bluuebunny/crossref_metadata_2025_split huggingface dataset:
PAIRWISE: Deep Learning-based Prediction of Effective Personalized Drug Combinations in Cancer
Authors: Xu Chengqi , Us Ilkay , Cohen-Setton Jake , Milo Marta , Sidders Ben , Fitzgibbon Jude , Melnick Ari M. , Pan Heng , Elemento Olivier , Bulusu Krishna C. 
Published: November 2024

AbstractCombination therapies offer promise for improving cancer treatment efficacy and preventing recurrence. However, identifying optimal drug combinations tailored to specific cancer subtypes and individual patients is extremely challenging due to the vast number of possible combinations and tumor heterogeneity. To address this gap, we take a machine learning approach combining deep learning with transfer learning to incorporate prior scientific knowledge and predict drug synergy based on tumor-specific transcriptome profiles. This approach, called PAIRWISE, explicitly modeled synergistic effects of drug combinations in cancer cell lines or individual tumor samples based on drug chemical structures, drug targets, and transcriptomes of inferred samples. PAIRWISE outperformed competing models with an area under the receiver operating characteristic curve (AUROC) of 0.85 on held-out cancer cell lines. When applied to an independent dataset of combinations with Bruton Tyrosine Kinase inhibitors (BTKi) in Diffuse Large B Cell Lymphoma (DLBCL) cell lines, PAIRWISE accurately predicted synergistic drug combinations with an AUROC of 0.72. To further confirm the robustness of PAIRWISE predictions, we performed an in silico, patient profile-directed screen for other compounds that would synergize with BTKi in DLBCL patients, and confirmed the synergy of the predictions using a panel of eight non-Hodgkin lymphoma cell lines. These findings demonstrate the ability of PAIRWISE to nominate effective personalized drug combinations, accelerating the development of precision oncology.
Characterization of A Bronchoscopically Induced Transgenic Lung Cancer Pig Model for Human Translatability
Authors: Joshi Kirtan , Suvilesh Kanve N. , Natesh Nagabhishek Sirpu , Manjunath Yariswamy , Coberly Jared , Schlink Sarah , Kunin Jeffrey R. , Prather Randall S. , Whitworth Kristin , Nelson Benjamin , Bryan Jeffrey N. , Hoffman Timothy , Golzy Mojgan , Raju Murugesan , Teixeiro Emma , Telugu Bhanu P. , Kaifi Jussuf T. , Rachagani Satyanarayana 
Published: November 2024

ABSTRACTBackgroundThere remains a need for animal models with human translatability in lung cancer (LC) research. Findings in pigs have high impact on humans due to similar anatomy and physiology. We present the characterization of a bronchoscopically-induced LC model in Oncopigs carrying inducible KRASG12Dand TP53R167Hmutations.MethodsTwelve Oncopigs underwent 29 injections via flexible bronchoscopy. Eighteen Adenovirus-Cre recombinase gene (AdCre) inductions were performed endobronchially (n=6) and transbronchially with a needle (n=12). Eleven control injections were performed without AdCre. Oncopigs underwent serial contrast-enhanced chest CT with clinical follow-up for 29 weeks. Following autopsy, lung and organ tissues underwent histopathology, immunohistochemistry, and RNA-sequencing with comparative analysis with The Cancer Genome Atlas (TCGA) human LC data.ResultsAll 18 sites of AdCre injections had lung consolidations on CT imaging. Transbronchial injections led to histopathologic invasive cancer and/or carcinoma in situ (CIS) in 11/12 (91.7%), and invasive cancer (excluding CIS) in 8/12 (66.6%). Endobronchial inductions led to invasive cancer in 3/6 (50%). A soft tissue metastasis was observed in one Oncopig. Immunohistochemistry confirmed expression of Pan-CK+/epithelial cancer cells, with macrophages and T cells infiltration in the tumor microenvironment. Transcriptome comparison showed 54.3% overlap with human LC (TCGA), in contrast to 29.88% overlap of KRAS-mutant mouse LC with human LC.ConclusionsThe transgenic and immunocompetent Oncopig model has a high rate of LC following bronchoscopic transbronchial induction. Overlap of the Oncopig LC transcriptome with human LC transcriptome was noted. This pig model is expected to have high clinical translatability to the human LC patient.
Evolution and functioning of an X-A balance sex determination system in hops
Authors: Akagi Takashi , Segawa Tenta , Uchida Rika , Tanaka Hiroyuki , Shirasawa Kenta , Yamagishi Noriko , Yaegashi Hajime , Natsume Satoshi , Takagi Hiroki , Abe Akira , Okuno Miki , Toyoda Atsushi , Sato Kyoko , Honniden Yuka , Zhang Cheng , Ushijima Koichiro , Patzak Josef , Horáková Lucie , Bačovský Václav , Hobza Roman , Charlesworth Deborah , Itoh Takehiko , Ono Eiichiro 
Published: November 2024

