tbuckley/cabot-search huggingface dataset:
CRISPR-Mediated Kinome Editing Prioritizes a Synergistic Combination Therapy for <i>FGFR1</i>-Amplified Lung Cancer
Authors: Zhang Yang, Shun-Qing Liang, Haitang Yang, Duo Xu, Rémy Bruggmann, Yanyun Gao, Haibin Deng, Sabina Berezowska, Sean R.R. Hall, Thomas M. Marti, Gregor J. Kocher, Qinghua Zhou, Ralph A. Schmid, Ren-Wang Peng
Journal: Cancer Research (2021)

Oncogenic activation of the FGFR pathway is frequent in lung and other cancers. However, due to drug resistance, pharmacological blockage of aberrant FGFR signaling has provided little clinical benefit in patients with FGFR-amplified tumors. The determining factors for the limited efficacy of FGFR-targeted therapy remain incompletely understood. In this study, we performed kinome-wide CRISPR/Cas9 loss-of-function screens in FGFR1-amplified lung cancer cells treated with an FGFR inhibitor. These screens identified PLK1 as a potent synthetic lethal target that mediates a resistance mechanism by overriding DNA damage and cell-cycle arrest upon FGFR1 inhibition. Genetic and pharmacological antagonism of PLK1 in combination with FGFR inhibitor therapy synergized to enhance antiproliferative effects and drove cancer cell death in vitro and in vivo through activation of the γH2AX-CHK-E2F1 axis. These findings suggest a previously unappreciated role for PLK1 in modulating FGFR1 inhibitor sensitivity and demonstrate a synergistic drug combination for treating FGFR1-amplified lung cancer. SIGNIFICANCE: The identification of PLK1 as a potent synthetic lethal target for FGFR-targeted therapy provides an innovative rationale for the treatment of lung and other FGFR1-amplified cancers.
Interferon-alpha for treating polycythemia vera yields improved myelofibrosis-free and overall survival
Authors: Ghaith Abu-Zeinah, Spencer Krichevsky, Tatiana Cruz, Gabriela Hoberman, Diana Jaber, Niamh Savage, Claudia Sosner, Ellen K. Ritchie, Joseph M. Scandura, Richard T. Silver
Journal: Leukemia (2021)
Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation
Authors: Marcel S. Woo, Friederike Ufer, Nicola Rothammer, Giovanni Di Liberto, Lars Binkle, Undine Haferkamp, Jana K. Sonner, Jan Broder Engler, Sönke Hornig, Simone Bauer, Ingrid Wagner, Kristof Egervari, Jacob Raber, Robert M. Duvoisin, Ole Pless, Doron Merkler, Manuel A. Friese
Journal: The Journal of Experimental Medicine (2021)

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with continuous neuronal loss. Treatment of clinical progression remains challenging due to lack of insights into inflammation-induced neurodegenerative pathways. Here, we show that an imbalance in the neuronal receptor interactome is driving glutamate excitotoxicity in neurons of MS patients and identify the MS risk–associated metabotropic glutamate receptor 8 (GRM8) as a decisive modulator. Mechanistically, GRM8 activation counteracted neuronal cAMP accumulation, thereby directly desensitizing the inositol 1,4,5-trisphosphate receptor (IP3R). This profoundly limited glutamate-induced calcium release from the endoplasmic reticulum and subsequent cell death. Notably, we found Grm8-deficient neurons to be more prone to glutamate excitotoxicity, whereas pharmacological activation of GRM8 augmented neuroprotection in mouse and human neurons as well as in a preclinical mouse model of MS. Thus, we demonstrate that GRM8 conveys neuronal resilience to CNS inflammation and is a promising neuroprotective target with broad therapeutic implications.
Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies
Authors: Rita E. Chen, Xianwen Zhang, James Brett Case, Emma S. Winkler, Yang Liu, Laura A. VanBlargan, Jianying Liu, John M. Errico, Xuping Xie, Naveenchandra Suryadevara, Pavlo Gilchuk, Seth J. Zost, Stephen Tahan, Lindsay Droit, Jackson S. Turner, Wooseob Kim, Aaron J. Schmitz, Mahima Thapa, David Wang, Adrianus C. M. Boon, Rachel M. Presti, Jane A. O’Halloran, Alfred H. J. Kim, Parakkal Deepak, Dora Pinto, Daved H. Fremont, James E. Crowe, Davide Corti, Herbert W. Virgin, Ali H. Ellebedy, Pei-Yong Shi, Michael S. Diamond
Journal: Nature Medicine (2021)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo. A comprehensive analysis of antibody neutralization activity against a panel of authentic isolates and chimeric SARS-CoV-2 variants shows markedly diminished neutralizing activity against the variant B.1.351, first identified in South Africa.
Association of Socioeconomic Status With Risk Factor Target Achievements and Use of Secondary Prevention After Myocardial Infarction
Authors: Joel Ohm, Per H. Skoglund, Henrike Häbel, Johan Sundström, Kristina Hambraeus, Tomas Jernberg, Per Svensson
Journal: JAMA Network Open (2021)

