets; 35%), and hundreds of quality markers are present in more than 50% of the datasets. Enrichment analysis suggests common stress-driven effects among the low-quality samples and highlights a complementary role of transcription factors and miRNAs to regulate stress response. Preliminary ChIP-seq results show similar trends. Quality imbalance has an impact on the number of differential genes derived by comparing control to disease samples (the higher the imbalance, the higher the number of genes), on the proportion of quality markers in top differential genes (the higher the imbalance, the higher the proportion; up to 22%) and on the proportion of known disease genes in top differential genes (the higher the imbalance, the lower the proportion). We show that removing outliers based on their quality score improves the resulting downstream analysis. Conclusions Thanks to a stringent selection of well-designed datasets, we demonstrate that quality imbalance between groups of samples can significantly reduce the relevance of differential genes, consequently reducing reproducibility between studies. Appropriate experimental design and analysis methods can substantially reduce the problem.
Self‐Assembled Peptide Hydrogels Loaded with Umbilical Cord‐Derived Mesenchymal Stem Cells Repairing Injured Endometrium and Restoring Fertility
Authors: Xue Lv, Wenjing Niu, Bin Zhang, Jingbo Chen, Shicong Yang, Yuhuan Xue, Yutian Dong, Peiyan Yuan, Yue Pan, Jeremy Tan, Yi Yan Yang, Xin Ding, Xiaomiao Zhao
Journal: Advanced Healthcare Materials (2024)

Abstract Endometrial injury is a major cause of infertility and recurrent miscarriage. However, no clinically available methods currently exist to effectively repair the damaged endometrium. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for promoting tissue regeneration, yet a biocompatible scaffold capable of delivering MSCs and supporting their growth is needed. Herein, the study reports a peptide hydrogel scaffold, self‐assembled from a peptide IVK8‐RGD consisting of an ionic complementary peptide sequence IEVEIRVK and a bioactive sequence RGD, to load umbilical cord‐derived mesenchymal stem cells (UC‐MSCs). This peptide forms a hydrogel under the physiological condition through self‐assembly, and the peptide hydrogel exhibits injectability and adhesiveness to uterus, making it suitable for endometrial repair. Importantly, this hydrogel supports the adhesion and proliferation of UC‐MSCs in a 3D environment. In vivo experiments using rats with endometrial injury have shown that treatment with IVK8‐RGD hydrogel loaded with UC‐MSCs effectively restores endometrial thickness, inhibits fibrosis, and facilitates angiogenesis through activating Raf/MEK/ERK pathway, leading to significantly improved fertility and live birth rate. These findings demonstrate the potential of the UC‐MSCs‐loaded hydrogel in repairing damaged endometrium and may address the unmet clinical needs of treating recurrent miscarriage and infertility induced by endometrial damage.
Abstract 892: The Importance of Mitochondrial Oxidative Stress and Integrity of Mitochondrial DNA in Coronary Arteriogenesis
Authors: Petra Rocic, Glenn Wilson, Inna Shokolenko, Joy Joseph, Balaraman Kalyanaraman, William Chilian
Journal: Circulation (2007)

