tbuckley/cabot-search huggingface dataset:
Encorafenib plus cetuximab with or without binimetinib for <i>BRAF</i> V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC).
Authors: Scott Kopetz, Axel Grothey, Eric Van Cutsem, Rona Yaeger, Harpreet Singh Wasan, Takayuki Yoshino, Jayesh Desai, Fortunato Ciardiello, Fotios Loupakis, Yong Sang Hong, Neeltje Steeghs, Tormod Kyrre Guren, Hendrik-Tobias Arkenau, Pilar Garcia-Alfonso, Ashwin Gollerkeri, Kati Maharry, Janna Christy-Bittel, Christopher Hunt Keir, Michael D Pickard, Josep Tabernero
Journal: Journal of Clinical Oncology (2020)

4039 Background: In the BEACON CRC study, the triplet regimen of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) significantly improved overall survival (OS, HR:0.52, P &lt; 0.0001) and objective response rates (ORR, 26% vs 2%, P &lt; 0.0001) in patients (pts) with BRAFV600E metastatic colorectal cancer (mCRC) compared with current standard of care. This analysis focuses on the patient-reported quality of life (QOL) assessments from this study. Methods: The BEACON CRC study was a randomized, open-label, 3-arm, phase 3 global study which evaluated triplet (ENCO+BINI+CETUX) or doublet (ENCO+CETUX) vs. investigator’s choice of irinotecan + CETUX or FOLFIRI + CETUX in pts with BRAFV600E mCRC. QOL assessments (secondary endpoints in the trial) included the EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer (FACT C), EuroQol 5D 5L, and Patient Global Impression of Change (PGIC). The primary assessment for the QOL variables was the time to definitive 10% deterioration. The study is ongoing. Results: 665 pts were randomly assigned to receive either triplet (n = 224), doublet (n = 220), or control (n = 221). Reduction in the risk of QOL deterioration was an estimated 45% (HR 0.55, 95% CI: 0.43, 0.70) and 52% (HR 0., 9485% CI: 0.38, 0.62) in EORTC QLQ C30 and FACT C assessments, respectively, in favor of the triplet regimen over control. For the doublet vs. control, reduction in risk of QOL deterioration was an estimated 46% (HR 0.54, 95% CI: 0.43, 0.69) and 54% (HR 0.46, 95% CI: 0.36, 0.59) in EORTC QLQ C30 and FACT C, respectively in favor of the doublet. Similar results were observed in EuroQol 5D 5L and PGIC assessments. There were no overall differences in QOL between triplet and doublet across the 4 instruments. Conclusions: In BEACON CRC, triplet and doublet demonstrated substantial improvement in patient-reported QOL assessments over the current standard of care in pts with BRAFV600E-mutant metastatic CRC whose disease had progressed after 1 or 2 prior regimens. Clinical trial information: NCT02928224 .
PD-L1 expression, tumor mutational burden, and microsatellite instability status in 746 pancreas ductal adenocarcinomas.
Authors: Amanda Hemmerich, Claire I. Edgerly, Daniel Duncan, Richard Huang, Natalie Danziger, Garrett M. Frampton, Julia Andrea Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Douglas I. Lin, Erik Williams, Siraj Mahamed Ali, Prasanth Reddy, Vincent A. Miller, Clarence Owens, Charlotte Brown, Brian M Alexander, Jeffrey S. Ross, Eric Allan Severson, Shakti H. Ramkissoon
Journal: Journal of Clinical Oncology (2020)

757 Background: Pancreas ductal adenocarcinomas (PDA) has a 5-year survival rate of 6% with a need for new therapeutic options. The approval of pembrolizumab for some gastrointestinal cancers shows the potential of immunotherapy (IMT) in PDA. We evaluated the IMT-associated biomarkers of PD-L1 expression, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 amplification in PDAs. Methods: 746 formalin-fixed paraffin embedded samples were evaluated for PD-L1 IHC using the Dako 22C3 pharmDx assay and scored using tumor proportion score (TPS). The cases had comprehensive genomic profiling (CGP) via DNA sequencing, using a hybrid-capture next-generation sequencing assay (FoundationOne and FoundationOneCDx) for genomic alterations (GAs), TMB, and MSI. Results: PD-L1 was positive (TPS ≥ 1%) in 29% (214/746) and negative in 71% (532/746). 43/214 (20%) of positive cases were high positive (TPS ≥ 50%). TMB (590 cases) had a mean of 3.20, 3.46, and 3.61 mutations/Mb for PD-L1 negative, positive, and high positive groups. 3 hypermutated (TMB ≥ 20) were negative for PD-L1 expression. 3/581 cases were MSI-high with a high TMB score (average 23.53 mutations/Mb). 2 MSI-high cases were negative for PD-L1 and 1 was high positive. PD-L1 amplification was not detected (0/746). Only BCOR was significantly different between PD-L1 high positive and PD-L1 negative tumors (Table). Conclusions: Of 729 PDA cases, 29% were positive (TPS ≥ 1%) for PD-L1 expression while only 6% of all cases showed a high level of PD-L1 expression on tumor cells. TMB high (3/729) and MSI-High (3/729) cases were rare. Only 2 of the TMB high cases were also MSI-high. PD-L1 amplification was not detected. Comparing GAs in PD-L1 high positive vs negative cases was only significantly different for BCOR. Further investigation is needed to see if a combined positive score of PD-L1 expression may identify a subset of patients with PDA who are more likely to respond to IMT. [Table: see text]
Extensive Clonal Branching Shapes the Evolutionary History of High-Risk Pediatric Cancers
Authors: Natalie Andersson, Bjorn Bakker, Jenny Karlsson, Anders Valind, Linda Holmquist Mengelbier, Diana C.J. Spierings, Floris Foijer, David Gisselsson
Journal: Cancer Research (2020)