Low socioeconomic status (SES) is associated with poor long-term prognosis after myocardial infarction (MI). Plausible underlying mechanisms have received limited study.To assess whether SES is associated with risk factor target achievements or with risk-modifying activities, including cardiac rehabilitation programs, monitoring, and drug therapies, during the first year after MI.This cohort study included a population-based consecutive sample of 30 191 one-year survivors of first-ever MI who were 18 to 76 years of age, resided in the general community in Sweden, were followed up until their routine 11- to 15-month revisit, and were registered in the national registry Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) from 2006 through 2013. Data analyses were performed from January to August 2020.Individual-level SES by proxy disposable income quintile. Secondary exposures were educational level and marital status.Odds ratios (ORs) with 95% CIs for achieved risk factor targets at the 1-year revisit and for use of guideline-recommended secondary prevention activities.The study comprised 30 191 participants (72.9% men) with a mean (SD) age of 63.0 (8.6) years. Overall, higher SES was associated with better target achievements and use of most secondary prevention. The highest (vs lowest) income quintile was associated with achieved smoking cessation (OR, 2.05; 95% CI, 1.78-2.35), target blood pressure levels (OR, 1.17; 95% CI, 1.07-1.27), and glycated hemoglobin levels (OR, 1.57; 95% CI, 1.19-2.06). The highest-income quintile was associated not only with participation in physical training programs (OR, 2.28; 95% CI, 2.11-2.46) and patient educational sessions (OR, 2.29; 95% CI, 2.12-2.47) in cardiac rehabilitation but also with more monitoring of lipid profiles (OR, 1.20; 95% CI, 1.08-1.33) and intensification of statin therapy (OR, 1.22; 95% CI, 1.11-1.35) during the first year after MI. One year after MI, the highest-income quintile was associated with persistent use of statins (OR, 1.26; 95% CI, 1.10-1.45), high-intensity statins (OR, 1.10; 95% CI, 1.00-1.21), and renin-angiotensin-aldosterone system inhibitors (OR, 1.27; 95% CI, 1.08-1.49).Findings indicated that, in a publicly financed health care system, higher SES was associated with better achievement of most risk factor targets, programs aimed at lifestyle change, and evidence-based drug therapies after MI. Observed differences in secondary prevention activity may be a factor in higher long-term risk of recurrent disease among individuals with low SES.
Human cardiosphere-derived stromal cells exposed to SARS-CoV-2 evolve into hyper-inflammatory/<i>pro</i>-fibrotic phenotype and produce infective viral particles depending on the levels of ACE2 receptor expression
Authors: Alessandra Amendola, Gloria Garoffolo, Paola Songia, Roberta Nardacci, Silvia Ferrari, Giacomo Bernava, Paola Canzano, Veronika Myasoedova, Francesca Colavita, Concetta Castilletti, Giuseppe Sberna, Maria Rosaria Capobianchi, Mauro Piacentini, Marco Agrifoglio, Gualtiero Ivanoe Colombo, Paolo Poggio, Maurizio Pesce
Journal: Cardiovascular Research (2021)