The prediabetic metabolic syndrome (pdMS) leads to many pathological cardiac and vascular phenotypes including impaired arteriogenesis. Mitochondrial (mt) oxidative stress (mtOxStress) is postulated to contribute to the development of such phenotypes, but whether reduction of mtOxStress, or imposition of a maneuver to mimic its effects, would restore or inhibit coronary arteriogenesis (CA), respectively, has not been determined. We tested the hypothesis that in the pdMS, mtOxStress plays a key role in inhibition of coronary arteriogenesis. Lean (LN, n = 6) and obese (OB, n = 6) Zucker obese fatty rats (model of pdMS) were instrumented with a pneumatic snare around the left anterior descending artery (LAD), and subjected to a protocol of repetitive ischemia (RI: 24, 40 sec occlusions/day for 10 days) to stimulate growth. CA was determined from the ratio of flows (radioactive microspheres) measured during LAD occlusion to collateral-dependent and normal zones (CZ/NZ). Prior to RI, CZ/NZ in all groups was less than 0.2 indicating that the native collateral conductance could supply less than 20% of the normally occurring flow during LAD occlusion. After RI, CZ/NZ was 0.82Â ± 0.09 in LN, which was markedly higher (p &lt; 0.05) than that in the OB (0.21Â ± 0.08) indicating impaired CA in the OB rats. To reduce mtOxStress, OB animals (n = 5) were given mito-Quinone (mt-directed free radical scavenger) in drinking water (750 mg/L); this treatment restored CA (CZ/NZ = 0.79Â ± 0.03) comparable to that in LN. Because one manifestation of mt-OxStress is mt-DNA fragmentation, which results in impaired expression of key mt-proteins and compromised mt-function, we determined if administration of a recombinant protein engineered with a TAT sequence to enable intracellular delivery, a mt-localization sequence, and exonuclease ExoIII (mt-tat-ExoIII) to fragment mtDNA would impair coronary arteriogenesis in LN (n = 5). Mt-tat-ExoIII (iv, 0.2 ug/g, every other day) in LN rats impaired CA in response to RI (CZ/NZ = 0.32Â ± 0.09, p &lt; 0.05 vs. LN controls). We conclude that mitochondrial oxidative stress, and its effects on mtDNA integrity, are pivotal in the abrogation of CA in the pdMS.
An Optimized Decellularized Extracellular Matrix from Dental Pulp Stem Cell Sheets Promotes Axonal Regeneration by Multiple Modes in Spinal Cord Injury Rats
Authors: Wei Qiu, Bangyi Zhou, Yifei Luo, Yuanting Chen, Zehao Chen, Keke Wu, Hongle Wu, Buling Wu, Jinshan Guo, Fuchun Fang
Journal: Advanced Healthcare Materials (2024)

Abstract In the field of tissue engineering, the extracellular matrix (ECM) is considered an important element for promoting neural regeneration after spinal cord injury (SCI). Dental pulp stem cells (DPSCs), mesenchymal stem cells that originate from the neural crest, are easy to harvest and culture in vitro, express a variety of neurotrophic factors (NTFs) and deposit a large amount of ECM, making them a good choice for stem cell‐ or ECM‐based treatment of SCI. In the present study, decellularized extracellular matrix (dECM) derived from DPSC sheets is used for the treatment of SCI. Optimization experiments reveal that incubating DPSC sheets with 1% Triton X‐100 for 5 min is the best procedure for preparing DPSC dECM. It is found that DPSC dECM promotes nerve repair and regeneration after SCI and restores hindlimb motor function in rats. Mechanistically, DPSC dECM facilitates the migration and neural differentiation of neural stem cells, as well as M2 polarization of microglia, and inhibits the formation of glial scars. This study suggests that the use of DPSC dECM is a potential strategy for the treatment of SCI.
Robust and cost‐effective CRISPR/Cas9 gene editing of primary tumor B cells in Eµ‐TCL1 model of chronic lymphocytic leukemia
Authors: Rosita Del Prete, Roberta Drago, Federica Nardi, Gaia Bartolini, Erika Bellini, Antonella De Rosa, Silvia Valensin, Anna Kabanova
Journal: HemaSphere (2024)
Immunometabolic Approaches Mitigating Foreign Body Response and Transcriptome Characterization of the Foreign Body Capsule
Authors: Sabrina L. Macias, Olivia Palmer, Jennifer A. Simonovich, Ryan A. Clark, Gregory A. Hudalla, Benjamin G. Keselowsky
Journal: Advanced Healthcare Materials (2024)