Abstract Darwinian evolution of tumor cells remains underexplored in childhood cancer. We here reconstruct the evolutionary histories of 56 pediatric primary tumors, including 24 neuroblastomas, 24 Wilms tumors, and 8 rhabdomyosarcomas. Whole-genome copy-number and whole-exome mutational profiling of multiple regions per tumor were performed, followed by clonal deconvolution to reconstruct a phylogenetic tree for each tumor. Overall, 88% of the tumors exhibited genetic variation among primary tumor regions. This variability typically emerged through collateral phylogenetic branching, leading to spatial variability in the distribution of more than 50% (96/173) of detected diagnostically informative genetic aberrations. Single-cell sequencing of 547 individual cancer cells from eight solid pediatric tumors confirmed branching evolution to be a fundamental underlying principle of genetic variation in all cases. Strikingly, cell-to-cell genetic diversity was almost twice as high in aggressive compared with clinically favorable tumors (median Simpson index of diversity 0.45 vs. 0.88; P = 0.029). Similarly, a comparison of multiregional sampling data from a total of 274 tumor regions showed that new phylogenetic branches emerge at a higher frequency per sample and carry a higher mutational load in high-risk than in low-risk tumors. Timelines based on spatial genetic variation showed that the mutations most influencing relapse risk occur at initiation of clonal expansion in neuroblastoma and rhabdomyosarcoma, whereas in Wilms tumor, they are late events. Thus, from an evolutionary standpoint, some high-risk childhood cancers are born bad, whereas others grow worse over time. Significance: Different pediatric cancers with a high risk of relapse share a common generic pattern of extensively branching evolution of somatic mutations.
Efficacy and safety of nab-paclitaxel plus ramucirumab versus paclitaxel plus ramucirumab as second-line treatment for patients with advanced gastric cancer: A single institutional experience.
Authors: Mashiro Okunaka, Daisuke Kotani, Ken Demachi, Akihito Kawazoe, Takayuki Yoshino, Kohei Shitara
Journal: Journal of Clinical Oncology (2020)

322 Background: Nanoparticle albumin-bound (nab)- paclitaxel (PTX) was non-inferiority to solvent-based paclitaxel as second-line for advanced gastric cancer (AGC) with fewer infusion-related reactions and a trend toward improved overall survival (OS) in patients (pts) with peritoneal metastasis (PM) or ascites in ABSOLUTE trial (Shitara K et al. Lancet Gastroenterol Hepatol. 2017). Furthermore, safety and efficacies of nab-PTX plus ramucirumab (RAM) was reported in a phase II trial (Bando H, et al. EJC 2018), although no randomised trial with PTX plus RAM is reported so far. Methods: We retrospectively reviewed consecutive pts with AGC receiving nab-PTX plus RAM or PTX plus RAM as second-line chemotherapy from June 2015 to January 2019 at the National Cancer Center Hospital East. Adverse events were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Progression-free survival (PFS) was calculated using the Kaplan-Meier method, and the differences were evaluated using the log-rank test. Results: A total of 257 pts were included for analysis with 118 pts treated with nab-PTX plus RAM and 139 pts with PTX plus RAM. 151 pts (59%) had peritoneal metastasis and 76 pts (30%) were associated with moderate or massive amounts of ascites. Objective response rates were similar between two groups (nab-PTX plus RAM 34.1% vs. PTX plus RAM 28.0%, p = 0.36). There were no significant differences in PFS (median 3.9 vs. 3.9 months, log-rank p = 0.34; hazard ratio [HR] = 1.14). HR of PFS was 0.96 in pts with PM and 0.79 in pts with moderate or massive ascites. The major grade 3 or higher adverse events were neutropenia (nab-PTX plus RAM 55.1% vs. PTX plus RAM 55.4%), leucopenia (28.8 vs. 35.3%), thrombocytopenia (5.1 vs. 2.9%), and febrile neutropenia (5.1 vs 9.4%). Conclusions: Efficacy and safety of nab-PTX plus RAM were comparable to those of PTX plus RAM in pts with AGC in clinical practice. nab-PTX plus RAM is a treatment option as second-line treatment in pts with AGC.
IQ-TREE 2: New Models and Efficient Methods for Phylogenetic Inference in the Genomic Era
Authors: Bui Quang Minh, Heiko A Schmidt, Olga Chernomor, Dominik Schrempf, Michael D Woodhams, Arndt von Haeseler, Robert Lanfear
Journal: Molecular Biology and Evolution (2020)

