tbuckley/cabot-search huggingface dataset:
Exploring a Local Genetic Interaction Network Using Evolutionary Replay Experiments
Authors: Ryan C Vignogna, Sean W Buskirk, Gregory I Lang
Journal: Molecular Biology and Evolution (2021)

Understanding how genes interact is a central challenge in biology. Experimental evolution provides a useful, but underutilized, tool for identifying genetic interactions, particularly those that involve non-loss-of-function mutations or mutations in essential genes. We previously identified a strong positive genetic interaction between specific mutations in KEL1 (P344T) and HSL7 (A695fs) that arose in an experimentally evolved Saccharomyces cerevisiae population. Because this genetic interaction is not phenocopied by gene deletion, it was previously unknown. Using "evolutionary replay" experiments, we identified additional mutations that have positive genetic interactions with the kel1-P344T mutation. We replayed the evolution of this population 672 times from six timepoints. We identified 30 populations where the kel1-P344T mutation reached high frequency. We performed whole-genome sequencing on these populations to identify genes in which mutations arose specifically in the kel1-P344T background. We reconstructed mutations in the ancestral and kel1-P344T backgrounds to validate positive genetic interactions. We identify several genetic interactors with KEL1, we validate these interactions by reconstruction experiments, and we show these interactions are not recapitulated by loss-of-function mutations. Our results demonstrate the power of experimental evolution to identify genetic interactions that are positive, allele specific, and not readily detected by other methods, shedding light on an underexplored region of the yeast genetic interaction network.
Protective Role of the M-Sec–Tunneling Nanotube System in Podocytes
Authors: Federica Barutta, Shunsuke Kimura, Koji Hase, Stefania Bellini, Beatrice Corbetta, Alessandro Corbelli, Fabio Fiordaliso, Antonella Barreca, Mauro Giulio Papotti, Gian Marco Ghiggeri, Gennaro Salvidio, Dario Roccatello, Valentina Audrito, Silvia Deaglio, Roberto Gambino, Stefania Bruno, Giovanni Camussi, Miriam Martini, Emilio Hirsch, Marilena Durazzo, Hiroshi Ohno, Gabriella Gruden
Journal: Journal of the American Society of Nephrology (2021)

Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored.We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy).Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury.These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.
P18.02 Factors Influencing Multi-Disciplinary Tumor Board Recommendations in Stage III Non-Small Cell Lung Cancer
Authors: M. Ronden, I. Bahce, S. Hashemi, M. Paul, P. De Haan, A. Becker, F. Spoelstra, M. Dahele, C. Dickhoff, M. Tiemessen, D. Van Diepen, S. Tarasevych, E. Looysen, K. Maassen Van Den Brink, N. Haasbeek, J. Daniels, M. Van Laren, R. Roeleveld, B. Alberts, D. De Fraiture, J. Veltman, W. Verbakel, S. Senan
Journal: Journal of Thoracic Oncology (2021)
Abstract 12919: Quantitative Assessment of Cardiovascular Autonomic Impairment in Cancer Survivors: A Single Center Experience
Authors: Benjamin Noor, Shannel Akhavan, Michael Leuchter, Eric H Yang, Olujimi A Ajijola
Journal: Circulation (2020)