Abstract Directing immunometabolism presents new opportunities to modulate key cell types associated with the formation of foreign body response (FBR) capsule. Contrasting approaches directing immunometabolism are investigated to mitigate FBR: a broadly suppressive metabolic inhibitor (MI) cocktail comprised of 2‐deoxyglucose (2‐DG), metformin, and 6‐diazo‐5‐oxo‐l‐norleucine (DON) with daily systemic dosing regimen, and local weekly injection of the more narrowly focused tryptophan catabolizing IDO‐Gal3 fusion protein. Treatments significantly decrease FBR capsule formed around subcutaneously implanted cellulose disks. MI cocktail results in a substantially thinner FBR capsule (40% of control), while weekly local injection of IDO‐Gal3 also results in a thinner FBR capsule (69% of control). RNA‐sequencing capsule transcripts reveal MI cocktail promotes quiescence, with decreased antigen processing and presentation, T helper subset differentiation, and cytokine‐cytokine receptor pathway. IDO‐Gal3 promotes pro‐regenerative, alternatively activated M2‐like macrophages and T helper 2 cells, with increased expression of type 2 response‐associated genes ( Il4 , Il13 , Arg1 , Mrc1 , Chil3 , Gata3 ). IDO‐Gal3 decreases pro‐inflammatory innate sensing pathways, and C‐type lectin receptor, NOD‐like receptor, RIG‐I‐like receptor, and Toll‐like receptor signaling. This work helps define key gene targets and pathways concomitantly regulated in the FBR capsule during immunometabolic modulation compared to control FBR capsule.
Intra‐tumoral and peripheral blood <scp>TIGIT</scp> and <scp>PD</scp>‐1 as immune biomarkers in nodular lymphocyte predominant Hodgkin lymphoma
Authors: Jay Gunawardana, Soi C. Law, Muhammed B. Sabdia, Éanna Fennell, Aoife Hennessy, Ciara I. Leahy, Paul G. Murray, Karolina Bednarska, Sandra Brosda, Judith Trotman, Leanne Berkahn, Andreea Zaharia, Simone Birch, Melinda Burgess, Dipti Talaulikar, Justina N. Lee, Emily Jude, Eliza A. Hawkes, Sanjiv Jain, Karthik Nath, Cameron Snell, Fiona Swain, Joshua W. D. Tobin, Colm Keane, Mohamed Shanavas, Emily Blyth, Christian Steidl, Kerry Savage, Pedro Farinha, Merrill Boyle, Barbara Meissner, Michael R. Green, Francisco Vega, Maher K. Gandhi
Journal: American Journal of Hematology (2024)

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or TIGIT+) CD4+ T-cells and PD-1+CD8+ T-cells in NLPHL compared to cHL. This included T-cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed-Sternberg (HRS) cells. In NLPHL, intra-tumoral PD-1+CD4+ T-cells frequently expressed TCF-1, a marker of heightened T-cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD-1+TIGIT+ in TH1, TH2, and regulatory CD4+ T-cells in NLPHL versus cHL. Circulating PD-1+CD4+ had high levels of TCF-1. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD-1+CD4+ and TIGIT+PD-1+CD8+ T-cells in the blood were also present in the TME, indicating that immune-checkpoint expressing T-cells circulated between intra-tumoral and blood compartments. In in vitro assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL.
Serum iron and transferrin saturation variation are circadian regulated and linked to the harmonic circadian oscillations of erythropoiesis and hepatic <scp><i>Tfrc</i></scp> expression in mice
Authors: Cavan Bennett, Anne Pettikiriarachchi, Alistair R. D. McLean, Rebecca Harding, Marnie E. Blewitt, Cyril Seillet, Sant‐Rayn Pasricha
Journal: American Journal of Hematology (2024)