Patients with severe respiratory syndrome caused by SARS-CoV-2 undergo cardiac complications due to hyper-inflammatory conditions. Although the presence of the virus has been detected in the myocardium of infected patients, and infection of induced pluripotent cell-derived cardiomyocytes has been demonstrated, the reported expression of Angiotensin-Converting Enzyme-2 (ACE2) in cardiac stromal cells suggests that SARS-CoV-2 may determine cardiac injury by sustaining productive infection and increasing inflammation.We analysed expression of ACE2 receptor in primary human cardiac stromal cells derived from cardiospheres, using proteomics and transcriptomics before exposing them to SARS-CoV-2 in vitro. Using conventional and high sensitivity PCR methods, we measured virus release in the cellular supernatants and monitored the intracellular viral bioprocessing. We performed high-resolution imaging to show the sites of intracellular viral production and demonstrated the presence of viral particles in the cells with electron microscopy. We finally used RT-qPCR assays to detect genes linked to innate immunity and fibrotic pathways coherently regulated in cells after exposure to the virus.Our findings indicate that cardiac stromal cells are susceptible to SARS-CoV-2 infection and produce variable viral yields depending on the extent of cellular ACE2 receptor expression. Interestingly, these cells also evolved towards hyper-inflammatory/pro-fibrotic phenotypes independently of ACE2 levels. Thus, SARS-CoV-2 infection of myocardial stromal cells could be involved in cardiac injury and explain the high number of complications observed in severe cases of COVID-19.
Development of a Biomimetic Hydrogel Based on Predifferentiated Mesenchymal Stem‐Cell‐Derived ECM for Cartilage Tissue Engineering
Authors: Cristina Antich, Gema Jiménez, Juan de Vicente, Elena López‐Ruiz, Carlos Chocarro‐Wrona, Carmen Griñán‐Lisón, Esmeralda Carrillo, Elvira Montañez, Juan A. Marchal
Journal: Advanced Healthcare Materials (2021)

The use of decellularized extracellular matrix (dECM) as a biomaterial has been an important step forward for the development of functional tissue constructs. In addition to tissues and organs, cell cultures are gaining a lot of attention as an alternative source of dECM. In this work, a novel biomimetic hydrogel is developed based on dECM obtained from mesenchymal stem cells (mdECM) for cartilage tissue engineering. To this end, cells are seeded under specific culture conditions to generate an early chondrogenic extracellular matrix (ECM) providing cues and elements necessary for cartilage development. The composition is determined by quantitative, histological, and mass spectrometry techniques. Moreover, the decellularization process is evaluated by measuring the DNA content and compositional analyses, and the hydrogel is formulated at different concentrations (3% and 6% w/v). Results show that mdECM derived hydrogels possess excellent biocompatibility and suitable physicochemical and mechanical properties for their injectability. Furthermore, it is evidenced that this hydrogel is able to induce chondrogenesis of mesenchymal stem cells (MSCs) without supplemental factors and, furthermore, to form hyaline cartilage-like tissue after in vivo implantation. These findings demonstrate for the first time the potential of this hydrogel based on mdECM for applications in cartilage repair and regeneration.
Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER.
Authors: Robert J. Motzer, Toni K. Choueiri, Thomas Powles, Mauricio Burotto, Maria Teresa Bourlon, James J Hsieh, Marco Maruzzo, Amishi Yogesh Shah, Cristina Suarez, Carlos H. Barrios, Martin Eduardo Richardet, Camillo Porta, Jeffrey C. Goh, Yoshihiko Tomita, Jens Bedke, Joshua Zhang, Burcin Simsek, Christian Scheffold, Saurabh Gupta, Andrea B. Apolo
Journal: Journal of Clinical Oncology (2021)