Background: Cardiovascular autonomic dysfunction in cancer survivors is poorly understood. Objectives: To better characterize the clinical characteristics and types of autonomic dysfunction in this population. Methods: A retrospective analysis of cancer survivors within an academic cardio-oncology program referred for suspected autonomic dysfunction was performed. Autonomic reflex testing of adrenergic, cardiovagal, and sudomotor function was done. Patients with pre-existing autonomic dysfunction prior to their cancer diagnosis were excluded. Results: Of approximately 282 patients in the UCLA Cardio-Oncology program, twenty-four patients met the inclusion criteria. Twenty-two had autonomic impairment on autonomic reflex testing. Eight patients were female, and the mean age at time of autonomic testing was 51.3 years. The average duration from cancer diagnosis to autonomic testing was 10.3 years. The reasons for referral included dizziness, tachycardia, palpitations, and syncope. The majority of patients (75%) had hematologic disorders. The most common chemotherapies administered were vinca alkaloids (54.2%), alkylating agents (66.7%), and anthracyclines (54.2%). Most patients received radiation to the thorax (66.7%) and neck (53.3%). Eleven patients had mild autonomic impairment, seven had moderate, and four had severe autonomic impairment. Dysfunction was commonly present in the sympathetic and parasympathetic branches, but most pronounced in the sympathetic system. The majority of patients were diagnosed with orthostatic hypotension (50%), inappropriate sinus tachycardia (20.8%), and postural orthostatic tachycardia syndrome (12.5%) and had subjective improvement with treatment. Conclusion: Cardiovascular autonomic dysfunction occurs in cancer survivors, and commonly affects both the sympathetic and parasympathetic systems. Symptom recognition in patients should prompt autonomic testing and treatment where appropriate.
MA08.11 Identification of Clinical Features to Predict the Consistency of Mutational Profiles Obtained From Plasma and Tissue of Advanced NSCLC Patient
Authors: X. Jiao, B. Qin, K. Liu, Y. Wu, J. Liu, X. He, M. Lin, Y. Lin, X. Duan, H. Wang, L. Shao, J. Zheng, Y. Zang
Journal: Journal of Thoracic Oncology (2021)
P43.04 Efficient Isolation and Quantification of CTC in NSCLC Patients using Peptide-Functionalized Magnetic Nanoparticles
Authors: N. Liang, L. Liu, P. Li, Y. Xu, Y. Hou, J. Peng, Y. Song, Z. Bing, Y. Wang, Y. Wang, Z. Jia, X. Yang, D. Li, H. Xu, Q. Yu, S. Li, Z. Hu, Y. Yang
Journal: Journal of Thoracic Oncology (2021)
What is my covid risk?
Authors: Samuel Finnikin, David J Spiegelhalter
Journal: BMJ (2021)

Bupropion, widely used as an antidepressant and smoking cessation aid, undergoes complex metabolism to yield numerous metabolites with unique disposition, effect, and drug–drug interactions (DDIs) in humans. The stereoselective plasma and urinary pharmacokinetics of bupropion and its metabolites were evaluated to understand their potential contributions to bupropion effects. Healthy human volunteers (<i>n</i> = 15) were administered a single oral dose of racemic bupropion (100 mg), which was followed by collection of plasma and urine samples and determination of bupropion and metabolite concentrations using novel liquid chromatography–tandem mass spectrometry assays. Time-dependent, elimination rate–limited, stereoselective pharmacokinetics were observed for all bupropion metabolites. Area under the plasma concentration-time curve from zero to infinity ratios were on average approximately 65, 6, 6, and 4 and <i>C</i><sub>max</sub> ratios were approximately 35, 6, 3, and 0.5 for (2<i>R</i>,3<i>R</i>)-/(2<i>S</i>,3<i>S</i>)-hydroxybupropion, <i>R</i>-/<i>S</i>-bupropion, (1<i>S</i>,2<i>R</i>)-/(1<i>R</i>,2<i>S</i>)-erythrohydrobupropion, and (1<i>R</i>,2<i>R</i>)-/(1<i>S</i>,2<i>S</i>)-threohydrobupropion, respectively. The <i>R</i>-/<i>S</i>-bupropion and (1<i>R</i>,2<i>R</i>)-/(1<i>S</i>,2<i>S</i>)-threohydrobupropion ratios are likely indicative of higher presystemic metabolism of <i>S</i>- versus <i>R</i>-bupropion by carbonyl reductases. Interestingly, the apparent renal clearance of (2<i>S</i>,3<i>S</i>)-hydroxybupropion was almost 10-fold higher than that of (2<i>R</i>,3<i>R</i>)-hydroxybupropion. The prediction of steady-state pharmacokinetics demonstrated differential stereospecific accumulation [partial area under the plasma concentration-time curve after the final simulated bupropion dose (300–312 hours) from 185 to 37,447 nM⋅h] and elimination [terminal half-life of approximately 7–46 hours] of bupropion metabolites, which may explain observed stereoselective differences in bupropion effect and DDI risk with CYP2D6 at steady state. Further elucidation of bupropion and metabolite disposition suggests that bupropion is not a reliable in vivo marker of CYP2B6 activity. In summary, to our knowledge, this is the first comprehensive report to provide novel insight into mechanisms underlying bupropion disposition by detailing the stereoselective pharmacokinetics of individual bupropion metabolites, which will enhance clinical understanding of bupropion’s effects and DDIs with CYP2D6.
Covid-19: Middle aged women face greater risk of debilitating long term symptoms
Authors: Ingrid Torjesen
Journal: BMJ (2021)