Abstract Serum iron has long been thought to exhibit diurnal variation and is subsequently considered an unreliable biomarker of systemic iron status. Circadian regulation (endogenous ~24‐h periodic oscillation of a biologic function) governs many critical physiologic processes. It is unknown whether serum iron levels are regulated by circadian machinery; likewise, the circadian nature of key players of iron homeostasis is unstudied. Here we show that serum iron, transferrin saturation (TSAT), hepatic transferrin receptor (TFR1) gene ( Tfrc ) expression, and erythropoietic activity exhibit circadian rhythms. Daily oscillations of serum iron, TSAT, hepatic Tfrc expression, and erythropoietic activity are maintained in mice housed in constant darkness, where oscillation reflects an endogenous circadian period. Oscillations of serum iron, TSAT, hepatic Tfrc, and erythropoietic activity were ablated when circadian machinery was disrupted in Bmal1 knockout mice. Interestingly, we find that circadian oscillations of erythropoietic activity and hepatic Tfrc expression are maintained in opposing phase, likely allowing for optimized usage and storage of serum iron whilst maintaining adequate serum levels and TSAT. This study provides the first confirmatory evidence that serum iron is circadian regulated, discerns circadian rhythms of TSAT, a widely used clinical marker of iron status, and uncovers liver‐specific circadian regulation of TFR1, a major player in cellular iron uptake.
The Emerging Field of Viroimmunotherapy for Pediatric Brain Tumors
Authors: Marc Garcia-Moure, Virginia Laspidea, Sumit Gupta, Andrew G Gillard, Soumen Khatua, Akhila Parthasarathy, Jiasen He, Frederick F Lang, Juan Fueyo, Marta M Alonso, Candelaria Gomez-Manzano
Journal: Neuro-Oncology (2024)

Abstract Pediatric brain tumors are the most common solid tumors in children. Even to date, with the advances in multimodality therapeutic management, survival outcomes remain dismal in some types of tumors, such as pediatric-type diffuse high-grade gliomas or central nervous system embryonal tumors. Failure to understand the complex molecular heterogeneity and the elusive tumor and microenvironment interplay continues to undermine therapeutic efficacy. Developing a strategy that would improve survival for these fatal tumors remains unmet in pediatric neuro-oncology. Oncolytic viruses (OVs) are emerging as a feasible, safe, and promising therapy for brain tumors. The new paradigm in virotherapy implies that the direct cytopathic effect is followed, under certain circumstances, by an antitumor immune response responsible for the partial or complete debulking of the tumor mass. OVs alone or combined with other therapeutic modalities have been primarily used in adult neuro-oncology. A surge in encouraging preclinical studies in pediatric brain tumor models recently led to the clinical translation of OVs with encouraging results in these tumors. In this review, we summarize the different virotherapy tested in preclinical and clinical studies in pediatric brain tumors, and we discuss the limitations and future avenues necessary to improve the response of these tumors to this type of therapy.
Disseminated Juvenile Xanthogranuloma Harboring a <i>GAB2::BRAF</i> fusion Successfully Treated with Trametinib: a Case Report
Authors: Kai-ni Shen, He Lin, Long Chang, Xin-xin Cao
Journal: British Journal of Dermatology (2024)

We present an interesting case of disseminated juvenile xanthogranuloma harbouring a GAB2::BRAF fusion that exhibited dramatic response to trametinib, highlighting the utility of RNA sequencing and targeted next-generation sequencing in non-Langerhans cell histiocytosis in identifying potential therapeutic targets.
ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses
Authors: Irem Kaymak, McLane J. Watson, Brandon M. Oswald, Shixin Ma, Benjamin K. Johnson, Lisa M. DeCamp, Batsirai M. Mabvakure, Katarzyna M. Luda, Eric H. Ma, Kin Lau, Zhen Fu, Brejnev Muhire, Susan M. Kitchen-Goosen, Alexandra Vander Ark, Michael S. Dahabieh, Bozena Samborska, Matthew Vos, Hui Shen, Zi Peng Fan, Thomas P. Roddy, Gillian A. Kingsbury, Cristovão M. Sousa, Connie M. Krawczyk, Kelsey S. Williams, Ryan D. Sheldon, Susan M. Kaech, Dominic G. Roy, Russell G. Jones
Journal: The Journal of Experimental Medicine (2024)

Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.
Prevalence of abdominal aortic aneurysm in patients with hidradenitis suppurativa in the Veterans Affairs Health Care System
Authors: Zachary Wendland, Katelyn Rypka, Claire Herzog, Lindsey Greenlund, Travis Fulk, Amy Gravely, Anders Westanmo, Amit Garg, Noah Goldfarb
Journal: British Journal of Dermatology (2024)