AbstractChromosomal sex determining systems with male heterogamety include actively male-determining-Y and X-A balance systems, both of which are found in animals and plants. The sex-determining genes have been identified in several active-Y plant systems, but the evolution and functioning of X-A balance systems remains mysterious. To study this, we sequenced and compared the genomes of two hop species. The evolution of the hop X-A balance system involved an ancient recombination suppression event across a large X chromosome region shared by both species. In one species, an autosome fused to this ancestral sex chromosome, and recombination was subsequently suppressed again. The two evolutionary strata created in this neo-X have degenerated to different degrees, and evolved correspondingly different dosage compensation levels that correlate with histone modification patterns. Finally, we identified an X-specific ETR1-like ethylene receptor in the ancestral X region. Its dosage may affect sex determination, as part of the counting mechanism of this X-A balance system.One sentence summaryBased on whole genome sequences of the cultivated hop,Humulus lupulus, and its wild relativeH. japonicus, we describe the evolution of sex chromosomal regions, three of which that evolved region-specific dosage compensation, and identify a candidate gene involved in their X-A balance sex determining system.
Inducible FAK Deletion but not FAK Inhibition in Endothelial Cells Activates p53 to Suppress Tumor Growth in PYK2-null Mice
Authors: Chen Xiao Lei , Ojalill Marjaana , Jean Christine , Tancioni Isabelle , Jiang Shulin , Boyer Antonia , Ozmadenci Duygu , Uryu Sean , Tarin David , Schlessinger Joseph , Stupack Dwayne G. , Schlaepfer David D. 
Published: November 2024

AbstractFocal adhesion kinase (FAK) functions as a signaling and scaffolding protein within endothelial cells (ECs) impacting blood vessel function and tumor growth. Interpretations of EC FAK-null phenotypes are complicated by related PYK2 (protein tyrosine kinase 2) expression, and to test this, we created PYK2-/-FAKfl/flmice with tamoxifen-inducible EC-specific Cre recombinase expression. At 11 weeks of age, EC FAK inactivation resulted in increased heart and lung mass and vascular leakage only on a PYK2-/-background. Surprisingly, ∼90% of PYK2-/-EC FAK-/-mice survived to 75 weeks of age. Syngeneic melanoma, breast, or lung carcinoma tumors did not grow in PYK2-/-EC FAK-/-mice, but tumors grew normally in PYK2-/-EC FAKfl/flmice lacking Cre. This tumor inhibitory phenotype was associated with abortive EC vessel sprouting, enhanced EC p53 tumor suppressor and p21CIP1 (cyclin-dependent inhibitor 1) expression, and alterations in serum cytokine levels. To discern the role of FAK kinase versus scaffolding activity in ECs, we generated kinase defective (FAK K454R, KD) PYK2-/-EC FAKfl/KDand PYK2-/-EC FAKfl/WT(WT, wildtype) mice. Hemizygous EC FAK-/KDexpression supported primary tumor growth but not metastasis, implicating EC FAK activity in tumor dissemination.In vitro, hemizygous expression of either WT or KD FAK suppressed EC p21CIP1 levels and cell death observed in primary PYK2-/-EC FAK-/-ECs. Combined FAK and PYK2 knockdown in tumor cells also increased p21CIP1 and PARP1 (poly ADP-ribose polymerase 1) levels in a p53-associated manner impacting anchorage-independent growth. Together, these results underscore the linkage between PYK2 and FAK loss with p53 activation impacting tumor growth.Impact StatementPYK2-null combined with endothelial cell-specific FAK transgenic mouse models show that loss of FAK activity limits tumor spread and that genetic or chemical degradation preventing combined FAK-PYK2 expression may be an approach to induce a p53-associated anti-tumor response.
Factors Associated with Failure of Fecal Microbiota Transplant for RecurrentClostridioides difficileInfection
Authors: Nguyen Joseph D. K. , Yohannes Kibret G. , Setiady Initha , Phillips Emma C. , Hays R. Ann , Behm Brian W. , Warren Cirle A. , Shin Jae Hyun 
Published: November 2024

