tbuckley/cabot-search huggingface dataset:
In critically ill adults, IV fluid bolus infused at slower vs. faster rates did not differ for 90-d mortality
Authors: Natalia Ovtcharenko, Simon Oczkowski
Journal: Annals of Internal Medicine (2022)

Zampieri FG, Machado FR, Biondi RS, et al. Effect of slower vs faster intravenous fluid bolus rates on mortality in critically ill patients: the BaSICS randomized clinical trial. JAMA. 2021;326:830-8. 34547081.
Oncogenic circRNA C190 Promotes Non–Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway
Authors: Afeez Adekunle Ishola, Chian-Shiu Chien, Yi-Ping Yang, Yueh Chien, Aliaksandr A. Yarmishyn, Ping-Hsing Tsai, Jerry Chieh-Yu Chen, Po-Kuei Hsu, Yung-Hung Luo, Yuh-Min Chen, Kung-Hou Liang, Yuan-Tzu Lan, Teh-Ia Huo, Hsin-I. Ma, Ming-Teh Chen, Mong-Lien Wang, Shih-Hwa Chiou
Journal: Cancer Research (2021)

Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non-small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis in NSCLC. We previously identified a circular noncoding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through a MAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR-MAPK-ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC. SIGNIFICANCE: The circRNA C190 is identified as a mediator of multiple pro-oncogenic signaling pathways in lung cancer and can be targeted to suppress tumor progression.
Functional Impact of Genomic Complexity on the Transcriptome of Multiple Myeloma
Authors: Bachisio Ziccheddu, Matteo C. Da Vià, Marta Lionetti, Akihiro Maeda, Silvia Morlupi, Matteo Dugo, Katia Todoerti, Stefania Oliva, Mattia D'Agostino, Paolo Corradini, Ola Landgren, Francesco Iorio, Loredana Pettine, Alessandra Pompa, Martina Manzoni, Luca Baldini, Antonino Neri, Francesco Maura, Niccolò Bolli
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Multiple myeloma is a biologically heterogenous plasma-cell disorder. In this study, we aimed at dissecting the functional impact on transcriptome of gene mutations, copy-number abnormalities (CNA), and chromosomal rearrangements (CR). Moreover, we applied a geno-transcriptomic approach to identify specific biomarkers for personalized treatments. Experimental Design: We analyzed 514 newly diagnosed patients from the IA12 release of the CoMMpass study, accounting for mutations in multiple myeloma driver genes, structural variants, copy-number segments, and raw-transcript counts. We performed an in silico drug sensitivity screen (DSS), interrogating the Cancer Dependency Map (DepMap) dataset after anchoring cell lines to primary tumor samples using the Celligner algorithm. Results: Immunoglobulin translocations, hyperdiploidy and chr(1q)gain/amps were associated with the highest number of deregulated genes. Other CNAs and specific gene mutations had a lower but very distinct impact affecting specific pathways. Many recurrent genes showed a hotspot (HS)-specific effect. The clinical relevance of double-hit multiple myeloma found strong biological bases in our analysis. Biallelic deletions of tumor suppressors and chr(1q)-amplifications showed the greatest impact on gene expression, deregulating pathways related to cell cycle, proliferation, and expression of immunotherapy targets. Moreover, our in silico DSS showed that not only t(11;14) but also chr(1q)gain/amps and CYLD inactivation predicted differential expression of transcripts of the BCL2 axis and response to venetoclax. Conclusions: The multiple myeloma genomic architecture and transcriptome have a strict connection, led by CNAs and CRs. Gene mutations impacted especially with HS-mutations of oncogenes and biallelic tumor suppressor gene inactivation. Finally, a comprehensive geno-transcriptomic analysis allows the identification of specific deregulated pathways and candidate biomarkers for personalized treatments in multiple myeloma.
Abstract MP30: Circulating MicroRNA-128-1 And Changes In Energy Metabolism And Insulin Sensitivity In Response To Weight Loss Diet Interventions: The Pounds Lost Trial
Authors: Yoriko Heianza, Qiaochu Xue, Jennifer Rood, George Bray, Frank Sacks, Lu Qi
Journal: Circulation (2022)

