tbuckley/cabot-search huggingface dataset:
Preclinical and Clinical Characterization of Fibroblast-derived Neuregulin-1 on Trastuzumab and Pertuzumab Activity in HER2-positive Breast Cancer
Authors: Cristina Guardia, Giampaolo Bianchini, Oriol Arpí-LLucià, Silvia Menendez, David Casadevall, Barbara Galbardi, Matteo Dugo, Sonia Servitja, Juan Carlos Montero, Luis Soria-Jiménez, MohammadA Sabbaghi, Raul Peña, Juan Madoz-Gúrpide, Belen Lloveras, Ana Lluch, Pilar Eroles, Joaquin Arribas, Atanasio Pandiella, Luca Gianni, Federico Rojo, Ana Rovira, Joan Albanell
Journal: Clinical Cancer Research (2021)

To characterize expression of neuregulin-1 (NRG1), an HER3 ligand, in HER2-positive breast cancer and its relation with the efficacy of trastuzumab with or without pertuzumab.Characterization of NRG1 expression in tumor cell lines, in tumor specimens, and in cancer-associated fibroblasts (CAFs). Patient-derived CAFs were used to investigate NRG1 impact on the activity of trastuzumab with or without pertuzumab in HER2-positive breast cancer cells. The relationship between NRG1 expression and pathologic response to anti-HER2-based neoadjuvant therapy was assessed in a retrospective patient cohort and in the NeoSphere trial.NRG1 was expressed in HER2-positive breast cancer-derived fibroblasts at significantly higher levels than in cancer cells. NRG1 and the conditioned media (CM) from CAFs phosphorylated HER3 and AKT in cancer cells and mediated trastuzumab resistance. Stable genetic depletion of NRG1 from CAFs overcame trastuzumab resistance. Pertuzumab effectively suppressed trastuzumab resistance mediated by either NRG1 or CAF's CM. NRG1 engaged an epithelial-to-mesenchymal transition that was prevented by trastuzumab and pertuzumab. In clinical samples, stromal and/or tumor cell expression of NRG1 determined by immunohistochemistry was uncommon (13.2%) yet significantly linked with residual disease following trastuzumab-based neoadjuvant therapy. In the NeoSphere trial, the magnitude of the difference of pathologic complete response rates favoring the pertuzumab arm was higher in the NRG1-high group.CAF-derived NRG1 mediates trastuzumab resistance through HER3/AKT, which might be reverted by pertuzumab. In patients with HER2-positive breast cancer, high expression of NRG1 was associated to poor response to trastuzumab, but not in combination with pertuzumab.
Shell-mediated phagocytosis to reshape viral-vectored vaccine-induced immunity
Authors: Fengling Feng, Haibin Hao, Jin Zhao, Yanjun Li, Ying Zhang, Ruiting Li, Ziyu Wen, Chunxiu Wu, Minchao Li, Pingchao Li, Ling Chen, Ruikang Tang, Xiaoyu Wang, Caijun Sun
Journal: Biomaterials (2021)
LncRNA BCYRN1-induced autophagy enhances asparaginase resistance in extranodal NK/T-cell lymphoma
Authors: Liang Wang, Jing Yang, He-nan Wang, Rui-ying Fu, Xin-di Liu, Ying-shi Piao, Li-qiang Wei, Jing-wen Wang, Luo Zhang
Journal: Theranostics (2020)

Background: Asparaginase (ASP) is the cornerstone drug in the treatment of extranodal NK/T-cell lymphoma (ENKTCL), and the mechanisms of resistance to ASP remain largely unknown. Long non-coding RNAs play important roles in chemotherapy resistance in various cancers. However, the expression of BCYRN1 and its role in ENKTCL still remain unidentified. Methods: Lentivirus-mediated BCYRN1 overexpression and knockdown were performed in SNK-6 cells. Cell autophagy was analyzed by adenovirus expressing GFP-LC3B fusion protein. RNA pull-down and RNA Binding Protein Immunoprecipitation Assay were performed to investigate the relationship between BCYRN1 and p53. Western blot analysis was performed to assess the effect of BCYRN1 on different autophagy pathways. Finally, in vivo xenograft tumor model was constructed to analyze the effect of BCYRN1 on tumor growth and ASP resistance. Results: BCYRN1 was overexpressed in ENKTCL than normal NK cells, and patients with higher expression had significantly inferior progression-free survival (PFS). The IC50 value of ASP was significantly increased in BCYRN1-overexpressed SNK-6 cells and BCYRN1 overexpression could resist the inhibitory effect of ASP on proliferation. ASP could induce concurrent apoptosis and autophagy in ENKTCL, and the latter process was enhanced by overexpression of BCYRN1, mainly through affecting both PI3K/AKT/mTOR and p53/mTOR pathways. BCYRN1 could induce the degradation of p53 via ubiquitination, thus resulting in enhancement of autophagy and ASP resistance, which could be reversed by drug-induced autophagy inhibition. The effect of BCYRN1 on tumor growth and autophagy were confirmed in vivo xenograft model. Conclusions: It was found that BCYRN1 was a valuable prognostic biomarker in ENKTCL. BCYRN1 could promote resistance to ASP by inducing autophagy, which could be reversed by inhibition of autophagy. Our findings highlight the feasibility of combining autophagy inhibition and ASP in the treatment of ENKTCL.
Prostatic Cancer, Hypogonadism, and Insulin Resistance
Authors: John A. Kiayias, Eugenia D. Vlachou, Sofoklis Bakides, Eudokia Petridou, Ilias N. Migdalis
Journal: Diabetes Care (2006)