AbstractBackgroundClostridioides difficileinfection (CDI) has emerged as a prevalent and recurrent antibiotic-associated infection. Fecal microbiota transplantation (FMT) is the most effective treatment for recurrent CDI (rCDI). Despite high success rates, FMT is ineffective in 5-20% of cases. Factors associated with failure have not been clearly defined. We seek to better understand factors predictive of FMT failure.MethodsA retrospective chart review was conducted on adult patients who were screened at the ComplicatedC. difficileClinic at the University of Virginia Health System and received FMT for rCDI between 2013 and 2022. Primary outcome was failure of FMT, defined as either rCDI or all-cause death within one year.Results240 patients underwent FMT: 70.4% were female, median age was 68, and median episodes of CDI was 4. 24.6% experienced failure within the year (18.3% had rCDI and 7.1% died). Age 70 or older (p=0.007), male sex (p=0.013), ≥4 episodes of CDI (p=0.010), hypertension (p=0.010), diabetes mellitus (p=0.002), malignancy (p=0.034), high thyroid-stimulating hormone (p=2.696×10−5), anemia (p=0.002), and low zinc (p=0.025) were significantly associated with FMT failure on univariate analysis; age 70 or older (OR=2.66 [1.29-5.67]), ≥4 episodes of CDI (OR=3.13 [1.47-7.09]), and diabetes mellitus (OR=2.82 [1.25-6.50]) persisted to be associated with failure on multivariate analysis.ConclusionsOur study shows that FMT remains an effective treatment for rCDI. We highlight several factors associated with FMT failure, such as older age, ≥4 episodes of CDI, anemia, elevated TSH, and low zinc, and the need for additional research to clearly define causality.
Increasing access to certified nurse-midwives prevents use of medical interventions during labor: an application of g-computation and target trial emulation
Authors: Simmons Elizabeth , Austin Anna , Wood Mollie , Mansfield Alyssa J. , Sheffield-Abdullah Karen , Singh Kavita 
Published: November 2024