Background: MicroRNA (miRNAs) are short non-coding RNAs that play important roles in regulating gene expression. Recently, miR-128-1 was identified as a potential thrifty miRNA that controls energy expenditure, contributing to obesity and metabolic diseases. miR-128-1 is located at the locus harboring the lactase ( LCT ) gene, a hallmark gene of the positive selection and evolutionary adaptation to famine by promoting energy storage. Hypothesis: We investigated whether circulating thrifty miR-128-1 was associated with insulin resistance, adiposity, and energy expenditure among adults with overweight and obesity and tested whether miR-128-1 was associated with changes in these metabolic conditions after low-calorie weight-loss diet interventions. Methods: We included 495 participants from the POUNDS Lost trial with available data on circulating miR-128-1-5p measured at baseline and 6 months after the intervention. The LCT genotype rs4988235, which is responsible for lactase persistence in Europeans, was assessed to analyze the relationship between miR-128-1 and the positive selection at this locus. Outcome measurements included adiposity (weight, waist circumference [WC], and body composition), insulin resistance (HOMA-IR), and energy metabolism. Habitual physical activity was assessed by the Baecke questionnaires; total, leisure time, sport, work index were calculated. Results: The LCT rs4988235 (A) allele was associated with higher levels of miR-128-1 ( p =0.04). Pre-intervention miR-128-1 was significantly and positively associated with HOMA-IR ( p =0.009), insulin ( p =0.008), BMI ( p =0.0002), WC ( p =0.036), and whole-body total % fat mass ( p =0.013), and energy metabolism (resting energy expenditure, oxygen consumption, and carbon dioxide production; p &lt;0.05 for all). Also, we found that higher miR-128-1 was related to lower total physical activity index ( p =0.001) and subscales (leisure index ( p =0.007) and sport index ( p =0.02)). We found significant interactions between miR-128-1 and physical activity on changes in adiposity and insulin resistance at 6 months after the interventions ( P interaction =0.03 for weight; P interaction =0.004 for WC; and P interaction =0.01 for HOMA-IR). Participants with lower levels of physical activity and higher miR-128-1 at baseline responded better to the intervention to improve HOMA-IR at 6 months. There were also significant interactions between changes in miR-128-1 and changes in physical activity on changes in HOMA-IR and energy expenditure. Conclusions: Elevated levels of circulating miR-128-1 were associated with greater adiposity and insulin resistance in adults with overweight and obesity. The thrifty miR-128-1 interacted with physical activity on changes in energy metabolism and insulin sensitivity in response to weight-loss diet interventions.
Abstract P198: Association Between Oral Microbiome, Inflammation, Endotoxemia, And Heart Failure Severity
Authors: Bruno Bohn, Melana Yuzefpolskaya, Drew D Onat, Alberto Pinsino, Koji Takeda, Naka Yoshifumi, Abigail Johnson, Renu Nandakumar, Anne-Catrin Uhlemann, Bruce Paster, Paolo C Colombo, Ryan Demmer
Journal: Circulation (2022)