A 47-year-old Greek diabetic man presented with erectile dysfunction and a decrease in sexual desire. The patient had type 2 diabetes for the previous 8 years and was on treatment with rosiglitazone and metformin with strict glycemic control (HbA1c 5.8%). No symptoms or signs of neuropathy were present. Hypogonadotrophic hypogonadism was found.

His plasma testosterone level was very low (100 ng/dl [reference range 300–1,000]) and there was no luetinizing hormone response to luetinizing hormone–releasing hormone (LHRH) test. Further work-up with a magnetic resonance imaging scan and hypophyseal function tests did not reveal any space-occupying lesions of the hypothalamic pituitary site.

The process led to the diagnosis of idiopathic hypogonadotropic hypogonadism. On further work-up, the patient was found to have a prostatic carcinoma. …
P-163 Real-world outcomes of cisplatin, capecitabine and gemcitabine with either epirubicin (PEXG) or docetaxel (PDXG) as first-line palliative treatment in metastatic or unresectable locally advanced pancreatic adenocarcinoma
Authors: N. Waldron, N. Hitchen, S. Deva, G. Rivalland, M. Findlay, B. Lawrence
Journal: Annals of Oncology (2021)
Effect of unplanned athletic movement on knee mechanics: a systematic review with multilevel meta-analysis
Authors: Florian Giesche, Felix Stief, David A Groneberg, Jan Wilke
Journal: British Journal of Sports Medicine (2021)

To compare the effects of pre-planned and unplanned movement tasks on knee biomechanics in uninjured individuals.Systematic review with meta-analysis.Five databases (PubMed, Google Scholar, Cochrane Library, ScienceDirect and Web of Science) were searched from inception to November 2020. Cross-sectional, (randomised) controlled/non-controlled trials comparing knee angles/moments of pre-planned and unplanned single-leg landings/cuttings were included. Quality of evidence was assessed using the tool of the Grading of Recommendations Assessment, Development and Evaluation working group.A multilevel meta-analysis with a robust random-effects meta-regression model was used to pool the standardised mean differences (SMD) of knee mechanics between pre-planned and unplanned tasks. The influence of possible effect modifiers (eg, competitive performance level) was examined in a moderator analysis.Twenty-five trials (485 participants) with good methodological quality (Downs and Black) were identified. Quality of evidence was downgraded due to potential risk of bias (eg, confounding). Moderate-quality evidence indicates that unplanned tasks evoked significantly higher external knee abduction (SMD: 0.34, 95% CI: 0.16 to 0.51, 14 studies) and tibial internal rotation moments (SMD: 0.51, 95% CI: 0.23 to 0.79, 11 studies). No significant between-condition differences were detected for sagittal plane mechanics (p>0.05). According to the moderator analysis, increased abduction moments particularly occurred in non-professional athletes (SMD: 0.55, 95% CI: 0.14 to 0.95, 5 studies).Unplanned movement entails higher knee abduction and tibial internal rotation moments, which could predispose for knee injury. Exercise professionals designing injury-prevention protocols, especially for non-elite athletes, should consider the implementation of assessments and exercises requiring time-constrained decision-making.CRD42019140331.
Using multimarker screening to identify biomarkers associated with cardiovascular death in patients with atrial fibrillation
Authors: Tymon Pol, Ziad Hijazi, Johan Lindbäck, Jonas Oldgren, John H Alexander, Stuart J Connolly, John W Eikelboom, Michael D Ezekowitz, Christopher B Granger, Renato D Lopes, Salim Yusuf, Agneta Siegbahn, Lars Wallentin
Journal: Cardiovascular Research (2021)