AbstractBackgroundPrenatal care (PNC) led by a certified nurse-midwife (CNM) may reduce medical interventions and complications during labor and delivery, compared to physician-led care. We estimated the prevalence of six outcomes if we intervened to increase the number of low-risk pregnant people enrolled in PNC with a CNM.MethodsWe used 2014-2019 Pregnancy to Early Life Longitudinal data. The study population comprised people aged 18-55 with a low-risk pregnancy who initiated PNC with a physician or CNM at <13 weeks gestation and had a live birth. We used g-computation to estimate the prevalence and prevalence difference of cesarean sections, labor inductions, epidural use, postpartum hemorrhage, maternal infection and obstetric trauma under hypothetical scenarios where 10%, 20% and 50% more people and 100% more people with government-funded insurance had CNM-led PNC. We adjusted for payer of delivery, maternal age, education, race, and estimated 95% confidence intervals (CI) using bootstrap resampling.ResultsAmong 130,835 pregnant people, one-fourth had CNM-led PNC. A 10% increase in CNM-led PNC resulted in a reduction in the prevalence of cesarean sections of -0.39 percentage-points (95% CI: 0.41 to -0.35), in labor inductions of -0.21 percentage-points (95% CI: -0.25 to -0.17), in epidural use of -0.85 percentage-points (95% CI: -0.89 to -0.80), and in maternal infections of-0.08 percentage-points (95% CI: -0.11 to -0.06), but an increase in prevalence of postpartum hemorrhage of 0.03 percentage-points (95% CI: 0.01 to 0.05) and no change in prevalence of obstetric trauma (0.00 percentage-points; 95% CI: -0.02 to 0.03). The effect estimates were larger for 20% and 50% increases.ConclusionsA scale-up of CNM-led care contributes to a decrease in use of some medical interventions and complications during labor and delivery.Key PointsOur results suggest that interventions to increase the number of low-risk pregnancies attended by CNMs versus physicians could reduce the use of some medical interventions and complications during labor and delivery.With 10% more low-risk pregnant individuals enrolled in prenatal care with a CNM, the prevalence of cesarean sections, labor inductions, epidural analgesia, and maternal infection decreased, while the prevalence of postpartum hemorrhage increased slightly, and the prevalence of obstetric trauma did not change.As barriers to accessing care with a CNM still exist for low-risk pregnant populations, policy makers and clinical providers should help to reduce barriers to access to CNMs to help improve clinical outcomes.
An Optimal Mass Transport Model for the Analysis of DCE-MRI and its Application to Breast Cancer Treatment Response
Authors: Chen Xinan , Huang Wei , Shukla-Dave Amita , Paudyal Ramesh , Gullo Roberto Lo , Perez Marcelina , Pinker Katja , Deasy Joseph O. 
Published: November 2024

AbstractPurposeDynamic contrast-enhanced MR imaging (DCE-MRI) is widely deployed in cancer care and research, but the methods conventionally used to quantify contrast agent kinetics do not account the cross-voxel movement characterized by advection and diffusion. We hypothesized that unbalanced optimal mass transport could be used to quantify and visualize such contrast agent flows across tumor volumes.MethodsWe developed a computational fluid dynamics model termed the unbalanced regularized optimal mass transport (urOMT) model. We tested the urOMT on a multi-institutional dataset of 153 longitudinal DCE-MRI scans from 39 breast cancer patients treated with neoadjuvant chemotherapy (NACT.)ResultsThe urOMT model can quantify dynamic fluid transport properties such as net speed, flux and rates of contrast entering and leaving the tumor (influx and efflux). The urOMT model can also visualize the trajectories and directions of net fluid flows. Quantitative metrics from urOMT exhibited distinct patterns that may be relevant to predicting pathological complete response (pCR) to NACT.ConclusionThe urOMT model can be used to estimate and visualize local fluid flow in DCE-MRI breast cancer images. Model-based estimates of flux, influx and efflux should be tested as potential predictive imaging biomarkers to measure treatment effectiveness in patients treated with NACT. The urOMT model in principle has applicability to other cancer imaging use cases, but this will require further testing.
Novel wheat germ agglutinin-based mass cytometry cell barcoding reagent for heterogeneous, live or fixed sample
Authors: Hannan Riley T , Barker Dayton , Cox Brendan P , Roosa Colleen A , Harper Taylor A. , Solga Michael D. , Griffin Donald R. , Sturek Jeffrey M. 
Published: November 2024

AbstractSample multiplexing in flow cytometry is a powerful technique which allows for reduction of error, inclusion of control samples for batch effect correction, and reduction in both time and consumable usage. Current industry standard for barcoding in mass cytometry is an intracellular reagent, which requires fixation and permeabilization of sample prior to barcoding. We developed a barcode using the ubiquitous and well-tolerated membrane labeling lectin, wheat germ agglutinin. This barcode effectively labels all tested cell types, both live and fixed. We determine that barcode yields, or the ratio of debarcoded cells to total input cells, is stable in live pooled sample for at least an hour. This barcode does not show differential performance across major PBMC lineages. Thus, this universal wheat germ agglutinin-based barcode represents an advance in gentle, non-reactive cell surface barcoding for live cells.
Biases in the Parsortix® system observed with pancreatic cancer cell lines
Authors: Vandenbussche Nele , Imschoot Renske , Lintermans Béatrice , Denolf Lode , Taminau Joachim , Fieuws Charlotte , Berx Geert , Gevaert Kris , Claes Kathleen B.M. 
Published: November 2024