Introduction: Gut microbial imbalance may contribute to endotoxemia, inflammation and oxidative stress in heart failure (HF). Changes occurring in the oral microbiota and inflammatory/oxidative milieu during HF progression are unknown. Hypothesis: The oral microbiome will be associated with HF severity New York Heart Association, Class I/II, III, IV. Methods: We enrolled 167 patients with HF with reduced ejection fraction (mean age 59±14, 85% Male, 47% White, mean LVEF 20±9, 49% smokers). Biomarkers of endotoxemia (LPS, sCD14) and inflammation (CRP, IL6, TNF-α) were measured in 150 blood samples. A total of 167 oral samples were analyzed using 16S rRNA sequencing. Alpha diversity was assessed via Shannon Index and regressed on HF severity and biomarker levels with linear models. The association between HF severity and Beta diversity (Bray-Curtis dissimilarity) was assessed with PERMANOVA. DESeq2 regressed taxa abundance on HF severity and below vs. above median biomarker levels; multiple comparisons were controlled with the false discovery rate. Models were adjusted for age, sex, race/ethnicity, and smoking status. Results: Mean Shannon Index values±SD across HF class I/II (N=50), III (N=65), and IV (N=52) were 3.28±0.47, 3.42±0.49, 3.20±0.78. NYHA class was associated with both Alpha (p&lt;.01) and Beta diversity (p&lt;.05). Decreased Alpha diversity was associated with ischemic etiology (p&lt;.05), but not with sex, smoking, age, race/ethnicity, or clinical variables, including antibiotic use. In unadjusted models, increased Alpha Diversity was associated with decreased inflammation: IL6 (r=-0.16), TNF-α (r=-0.18), CRP (r=-0.21); all p&lt;.05. Statistical significance was lost after adjustment. Several taxa differed by NYHA class, levels of inflammation, and endotoxemia in multivariable models ( Figure ). Conclusions: HF severity, inflammation, and endotoxemia were associated with oral microbial diversity and bacteria linked to poor oral health, including Treponema denticola and Porphyromonas gingivalis .
A very long-acting IL-15: implications for the immunotherapy of cancer
Authors: John A Hangasky, Wei Chen, Sigrid P Dubois, Anusara Daenthanasanmak, Jürgen R Müller, Ralph Reid, Thomas A Waldmann, Daniel V Santi
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Interleukin-15 (IL-15) is an important cytokine necessary for proliferation and maintenance of natural killer (NK) and CD8 + T cells, and with great promise as an immuno-oncology therapeutic. However, IL-15 has a very short half-life and a single administration does not provide the sustained exposure required for optimal stimulation of target immune cells. The purpose of this work was to develop a very long-acting prodrug that would maintain IL-15 within a narrow therapeutic window for long periods—similar to a continuous infusion. Methods We prepared and characterized hydrogel microspheres (MS) covalently attached to IL-15 (MS~IL-15) by a releasable linker. The pharmacokinetics and pharmacodynamics of MS~IL-15 were determined in C57BL/6J mice. The antitumor activity of MS~IL-15 as a single agent, and in combination with a suitable therapeutic antibody, was tested in a CD8 + T cell-driven bilateral transgenic adenocarcinoma mouse prostate (TRAMP)-C2 model of prostatic cancer and a NK cell-driven mouse xenograft model of human ATL (MET-1) murine model of adult T-cell leukemia. Results On subcutaneous administration to mice, the cytokine released from the depot maintained a long half-life of about 168 hours over the first 5 days, followed by an abrupt decrease to about ~30 hours in accordance with the development of a cytokine sink. A single injection of MS~IL-15 caused remarkably prolonged expansions of NK and ɣδ T cells for 2 weeks, and CD44 hi CD8 + T cells for 4 weeks. In the NK cell-driven MET-1 murine model of adult T-cell leukemia, single-agent MS~IL-15 50 μg or anti-CCR4 provided modest increases in survival, but a combination—through antibody-depedent cellular cytotoxicity (ADCC)—significantly extended survival. In a CD8 + T cell-driven bilateral TRAMP-C2 model of prostatic cancer, single agent subcutaneous MS~IL-15 or unilateral intratumoral agonistic anti-CD40 showed modest growth inhibition, but the combination exhibited potent, prolonged bilateral antitumor activity. Conclusions Our results show MS~IL-15 provides a very long-acting IL-15 with low C max that elicits prolonged expansion of target immune cells and high anticancer activity, especially when administered in combination with a suitable immuno-oncology agent.
Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities
Authors: Diana D Shi, Jimmy A Guo, Hannah I Hoffman, Jennifer Su, Mari Mino-Kenudson, Jaimie L Barth, Jason M Schenkel, Jay S Loeffler, Helen A Shih, Theodore S Hong, Jennifer Y Wo, Andrew J Aguirre, Tyler Jacks, Lei Zheng, Patrick Y Wen, Timothy C Wang, William L Hwang
Journal: The Lancet Oncology (2022)
Developmental and Family Implications of State-Controlled Video Game Play in China
Authors: Orsolya Király, Dillon T. Browne, Zsolt Demetrovics
Journal: JAMA Pediatrics (2022)