Covid-19: Middle aged women face greater risk of debilitating long term symptoms Ingrid TorjesenMiddle aged women have a higher risk of experiencing a range of debilitating ongoing symptoms, such as fatigue, breathlessness, muscle pain, anxiety, depression, and "brain fog" after hospital treatment for covid-19, suggest the findings of two unpublished studies available as preprints.
New machine learning model predicts who may benefit most from COVID-19 vaccination
Authors: Leia Wedlund, Joseph Kvedar
Journal: npj Digital Medicine (2021)

As the COVID-19 vaccine roll-out continues, a vigorous debate rages over who should receive the limited available doses.While the CDC and state governments struggle to prioritize vaccine recipients based on occupation, demographics, and comorbidities, researchers at Mass General Brigham have developed a precise new tool to identify which individuals may benefit most from vaccination.A new machine learning model, described in npj Digital Medicine this February by Estiri et al. 1 , uses electronic health records to accurately predict an individual's probability of death if they are infected with COVID-19.While many models created over the past year have predicted COVID-19 mortality based on vitals and labs collected during hospitalization 2,3 , this one provides a more widely applicable tool that allows clinicians to predict which currently uninfected individuals might derive the greatest benefit from vaccination.Until this point, attempts to identify and vaccinate the most vulnerable have relied on broad demographic categories (e.g.: age >65, obesity, history of cancer).However, these groupings describe heterogeneous populations, and sorting people in this way cannot guarantee that those most at risk truly receive the highest priority.The work of Estiri et al. represents a significant breakthrough because it is the first step towards a maximally precise resource-allocation system that could give individuals priority based on their unique health history and risk of mortality.This work has implications far beyond the distribution of COVID-19 vaccines.With hospitals worldwide facing finite resources, such a model could help allocate therapies and equipment to those most at-risk, maximizing survival.We have only scratched the surface of what is possible with an evergrowing electronic health record and increasingly accurate predictive analytics.
Manganese-deposited iron oxide promotes tumor-responsive ferroptosis that synergizes the apoptosis of cisplatin
Authors: Junjie Cheng, Yang Zhu, Xin Xing, Jianmin Xiao, Hui Chen, Hongwei Zhang, Dan Wang, Yuanyuan Zhang, Guilong Zhang, Zhengyan Wu, Yangzhong Liu
Journal: Theranostics (2021)