AbstractPancreatic cancer has a 5-year survival rate of merely 12%. The high rate of late-stage diagnoses underscores the need for reliable biomarkers for early detection and disease monitoring. Circulating tumor cells (CTCs) have emerged as a promising biomarker, yet their detection remains challenging due to their rarity and phenotypic diversity. This study evaluates the Parsortix® system, a microfluidic device designed to enrich CTCs based on size and deformability, using pancreatic cancer cell lines. As increasing evidence indicates that during epithelial to mesenchymal transition (EMT) a cell’s deformability increases, we evaluated to what extent the Parsortix® system was biased towards epithelial cancer cells. First, the EMT stage of three pancreatic cancer cell lines, CAPAN-1, PANC-1 and MIA PaCa-2, was assessed using immunocytochemistry, flow cytometry and proteomics. CAPAN-1 cells were classified as epithelial, MIA PaCa-2 cells exhibited a mesenchymal-like phenotype, and PANC-1 cells demonstrated a hybrid phenotype. Then, by spiking these cells into blood samples, we determined the Parsortix® system’s ability to recover the cancer cells. Our results indicated that epithelial and hybrid phenotypes are more efficiently captured (62.6 ± 18.5% and 65.4 ± 11.1%) than mesenchymal cancer cells (32.8 ± 10.2%). To confirm these findings, spike-in experiments were repeated using an EMT inducible cell line. Again, significantly lower recovery rates were found for the cells in a mesenchymal-like state (31.5 ± 6.4%) compared to those in an epithelial state (47.56 ± 7.2%). In conclusion, the Parsortix® system may underestimate the presence of mesenchymal CTCs.
L-lactic acid induces short- and long-term cardioprotective effects through MCT1 transport, induction of metabolic reprogramming, and gene expression modulation
Authors: Cler Marina , Pérez-Amodio Soledad , Valls-Lacalle Laura , Martínez-Fraiz Elena , Barba Ignasi , Ganse Freddy G. , Nicastro Laura , Terracciano Cesare M. , Rodríguez-Sinovas Antonio , Engel Elisabeth 
Published: November 2024

AbstractLactic acid is recognized as an alternative fuel source for various tissues and is acknowledged for its protective effects in the brain. However, its potential as a cardioprotective agent remains controversial. Here, we aimed to (1) evaluate the impact of acute L-lactic acid administration, given at the onset of reperfusion, on myocardial infarct size in isolated mouse hearts submitted to transient global ischemia, (2) assess the effects of chronic L-lactic acid exposure in living myocardial slices (LMS) from human hearts, and (3) elucidate the underlying mechanisms. Isolated mouse hearts were submitted to global ischaemia (35 min) followed by reperfusion (60 min), with L-lactic acid being or not administered during the first 15 min of reperfusion. L-lactic acid reduced infarct size by 23% at 20 mmol/L. An acidic Krebs induced less protection, and monocarboxylate transporter 1 (MCT1) inhibition with AR-C 141990 attenuated L-lactic acid’s protection to the level of acidic Krebs.1H NMR spectroscopy revealed significant metabolic changes in L-lactic acid-treated hearts, with pathway enrichment analysis showing a nearly a 3-fold enrichment in pyruvate metabolism, fatty acid biosynthesis, and gluconeogenesis, suggesting a metabolic shift. Moreover, electrically stimulated human LMS treated with L-lactic acid for 48 h exhibited improved contractility and upregulation of structural and functional cardiomyocyte components, stemness-related markers, and pro-angiogenic proteins. These findings support a cardioprotective role for L-lactic acid in both short- and long-term contexts, mediated in part by its uptake through the MCT1 transporter, induction of metabolic reprogramming, and gene expression modulation.
Discovery of A Chimeric Polyketide Family as Cancer Immunogenic Chemotherapeutic Leads
Authors: Xue Dan , Xu Mingming , Madden Michael D. , Lian Xiaoying , Older Ethan A. , Pulliam Conor , Hui Yvonne , Shang Zhuo , Gupta Gourab , Raja Manikanda K. , Wang Yuzhen , Sardi Armando , Long Yaoling , Chen Hexin , Fan Daping , Bugni Tim S. , Testerman Traci L. , Wu Qihao , Li Jie 
Published: November 2024