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MTH1 Inhibitor TH1579 Induces Oxidative DNA Damage and Mitotic Arrest in Acute Myeloid Leukemia
Authors: Kumar Sanjiv, José Manuel Calderón-Montaño, Therese M. Pham, Tom Erkers, Viktoriia Tsuber, Ingrid Almlöf, Andreas Höglund, Yaser Heshmati, Brinton Seashore-Ludlow, Akhilesh Nagesh Danda, Helge Gad, Elisee Wiita, Camilla Göktürk, Azita Rasti, Stefanie Friedrich, Anders Centio, Montserrat Estruch, Thea Kristin Våtsveen, Nona Struyf, Torkild Visnes, Martin Scobie, Tobias Koolmeister, Martin Henriksson, Olov Wallner, Teresa Sandvall, Sören Lehmann, Kim Theilgaard-Mönch, Mathew J. Garnett, Päivi Östling, Julian Walfridsson, Thomas Helleday, Ulrika Warpman Berglund
Journal: Cancer Research (2021)

Abstract Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, exhibiting high levels of reactive oxygen species (ROS). ROS levels have been suggested to drive leukemogenesis and is thus a potential novel target for treating AML. MTH1 prevents incorporation of oxidized nucleotides into the DNA to maintain genome integrity and is upregulated in many cancers. Here we demonstrate that hematologic cancers are highly sensitive to MTH1 inhibitor TH1579 (karonudib). A functional precision medicine ex vivo screen in primary AML bone marrow samples demonstrated a broad response profile of TH1579, independent of the genomic alteration of AML, resembling the response profile of the standard-of-care treatments cytarabine and doxorubicin. Furthermore, TH1579 killed primary human AML blast cells (CD45+) as well as chemotherapy resistance leukemic stem cells (CD45+Lin−CD34+CD38−), which are often responsible for AML progression. TH1579 killed AML cells by causing mitotic arrest, elevating intracellular ROS levels, and enhancing oxidative DNA damage. TH1579 showed a significant therapeutic window, was well tolerated in animals, and could be combined with standard-of-care treatments to further improve efficacy. TH1579 significantly improved survival in two different AML disease models in vivo. In conclusion, the preclinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rationale to investigate the clinical usefulness of TH1579 in AML in an ongoing clinical phase I trial. Significance: The MTH1 inhibitor TH1579 is a potential novel AML treatment, targeting both blasts and the pivotal leukemic stem cells while sparing normal bone marrow cells.
Virtual Reality Assisted Motor Imagery for Early Post-Stroke Recovery: A Review
Authors: Chi Sang Choy, Shaun L. Cloherty, Elena Pirogova, Qiang Fang
Journal: IEEE Reviews in Biomedical Engineering (2022)

Stroke is a serious neurological disease that may lead to long-term disabilities and even death for stroke patients worldwide. The acute period, ( <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">$\le$</tex-math></inline-formula> 1 mo post-stroke), is crucial for rehabilitation but the current standard clinical practice may be ineffective for patients with severe motor impairment, since most rehabilitation programs involve physical movement. Imagined movement – the so-called motor imagery (MI) – has been shown to activate motor areas of the brain without physical movement. MI therefore offers an opportunity for early rehabilitation of stroke patients. MI, however, is not widely employed in clinical practice due to a lack of evidence-based research. Here, we review MI-based approaches to rehabilitation of stroke patients and immersive virtual reality (VR) technologies to potentially assist MI and thus, promote recovery of motor function.
The Structural Determinants of Intra-Protein Compensatory Substitutions
Authors: Shilpi Chaurasia, Julien Y. Dutheil
Journal: Molecular Biology and Evolution (2022)