308 Background: First-line NIVO+CABO met primary and secondary efficacy endpoints by improving progression-free survival (PFS; HR 0.51, P &lt; 0.0001), overall survival (OS; HR 0.60, P = 0.0010), and objective response rate (ORR; 55.7% vs 27.1%; P &lt; 0.0001) vs SUN in patients (pts) with aRCC in CheckMate 9ER (Choueiri et al. ESMO 2020). Efficacy benefits with NIVO+CABO vs SUN were consistent across prespecified subgroups including by IMDC risk group, and regardless of tumor PD-L1 expression (database lock for primary analysis, March 30, 2020). Updated analyses are needed to establish durability of benefit with first-line NIVO+CABO and assess outcomes in aRCC pts with sarcomatoid features (sRCC)—an aggressive histologic subtype associated with poor prognoses. Methods: In this phase III open-label trial, adults with confirmed aRCC (with a clear cell component including those with sRCC) were randomized 1:1 (stratified by IMDC risk score, tumor PD-L1 expression, geographic region) to NIVO 240 mg IV Q2W + CABO 40 mg PO QD vs SUN 50 mg PO (4 weeks of 6-week cycles). The primary endpoint was RECIST v1.1-defined PFS by blinded independent central review (BICR) in all randomized (intent-to-treat [ITT]) pts; secondary endpoints included OS, ORR by BICR, and safety. Pts with and without sRCC were identified by local pathology report, and outcomes in these pts were evaluated via prespecified supportive subset analyses. Results: The presence of sRCC was assessed in ITT pts (N = 651) at enrollment. Overall, 75 (11.5%) pts had sRCC and 557 (85.6%) did not; sRCC status was not reported in 19 pts (2.9%). Overall, 34 vs 41 pts with sRCC were randomized to NIVO+CABO vs SUN, respectively. At a median follow-up of 18.1 months, NIVO+CABO improved PFS, OS, and ORR in sRCC pts vs SUN (Table). Notable PFS, OS, and ORR benefits were observed with NIVO+CABO vs SUN in the subgroup of pts without sRCC. Median PFS was doubled, the risk of death was lower, and ORR was consistently higher with NIVO+CABO vs SUN regardless of sarcomatoid status. Key updated PFS, OS, response, and safety outcomes in the ITT population and in pts with and without sRCC will be reported with additional follow-up based on a September 10, 2020 database lock. Conclusions: NIVO+CABO demonstrated improved efficacy and prolonged survival vs SUN in previously untreated aRCC pts regardless of sarcomatoid status. Updated results with extended follow-up will assess the durability of outcomes in this trial. Clinical trial information: NCT03141177 . [Table: see text]
Exploring the synergistic effects of cabozantinib (cabo) and a programmed cell death protein 1 (PD1) inhibitor in metastatic renal cell carcinoma (mRCC) with artificial intelligence (AI).
Authors: Ignacio Duran, Luis Costa, Javier Puente, Urbano Anido, Lidia Martin, Jessica Gómez, Daniel Castellano
Journal: Journal of Clinical Oncology (2021)

e16555 Background: Nonclinical and clinical data suggest that cabo with a PD1 inhibitor provides synergistic antitumor activity in patients with mRCC, possibly by a cabo-induced switch to an immunopermissive tumor microenvironment. We used a complementary, unbiased, AI approach to gain a holistic view of the complex interplay between multiple pathways, cells and molecules and identify the mechanisms that may underpin this synergism. Methods: Biological targets associated with mRCC pathophysiology or drug actions were identified from proteomic, genomic and transcriptomic databases and literature. Using systems- and AI-based technology, the data were integrated using machine learning into mathematical models of the human mRCC protein network topology. The combined effects of cabo and a PD1 inhibitor on biological targets were simulated assuming target receptors were fully activated or fully inhibited. Relevant effects on known cancer processes (e.g. angiogenesis, metastasis, cell proliferation, immune evasion) were identified using artificial neural networks. Biologically plausible synergistic mechanisms were described with sampling methods. Results: Inhibition of VEGF/VEGFR and GAS6/TAMR axes by cabo enhanced the known effects of PD1 inhibitors on immune evasion mechanisms by modulating multiple humoral and cellular components of the innate and adaptive immune responses (Table). PD1 inhibitors further enhanced the anti-angiogenic and tumor pro-apoptotic effects of cabo by modulating pro- and anti-angiogenic factors and T cell cytotoxicity. Conclusions: These data provide a mechanistic rationale and further support for the beneficial combination of cabo and a PD1 inhibitor and may guide future nonclinical and clinical research.[Table: see text]
Rosuvastatin for the prevention of venous thromboembolism: a pooled analysis of the HOPE-3 and JUPITER randomized controlled trials
Authors: Philip Joseph, Robert Glynn, Eva Lonn, Chinthanie Ramasundarahettige, John Eikelboom, Jean MacFadyen, Paul Ridker, Salim Yusuf
Journal: Cardiovascular Research (2021)