Atrial fibrillation (AF) is associated with higher mortality. Biomarkers may improve the understanding of key pathophysiologic processes in AF that lead to death. Using a new multiplex analytic technique, we explored the association between 268 biomarkers and cardiovascular (CV) death in anticoagulated patients with AF.A case-cohort design with 1.8- to 1.9-year follow-up. The identification cohort included 517 cases and 4057 randomly selected patients from ARISTOTLE. The validation cohort included 277 cases and 1042 randomly selected controls from RE-LY. Plasma collected at randomization was analysed with conventional immunoassays and the OLINK proximity extension assay panels: CVDII, CVDIII, and Inflammation. Association between biomarkers and CV death was evaluated using Random Survival Forest, Boruta, and adjusted Cox-regression analyses. The biomarkers most strongly and consistently associated with CV death were as follows (hazard ratio for inter-quartile comparison [95% CI]): N-terminal pro-B-type natriuretic peptide [NT-proBNP; 1.63 (1.37-1.93)], cardiac troponin T [cTnT-hs; 1.60 (1.35-1.88)], interleukin-6 [IL-6; 1.29 (1.13-1.47)], growth differentiation factor-15 [GDF-15; 1.30 (1.10-1.53)], fibroblast growth factor 23 [FGF-23; 1.21 (1.10-1.33)], urokinase receptor [uPAR; 1.38 (1.16-1.64)], trefoil factor 3 [TFF3; 1.27 (1.10-1.46)], tumour necrosis factor receptor 1 [TNFR1; 1.21 (1.01-1.45)], TNF-related apoptosis-inducing ligand receptor 2 [TRAILR2; 1.18 (1.04-1.34)], and cathepsin L1 [CTSL1; 1.22 (1.07-1.39)].In this comprehensive screening of 268 biomarkers in anticoagulated patients with AF, the underlying mechanisms most strongly associated with CV death were cardiorenal dysfunction (NT-proBNP, cTnT-hs, CTSL1, TFF3), oxidative stress (GDF-15), inflammation (IL-6, GDF-15), calcium balance, vascular and renal dysfunction (FGF-23), fibrinolysis (suPAR), and apoptosis (TNFR1, TRAILR2). These findings provide novel insights into pathophysiologic aspects associated with CV death in AF.NCT00412984 and NCT00262600.
Reduced pannexin 1–IL-33 axis function in donor livers increases risk of MRSA infection in liver transplant recipients
Authors: Hao Li, Xiaoyu Yu, Baojie Shi, Kun Zhang, Liyun Yuan, Xueni Liu, Pusen Wang, Junwei Lv, Guangxun Meng, Qiankun Xuan, Wenjuan Wu, Bin Li, Xiao Peng, Xuebin Qin, Wanqing Liu, Lin Zhong, Zhihai Peng
Journal: Science Translational Medicine (2021)

PANX1 modulates innate immunity in the liver via the ATP–P2X2–NLRP3–IL-33 axis and is a therapeutic target for posttransplantation MRSA infection.
Cigarette smoke promotes oral leukoplakia via regulating glutamine metabolism and M2 polarization of macrophage
Authors: Yanan Zhu, Shuo Zhang, Jiahui Sun, Tingting Wang, Qin Liu, Guanxi Wu, Yajie Qian, Weidong Yang, Yong Wang, Wenmei Wang
Journal: International Journal of Oral Science (2021)

Abstract Oral immunosuppression caused by smoking creates a microenvironment to promote the occurrence and development of oral mucosa precancerous lesions. This study aimed to investigate the role of metabolism and macrophage polarization in cigarette-promoting oral leukoplakia. The effects of cigarette smoke extract (CSE) on macrophage polarization and metabolism were studied in vivo and in vitro. The polarity of macrophages was detected by flow cytometric analysis and qPCR. Liquid chromatography-mass spectrometry (LC-MS) was used to perform a metabolomic analysis of Raw cells stimulated with CSE. Immunofluorescence and flow cytometry were used to detect the polarity of macrophages in the condition of glutamine abundance and deficiency. Cell Counting Kit-8 (CCK-8), wound-healing assay, and Annexin V-FITC (fluorescein isothiocyanate)/PI (propidium iodide) double-staining flow cytometry were applied to detect the growth and transferability and apoptosis of Leuk-1 cells in the supernatant of Raw cells which were stimulated with CSE, glutamine abundance and deficiency. Hyperkeratosis and dysplasia of the epithelium were evident in smoking mice. M2 macrophages increased under CSE stimulation in vivo and in vitro. In total, 162 types of metabolites were detected in the CSE group. The metabolites of nicotine, glutamate, arachidic acid, and arginine changed significantly. The significant enrichment pathways were also selected, including nicotine addiction, glutamine and glutamate metabolism, and arginine biosynthesis. The results also showed that the supernatant of Raw cells stimulated by CSE could induce excessive proliferation of Leuk-1 and inhibit apoptosis. Glutamine abundance can facilitate this process. Cigarette smoke promotes oral leukoplakia via regulating glutamine metabolism and macrophage M2 polarization.
Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2
Authors: Juan Ángel Patiño-Galindo, Ioan Filip, Ratul Chowdhury, Costas D. Maranas, Peter K. Sorger, Mohammed AlQuraishi, Raul Rabadan
Journal: Genome Medicine (2021)