Ferroptosis is a form of iron-dependent programmed cell death that differs from apoptosis with regards to both mechanism and cell morphology. Therefore, ferroptotic-based cancer therapy has shown significant potential to overcome the weaknesses of conventional therapeutics mediated by apoptosis pathways. Effective ferroptosis can be induced by the intracellular Fenton reaction that is dependent on the adequate supply of iron ions and H
MA11.05 Tepotinib in Patients with MET exon 14 (METex14) Skipping Advanced NSCLC: Updated Efficacy Results from VISION Cohort A
Authors: P. Paik, H. Sakai, E. Felip, R. Veillon, M.C. Garassino, J. Raskin, S. Viteri, J. Mazieres, A. Cortot, E. Smit, M. Thomas, B.C. Cho, P. Conte, J.C. Yang, M. Morise, Y. Chen, K. Park, M. Gottfried, C. Britschgi, R. Bruns, G. Otto, A. Johne, X. Le
Journal: Journal of Thoracic Oncology (2021)
Markers for the involvement of endothelial cells and the coagulation system in chronic urticaria: A systematic review
Authors: Yora Mostmans, Katleen De Smedt, Bertrand Richert, Daniel Elieh Ali Komi, Marcus Maurer, Olivier Michel
Journal: Allergy (2021)

Chronic urticaria (CU) is a chronic inflammatory mast cell-driven disorder. Endothelial cells (ECs) contribute importantly to key features of CU. Several markers of EC (dys)function in CU have been reported, but have not yet been systematically reviewed. In this study, we systematically reviewed and categorized all published markers of EC functions in CU through a comprehensive search in Pubmed, The Cochrane Library, Web of Science, and SCOPUS using the following Mesh terms: CU AND pathogenesis AND (vasculopathy OR microangiopathy OR ECs OR marker). In total, 79 articles were selected and the identified biomarkers were categorized according to EC (dys)function in CU. The most frequent and consistently reported upregulated biomarkers in CU skin were adhesion molecules, TF, and P-selectin. The most frequently reported upregulated and reliable biomarkers in sera of CU patients were F1+2 for coagulation cascade involvement, D-dimers for fibrinolysis, and MMP-9 for vascular permeability. Emerging biomarkers described in the selected articles were endostatin, heat shock proteins, cleaved high molecular weight kininogen, and adipokines. This systematic review contributes to the pool of growing evidence for vascular involvement in CU where EC dysfunction is present in different aspects of cell survival, maintenance of vascular structure, and coagulation/fibrinolysis balance.
Professional Use of Social Media by Hepatology Providers
Authors: Patricia P. Bloom, Scott Matherly, Sonal Kumar, Christopher Koh
Journal: Hepatology (2021)

Scenario 4 also raises the issue of the permanence and infinite audience reach of social media posts.While the provider in this scenario may think they only have a few followers, and those followers are their friends, public social media accounts are actually accessible by anyone.In addition, many posts are searchable and can be found years later.One solution is to have two separate accounts on a given platform.However, if your personal account can still be traced to you or your institution, all of the expectations of professional integrity stand. ConclusionWhile we enjoy the benefits of social media, it is important to simultaneously uphold institutional guidelines, maintain patient privacy, avoid providing medical care via social media, and most importantly, do no harm.
Adverse childhood experiences and asthma: trajectories in a national cohort
Authors: Kathrine Pape, Whitney Cowell, Camilla Sandal Sejbaek, Niklas Worm Andersson, Cecilie Svanes, Henrik Albert Kolstad, Xiaoqin Liu, Karin Sørig Hougaard, Rosalind J Wright, Vivi Schlünssen
Journal: Thorax (2021)