To examine the association between rosuvastatin and VTE risk, and whether effects vary in different subpopulations stratified by key demographic, cardiovascular disease (CVD) risk factors, and other risk factors associated with VTE.An individual participant data meta-analysis was conducted across two randomized controlled trials in 30 507 participants over a mean follow-up of 3.62 years, individuals had no prior history of vascular disease but were at intermediate CV risk. In both trials, participants were randomized to receive rosuvastatin or matching placebo. The primary outcome was VTE during follow-up, defined as either deep vein thrombosis or pulmonary embolism. Associations between rosuvastatin and VTE were examined in the overall pooled cohort, and subpopulations stratified by demographic risk factors (i.e. age and sex), CVD risk factors (i.e. obesity, smoking, lipid levels, blood pressure levels, and C-reactive protein level), and a history of cancer. Mean age was 65.96 (SD 7.19) years of age, and 17 832 (58.45%) were male and 5434 (17.82%) were smokers, median BMI was 27.6 [interquartile range (IQR) 24.7-31.1] kg/m2, and median CRP level was 3.4 (IQR 2.1-6.0) mg/L. There were 139 VTE events. In the pooled cohort, rosuvastatin was associated with a large proportional reduction in the risk of VTE (hazard ratio 0.53, 95% CI 0.37-0.75). No significant interactions were observed between treatment with rosuvastatin and the risk of VTE across subpopulations stratified by demographic, CVD risk factors, or a history of cancer (P-values for interactions >0.05 for all subgroups).Rosuvastatin is associated with a 47% proportional reduction in the risk of VTE, and its effect is consistent both in the presence or absence of VTE-related clinical risk factors.
Temporal Associations Among Body Mass Index, Fasting Insulin, and Systemic Inflammation
Authors: Natasha Wiebe, Feng Ye, Ellen T. Crumley, Aminu Bello, Peter Stenvinkel, Marcello Tonelli
Journal: JAMA Network Open (2021)

Obesity is associated with a number of noncommunicable chronic diseases and is purported to cause premature death.To summarize evidence on the temporality of the association between higher body mass index (BMI) and 2 potential mediators: chronic inflammation and hyperinsulinemia.MEDLINE (1946 to August 20, 2019) and Embase (from 1974 to August 19, 2019) were searched, although only studies published in 2018 were included because of a high volume of results. The data analysis was conducted between January 2020 and October 2020.Longitudinal studies and randomized clinical trials that measured fasting insulin level and/or an inflammation marker and BMI with at least 3 commensurate time points were selected.Slopes of these markers were calculated between time points and standardized. Standardized slopes were meta-regressed in later periods (period 2) with standardized slopes in earlier periods (period 1). Evidence-based items potentially indicating risk of bias were assessed.Of 1865 records, 60 eligible studies with 112 cohorts of 5603 participants were identified. Most standardized slopes were negative, meaning that participants in most studies experienced decreases in BMI, fasting insulin level, and C-reactive protein level. The association between period 1 fasting insulin level and period 2 BMI was positive and significant (β = 0.26; 95% CI, 0.13-0.38; I2 = 79%): for every unit of SD change in period 1 insulin level, there was an ensuing associated change in 0.26 units of SD in period 2 BMI. The association of period 1 fasting insulin level with period 2 BMI remained significant when period 1 C-reactive protein level was added to the model (β = 0.57; 95% CI, 0.27-0.86). In this bivariable model, period 1 C-reactive protein level was not significantly associated with period 2 BMI (β = -0.07; 95% CI, -0.42 to 0.29; I2 = 81%).In this meta-analysis, the finding of temporal sequencing (in which changes in fasting insulin level precede changes in weight) is not consistent with the assertion that obesity causes noncommunicable chronic diseases and premature death by increasing levels of fasting insulin.
SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma
Authors: Constantinos Kurt Wibmer, Frances Ayres, Tandile Hermanus, Mashudu Madzivhandila, Prudence Kgagudi, Brent Oosthuysen, Bronwen E. Lambson, Tulio de Oliveira, Marion Vermeulen, Karin van der Berg, Theresa Rossouw, Michael Boswell, Veronica Ueckermann, Susan Meiring, Anne von Gottberg, Cheryl Cohen, Lynn Morris, Jinal N. Bhiman, Penny L. Moore
Journal: Nature Medicine (2021)