The emergence of SARS-CoV-2 underscores the need to better understand the evolutionary processes that drive the emergence and adaptation of zoonotic viruses in humans. In the betacoronavirus genus, which also includes SARS-CoV and MERS-CoV, recombination frequently encompasses the receptor binding domain (RBD) of the Spike protein, which is responsible for viral binding to host cell receptors. In this work, we reconstruct the evolutionary events that have accompanied the emergence of SARS-CoV-2, with a special emphasis on the RBD and its adaptation for binding to its receptor, human ACE2.By means of phylogenetic and recombination analyses, we found evidence of a recombination event in the RBD involving ancestral linages to both SARS-CoV and SARS-CoV-2. We then assessed the effect of this recombination at protein level by reconstructing the RBD of the closest ancestors to SARS-CoV-2, SARS-CoV, and other Sarbecoviruses, including the most recent common ancestor of the recombining clade. The resulting information was used to measure and compare, in silico, their ACE2-binding affinities using the physics-based trRosetta algorithm.We show that, through an ancestral recombination event, SARS-CoV and SARS-CoV-2 share an RBD sequence that includes two insertions (positions 432-436 and 460-472), as well as the variants 427N and 436Y. Both 427N and 436Y belong to a helix that interacts directly with the human ACE2 (hACE2) receptor. Reconstruction of ancestral states, combined with protein-binding affinity analyses, suggests that the recombination event involving ancestral strains of SARS-CoV and SARS-CoV-2 led to an increased affinity for hACE2 binding and that alleles 427N and 436Y significantly enhanced affinity as well.We report an ancestral recombination event affecting the RBD of both SARS-CoV and SARS-CoV-2 that was associated with an increased binding affinity to hACE2. Structural modeling indicates that ancestors of SARS-CoV-2 may have acquired the ability to infect humans decades ago. The binding affinity with the human receptor would have been subsequently boosted in SARS-CoV and SARS-CoV-2 through further mutations in RBD.
Alternatively Spliced Tissue Factor promotes plaque progression, inflammation and angiogenesis in experimental atherosclerosis
Authors: Daniel Alicea, Aleksey Chudnovskiy, David T. Rodriguez, Dong Kwon Yang, Dongtak Jeong, Jason C. Kovacic, Juan J. Badimon, Thomas Weber, Miriam Merad, Roger J. Najjar, Valentin Fuster, Chiara Giannarelli
Journal: Circulation (2014)
The janus-kinase inhibitor ruxolitinib in SARS-CoV-2 induced acute respiratory distress syndrome (ARDS)
Authors: Andreas Neubauer, Johannes Johow, Elisabeth Mack, Andreas Burchert, Damaris Meyn, Andrea Kadlubiec, Iuliu Torje, Hinnerk Wulf, Claus F. Vogelmeier, Joachim Hoyer, Chrysanthi Skevaki, Ralf Michael Muellenbach, Christian Keller, Carmen Schade-Brittinger, Caroline Rolfes, Thomas Wiesmann
Journal: Leukemia (2021)