Objective Research has linked early adverse childhood experiences (ACEs) with asthma development; however, existing studies have generally relied on parent report of exposure and outcome. We aimed to examine the association of early life ACEs with empirically determined trajectories of childhood asthma risk, using independent register information on both exposures and outcome. Methods Based on nationwide registries, we established a study cohort of 466 556 children born in Denmark (1997–2004). We obtained information on ACEs during the first 2 years of life (bereavement, parental chronic somatic and/or mental illness) and childhood asthma diagnosis or medication use from birth through age 10 years from the Danish National Patient and Prescription Registries, respectively. We identified asthma phenotypes using group-based trajectory modelling. We then used multinomial logistic regression to examine the association between early ACEs and asthma phenotypes. Results We identified four asthma phenotypes: non-asthmatic, early-onset transient, early-onset persistent and late-onset asthma. Girls with early-onset transient asthma (OR 1.13, 95% CI 1.04 to 1.24), early-onset persistent asthma (1.27, 95% CI 1.08 to 1.48) or late-onset asthma (OR 1.28, 95% CI 1.11 to 1.48) vs no asthma were more likely to have early life ACE exposure compared with girls without ACE exposure. Results were similar for boys who also had experienced early life ACEs with ORs of 1.16 (95% CI 1.08 to 1.25), 1.34 (95% CI 1.20 to 1.51) and 1.11 (95% CI 0.98 to 1.25), respectively. Conclusion In a nationwide-population study, we identified three childhood onset asthma phenotypes and found that ACEs early in life were associated with increased odds for each of these asthma phenotypes among both girls and boys.
Peripheral Nerve Resident Macrophages and Schwann Cells Mediate Cancer-Induced Pain
Authors: Francesco De Logu, Matilde Marini, Lorenzo Landini, Daniel Souza Monteiro de Araujo, Niccolò Bartalucci, Gabriela Trevisan, Gennaro Bruno, Martina Marangoni, Brian L. Schmidt, Nigel W. Bunnett, Pierangelo Geppetti, Romina Nassini
Journal: Cancer Research (2021)

Abstract Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of Trpa1 revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain. Significance: Schwann cell TRPA1 sustains cancer pain through release of M-CSF and oxidative stress, which promote the expansion and the proalgesic actions of intraneural macrophages.
Bisphosphonate Use and Breast Cancer Risk among Women with Ductal Carcinoma <i>In Situ</i>
Authors: Christopher I. Li, Meghan R. Flanagan, Mei-Tzu C. Tang, Peggy L. Porter, Kathleen E. Malone
Journal: Cancer Research (2021)

Abstract Women with a history of ductal carcinoma in situ (DCIS) have an elevated risk of a subsequent invasive breast cancer, but there are few established potentially modifiable factors known to lower this risk. Bisphosphonates are a commonly used treatment for patients with osteoporosis and have been shown to lower risks of recurrence and mortality in patients with invasive breast cancer; however, their use has not previously been investigated within the context of DCIS. Utilizing a population-based nested case–control design, we compared 301 cases of women diagnosed with DCIS and a subsequent breast cancer and 587 individually matched controls (on age, DCIS diagnosis year, primary treatment, histology, grade, and disease-free survival time) who were diagnosed with DCIS but never a subsequent breast cancer. Information on recency and duration of bisphosphonate use was ascertained from patient interviews and medical record reviews. Current users of bisphosphonates had a reduced risk of developing an invasive breast cancer compared with never users [OR = 0.50; 95% confidence interval (CI): 0.26–0.99]. Users of bisphosphonates for ≥48 months had a similar reduction in risk (OR = 0.45; 95% CI, 0.24–1.06). This is the first study to document that bisphosphonate use is associated with a lower risk of subsequent invasive breast cancer among women with a history of DCIS. This finding is consistent with the protective effect of bisphosphonates observed in other breast cancer settings. If validated by others, bisphosphonates may be an effective risk-reducing approach with the potential added benefits of its positive impacts on bone health and fracture risk. Significance: This study finds that bisphosphonate use among women with a history of DCIS is associated with lower risk of subsequent invasive breast cancer, providing a potential preventative approach for this high-risk population.
P84.05 Efficacy and Safety of Ceritinib 450-mg Fed vs 750-mg Fasted in Patients with ALK+ NSCLC: Final Report of the ASCEND-8 Trial
Authors: B.C. Cho, D. Kim, S. Laurie, M. Mckeage, G. Borra, K. Park, S. Kim, M. Ghosn, A. Ardizzoni, A. Greystoke, M. Izquierdo, Y. Wang, L. Wang, A. Wrona
Journal: Journal of Thoracic Oncology (2021)