Abstract Compensatory substitutions happen when one mutation is advantageously selected because it restores the loss of fitness induced by a previous deleterious mutation. How frequent such mutations occur in evolution and what is the structural and functional context permitting their emergence remain open questions. We built an atlas of intra-protein compensatory substitutions using a phylogenetic approach and a dataset of 1,630 bacterial protein families for which high-quality sequence alignments and experimentally derived protein structures were available. We identified more than 51,000 positions coevolving by the mean of predicted compensatory mutations. Using the evolutionary and structural properties of the analyzed positions, we demonstrate that compensatory mutations are scarce (typically only a few in the protein history) but widespread (the majority of proteins experienced at least one). Typical coevolving residues are evolving slowly, are located in the protein core outside secondary structure motifs, and are more often in contact than expected by chance, even after accounting for their evolutionary rate and solvent exposure. An exception to this general scheme is residues coevolving for charge compensation, which are evolving faster than noncoevolving sites, in contradiction with predictions from simple coevolutionary models, but similar to stem pairs in RNA. While sites with a significant pattern of coevolution by compensatory mutations are rare, the comparative analysis of hundreds of structures ultimately permits a better understanding of the link between the three-dimensional structure of a protein and its fitness landscape.
In Stroke, When Is a Good Outcome Good Enough?
Authors: Lee H. Schwamm
Journal: New England Journal of Medicine (2022)

In this issue of the Journal, Yoshimura and colleagues1 report the favorable results of a well-conducted randomized trial comparing mechanical thrombectomy (endovascular therapy) with medical care in patients with large-vessel occlusion and large cerebral infarctions. Previous trials of endovascular therapy in selected populations of patients with small and medium-sized strokes have shown beneficial treatment effects, thereby setting the stage for randomized trials of endovascular therapy in patients with large infarctions.2 Neurologists have been reluctant to perform endovascular therapy in patients with large infarctions because of the putative risk of bleeding into the infarction and the likelihood that outcomes would be . . .
Abstract P067: Elite Female Athlete’S Heart Of Asians: The Chief Heart Study
Authors: Gen-min Lin, Pang-yen Liu, Joao A Ac Lima, Carl J LAVIE
Journal: Circulation (2022)

Background: Women have been reported with smaller cardiac size and blood volume in response to intensive physical training compared to men. However, adaptive cardiac characteristics to exercises have been rarely compared between elite and non-elite female athletes particularly among Asian athletes. Methods: This study included 177 women, aged 18-34 years, under a standard 6-month military training course in Taiwan. In 2020, all attended a 3000-meter run to assess endurance capacity, and 89 were randomly selected to complete a 2-minute push-up test to assess muscular strength. Elite athletes were those whose performance fell one standard deviation above the mean (16%) of each exercise modality. Cardiac characteristics evaluated by a 12-lead electro-cardiography (ECG) and transthoracic echocardiography were compared between elite and non-elite female athletes. Multiple logistic regression analysis was used to determine the predictors of elite female athletes’s cardiac adaptation to endurance versus strength exercise. Results: Compared to non-elite controls, elite female endurance athletes had greater QRS duration (92.12±10.35 ms vs. 87.26±9.89 ms, p =0.01) and higher prevalence of right axis deviation (34.9% vs. 11.1%, p &lt;0.001). There were no differences in any echocardiographic variables, i.e. left ventricular mass index and diastolic function. Greater QRS duration, right axis deviation and lower systolic blood pressure levels were independent predictors of elite endurance athletes [odds ratios (OR) and 95% confidence intervals: 1.05 (1.01-1.09), 2.91 (1.12-7.59) and 0.93 (0.88-0.98), respectively]. In contrast, elite female strength athletes had greater right ventricular outflow tract (RVOT) (28.06±3.57 mm vs. 25.38± 3.61 mm, p =0.007), while demonstrated no differences in ECG variables. Greater RVOT was the only predictor of elite strength athletes [OR: 1.26 (1.05-1.50)]. Conclusions: In physically active Asian women, QRS prolongation and right axis deviation in ECG rather than the heart structure and functional changes characterize the elite endurance athletes. However, the right ventricular outflow enlargement documented in elite strength athletes requires further investigations.
49P EGFR exon 20 insertion mutations in patients with locally advanced or metastatic NSCLC in the German prospective, CRISP Registry real-world cohort (AIO-TRK-0315)
Authors: F. Griesinger, M. Sebastian, A. Bethge, P. Christopoulos, P. Hoffknecht, C. Waller, R. Benkelmann, M. Jänicke, A. Fleitz, J. Hanselmann, A. Hipper, A. Groth, W. Weichert, A. Nusch, J. Rauh, T. Fietz, T. Illmer, R. Depenbusch, W.E.E. Eberhardt, M. Thomas
Journal: Annals of Oncology (2022)