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 (coronavirus disease 2019), which is associated with high morbidity and mortality, especially in elder patients. Acute respiratory distress syndrome (ARDS) is a life-threatening complication of COVID-19 and has been linked with severe hyperinflammation. Dexamethasone has emerged as standard of care for COVID-19 associated respiratory failure. In a non-randomized prospective phase II multi-center study, we asked whether targeted inhibition of Janus kinase-mediated cytokine signaling using ruxolitinib is feasible and efficacious in SARS-CoV-2- induced ARDS with hyperinflammation. Sixteen SARS-CoV-2 infected patients requiring invasive mechanical ventilation for ARDS were treated with ruxolitinib in addition to standard treatment. Ruxolitinib treatment was well tolerated and 13 patients survived at least the first 28 days on treatment, which was the primary endpoint of the trial. Immediate start of ruxolitinib after deterioration was associated with improved outcome, as was a lymphocyte-to-neutrophils ratio above 0.07. Together, treatment with the janus-kinase inhibitor ruxolitinib is feasible and might be efficacious in COVID-19 induced ARDS patients requiring invasive mechanical ventilation. The trial has been registered under EudraCT-No.: 2020-001732-10 and NCT04359290.
SO-20 Prospective validation of Ang-2 and Tie-2 plasma levels as predictors of benefit from regorafenib in metastatic colorectal cancer patients: REGOLAND study
Authors: C. Antoniotti, F. Marmorino, A. Boccaccino, M. Antista, N. Zaffaroni, G. Zucchelli, A. Martinetti, E. Campi, D. Rossini, E. Sottotetti, B. Borelli, F. Corti, V. Conca, R. Moretto, M. Germani, A. Falcone, M. Giordano, G. Masi, F. Pietrantonio, C. Cremolini
Journal: Annals of Oncology (2021)
Orthology Clusters from Gene Trees with<i>Possvm</i>
Authors: Xavier Grau-Bové, Arnau Sebé-Pedrós
Journal: Molecular Biology and Evolution (2021)

Possvm (Phylogenetic Ortholog Sorting with Species oVerlap and MCL [Markov clustering algorithm]) is a tool that automates the process of identifying clusters of orthologous genes from precomputed phylogenetic trees and classifying gene families. It identifies orthology relationships between genes using the species overlap algorithm to infer taxonomic information from the gene tree topology, and then uses the MCL to identify orthology clusters and provide annotated gene families. Our benchmarking shows that this approach, when provided with accurate phylogenies, is able to identify manually curated orthogroups with very high precision and recall. Overall, Possvm automates the routine process of gene tree inspection and annotation in a highly interpretable manner, and provides reusable outputs and phylogeny-aware gene annotations that can be used to inform comparative genomics and gene family evolution analyses.
PD-4 A phase I trial of trifluridine/tipiracil in combination with nanoliposomal irinotecan in advanced GI cancers
Authors: O. Alese, W. Shaib, M. Akce, M. Diab, M. Issa-Boube, F. Ekundayo, C. Wu, B. El-Rayes
Journal: Annals of Oncology (2021)
Metabolic Profiles of Maori, Pacific, and European New Zealanders With Type 2 Diabetes Over 25 Years
Authors: Dahai Yu, Yamei Cai, Uchechukwu Levi Osuagwu, Karen Pickering, John Baker, Richard Cutfield, Rawiri McKree Jansen, Brandon J. Orr-Walker, Gerhard Sundborn, Zhanzheng Zhao, David Simmons
Journal: Diabetes Care (2021)

The population of New Zealand includes a high proportion of Maori (Indigenous Polynesian) and Pacific (Pasifika) people, who have been shown to experience worse type 2 diabetes mellitus (T2DM) outcomes than New Zealand Europeans (NZE), a phenomenon persisting for >20 years (1). It remains unclear which metabolic targets are not being achieved concurrent with these long-standing disparities in diabetes complications. In this study we compared five key clinical measurements routinely assessed in primary care (systolic blood pressure [SBP], BMI, HbA1c, total cholesterol [TC], and triglyceride [TG]) over time among patients with T2DM from these three main ethnic groups (Maori, NZE, and Pasifika).

For this study we used the Diabetes Care Support Service (DCSS), a primary care diabetes audit program linked with national death registration, hospitalization, pharmaceutical claims, and socioeconomic databases, to identify a cohort of patients with T2DM (1). Ethics review was waived by the New Zealand Health and Disability Ethics Committees on 25 March 2019. Signed consent to participate was provided by an authorized signatory for each general practice.

Adjusted marginal mean SBP, BMI, HbA1c, TC, and TG over baseline and 1, 2, 3, 4, and 5 years of follow-up among Maori, Pasifika, and NZE patients were estimated with mixed-effects models with adjustment for baseline characteristics (age, sex, smoking, socioeconomic status); baseline outcomes (e.g., baseline BMI, HbA1c, TC, and TG for comparing SBP over time); baseline antihypertensive, antidiabetes and lipid-lowering treatments and anticoagulant therapy; and the enrollment period as fixed effects. Multiple …