AbstractDiscovery of cancer immunogenic chemotherapeutics represents an emerging, highly promising direction for cancer treatment that uses a chemical drug to achieve the efficacy of both chemotherapy and immunotherapy. Herein we report a high-throughput screening platform and the subsequent discovery of a new class of cancer immunogenic chemotherapeutic leads. Our platform integrates informatics-based activity metabolomics for rapid identification of microbial natural products with both novel structures and potent activities. Additionally, we demonstrate the use of microcrystal electron diffraction (MicroED) for direct structure elucidation of the lead compounds from partially purified mixtures. Using this strategy to screen geographically and phylogenetically diverse microbial metabolites against pseudomyxoma peritonei, a rare and severe cancer, we discovered a new class of leads, aspercyclicins. The aspercyclicins feature an unprecedented tightly packed polycyclic polyketide scaffold that comprises continuous fused, bridged, and spiro rings. The biogenesis of aspercyclicins involves two distinct biosynthetic pathways, leading to formation of chimeric compounds that cannot be predicted by bottom-up approaches mining natural products biosynthetic genes. With comparable potency to some clinically used anticancer drugs, aspercyclicins are active against multiple cancer cell types by inducing immunogenic cell death (ICD), including the release of damage-associated molecular patterns and subsequent phagocytosis of cancer cells. The broad-spectrum ICD-inducing activity of aspercyclicins, combined with their low toxicity to normal cells, represents a new class of potential cancer immunogenic chemotherapeutics and particularly the first drug lead for pseudomyxoma peritonei treatment.
NOLC1 Suppresses Immuno-chemotherapy by Inhibiting p53-mediated Ferroptosis in Gastric Cancer
Authors: Zhao Shengsheng , Lin Ji , Zhu Bingzi , Jin Yin , Dong Qiantong , Ruan Xiaojiao , Jin Dan , Yi Yongdong , Bai Binglong , Li Hongzheng , Liang Danna , Lu Jianhua , Meng Letian , Wang Xiang , Cui Yuekai , Gu Yuyang , Shen Xian , Lu Xufeng , Rao Shangrui , Sun Weijian 
Published: November 2024

AbstractGastric cancer (GC) is one of the most malignant cancers, and cisplatin (Cis)-based chemotherapy remains the main clinical treatment for GC. However, Cis resistance often occurs, largely limiting its therapeutic efficacy in tumors. Therefore, a better understanding of the drug resistance mechanism could reveal new approaches for improving GC treatment efficacy. Here, we define the integrative role of nucleolar and coiled-body phosphoprotein 1 (NOLC1), a molecular chaperone that is significantly upregulated in GC tissues and Cis-resistant GC cells. Knocking down NOLC1 increased GC sensitivity to Cis by regulating ferroptosis. Mechanistically, NOLC1 binds to the p53 DNA binding domain (DBD), decreasing p53 nuclear translocation stimulated by Cis and suppressing p53 transcriptional functions. Then, the p53-mediated ferroptosis is suppressed. Furthermore, the silence of NOLC1 promoted ferroptosis-induced immunogenic cell death (ICD) and reprogrammed the immunosuppressive tumor microenvironment, thereby increasing sensitivity to anti-programmed cell death-1 (PD-1) therapy plus Cis. The combination of anti-PD-1 plus Cis effectively inhibited GC growth without significant side effects. In summary, our findings reveal that targeting NOLC1 may be a novel therapeutic strategy for GC and may increase the efficacy of chemotherapy combined with immune checkpoint inhibitor (ICI) therapy.