Our study investigated the relationship between abdominal aortic aneurysm (AAA) and hidradenitis suppurativa (HS) in patients within the Veterans Affair Health Care System. Overall, we found that patients with HS had a higher prevalence of AAA than those without HS. Further research should consider clinical outcomes such as AAA rupture and associated mortality.
Loss of ARID3A perturbs intestinal epithelial proliferation–differentiation ratio and regeneration
Authors: Nikolaos Angelis, Anna Baulies, Florian Hubl, Anna Kucharska, Gavin Kelly, Miriam Llorian, Stefan Boeing, Vivian S.W. Li
Journal: The Journal of Experimental Medicine (2024)

Intestinal stem cells at the crypt divide and give rise to progenitor cells that proliferate and differentiate into various mature cell types in the transit-amplifying (TA) zone. Here, we showed that the transcription factor ARID3A regulates intestinal epithelial cell proliferation and differentiation at the TA progenitors. ARID3A forms an expression gradient from the villus tip to the upper crypt mediated by TGF-β and WNT. Intestinal-specific deletion of Arid3a reduces crypt proliferation, predominantly in TA cells. Bulk and single-cell transcriptomic analysis shows increased enterocyte and reduced secretory differentiation in the Arid3a cKO intestine, accompanied by enriched upper-villus gene signatures of both cell lineages. We find that the enhanced epithelial differentiation in the Arid3a-deficient intestine is caused by increased binding and transcription of HNF1 and HNF4. Finally, we show that loss of Arid3a impairs irradiation-induced regeneration with sustained cell death and reprogramming. Our findings imply that Arid3a functions to fine-tune the proliferation-differentiation dynamics at the TA progenitors, which are essential for injury-induced regeneration.
Development of an engineered extracellular vesicles-based vaccine platform for combined delivery of mRNA and protein to induce functional immunity
Authors: Xin Luo, Kathleen M McAndrews, Kent A Arian, Sami J Morse, Viktoria Boeker, Shreyasee V Kumbhar, Yingying Hu, Krishnan K Mahadevan, Kaira A Church, Sriram Chitta, Nicolas T Ryujin, Janine Hensel, Jianli Dai, Dara P Dowlatshahi, Hikaru Sugimoto, Michelle L Kirtley, Valerie S LeBleu, Shabnam Shalapour, Joe H Simmons, Raghu Kalluri
Journal: Journal of Controlled Release (2024)
Errors in Simulation Model
Journal: JAMA Network Open (2024)

Disease in a Simulation Model That Includes Caregiver and Societal Factors," 1 published on October 21, 2021, the authors have reported errors in some of the equations included in the simulation model.For the beta-amyloid load (AV45 level), a negative sign was erroneously reversed to positive.Correction of this error changes some of the estimated costs and incremental costeffectiveness ratios.There was also an error in the originally reported population, which was described as a "hypothetical cohort of patients selected from the ADNI database who received the diagnosis of MCI.Patients in this cohort scored between 24 and 30 on the Mini-Mental State Examination (MMSE) and had a global Clinical Dementia Rating scale (CDR) of 0.5, with a required memory box score of 0.5 or higher, at baseline… [and] an abnormal memory function score on the Wechsler Memory Scale."Applying these criteria in the model selects 870 patient records instead of the 873 originally reported in the Supplement of the original article.In addition, a discontinuation rate of 0% was originally reported, but in the corrected the model, this was set to 10% annually.Finally, 2 of the references for health state utility and costs were incorrect.These errors affect the Key Points, Abstract, main text, Tables 2 to 4, and the Supplement.Correcting for these errors does not affect the interpretations or conclusions if the study.
An Urban Farm–Anchored Produce Prescription Program — Food as Medicine and Economic Justice
Authors: Kaitlyn M Fruin, Elizabeth L Tung, Jean M Franczyk, Wayne M Detmer
Journal: New England Journal of Medicine (2024)

To reduce high levels of food insecurity among Black and Latinx residents of Chicago, three institutions partnered to create VeggieRx, a produce prescription program anchored by an urban agriculture facility.