Abstract IQ-TREE (http://www.iqtree.org, last accessed February 6, 2020) is a user-friendly and widely used software package for phylogenetic inference using maximum likelihood. Since the release of version 1 in 2014, we have continuously expanded IQ-TREE to integrate a plethora of new models of sequence evolution and efficient computational approaches of phylogenetic inference to deal with genomic data. Here, we describe notable features of IQ-TREE version 2 and highlight the key advantages over other software.
A Spatiotemporal Analysis of Organ‐Specific Lupus Flares in Relation to Atmospheric Variables and Fine Particulate Matter Pollution
Authors: George Stojan, Anton Kvit, Frank C. Curriero, Michelle Petri
Journal: Arthritis & Rheumatology (2020)

Objective To identify potential clusters of systemic lupus erythematosus ( SLE ) organ‐specific flares and their relationship to fine particulate matter pollution (PM2.5), temperature, ozone concentration, resultant wind, relative humidity, and barometric pressure in the Hopkins Lupus Cohort, using spatiotemporal cluster analysis. Methods A total of 1,628 patients who fulfilled the Systemic Lupus International Collaborating Clinics classification criteria for SLE and who had a home address recorded were included in the analysis. Disease activity was assessed using the Lupus Activity Index. Assessment of rash, joint involvement, serositis, and neurologic, pulmonary, renal, and hematologic activity was quantified on a 0–3 visual analog scale ( VAS ). An organ‐specific flare was defined as an increase in VAS of ≥1 point compared to the previous visit. Spatiotemporal clusters were detected using Sa TS can software. Regression models were used for cluster adjustment and included individual, county‐level, and environmental variables. Results Significant clusters unadjusted for environmental variables were identified for joint flares ( P &lt; 0.05; n = 3), rash flares ( P &lt; 0.05; n = 4), hematologic flares ( P &lt; 0.05; n = 3), neurologic flares ( P &lt; 0.05; n = 2), renal flares ( P &lt; 0.001; n = 4), serositis ( P &lt; 0.001; n = 2), and pulmonary flares ( P &lt; 0.001; n = 2). The majority of the clusters identified changed in significance, temporal extent, or spatial extent after adjustment for environmental variables. Conclusion We describe the first spatiotemporal clusters of lupus organ‐specific flares. Seasonal, as well as multi‐year, cluster patterns were identified, differing in extent and location for the various organ‐specific flare types. Further studies focusing on each individual organ‐specific flare are needed to better understand the driving forces behind these observed changes.
Antibodies and B cells recognising citrullinated proteins display a broad cross-reactivity towards other post-translational modifications
Authors: T Kissel, S Reijm, LM Slot, M Cavallari, CM Wortel, RD Vergroesen, G Stoeken-Rijsbergen, JC Kwekkeboom, ASB Kampstra, EWN Levarht, JW Drijfhout, H Bang, KM Bonger, GMC Janssen, PA van Veelen, TWJ Huizinga, HU Scherer, M Reth, REM Toes
Journal: Annals of the Rheumatic Diseases (2020)

Autoantibodies against antigens carrying distinct post-translational modifications (PTMs), such as citrulline, homocitrulline or acetyllysine, are hallmarks of rheumatoid arthritis (RA). The relation between these anti-modified protein antibody (AMPA)-classes is poorly understood as is the ability of different PTM-antigens to activate B-cell receptors (BCRs) directed against citrullinated proteins (CP). Insights into the nature of PTMs able to activate such B cells are pivotal to understand the 'evolution' of the autoimmune response conceivable underlying the disease. Here, we investigated the cross-reactivity of monoclonal AMPA and the ability of different types of PTM-antigens to activate CP-reactive BCRs.BCR sequences from B cells isolated using citrullinated or acetylated antigens were used to produce monoclonal antibodies (mAb) followed by a detailed analysis of their cross-reactivity towards PTM-antigens. Ramos B-cell transfectants expressing CP-reactive IgG BCRs were generated and their activation on stimulation with PTM-antigens investigated.Most mAbs were highly cross-reactive towards multiple PTMs, while no reactivity was observed to the unmodified controls. B cells carrying CP-reactive BCRs showed activation on stimulation with various types of PTM-antigens.Our study illustrates that AMPA exhibit a high cross-reactivity towards at least two PTMs indicating that their recognition pattern is not confined to one type of modification. Furthermore, our data show that CP-reactive B cells are not only activated by citrullinated, but also by carbamylated and/or acetylated antigens. These data are vital for the understanding of the breach of B-cell tolerance against PTM-antigens and the possible contribution of these antigens to RA-pathogenesis.
The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13
Authors: Floriana Mulas, Xu Wang, Shanshan Song, Gopala Nishanth, Wenjing Yi, Anna Brunn, Pia-Katharina Larsen, Berend Isermann, Ulrich Kalinke, Antonio Barragan, Michael Naumann, Martina Deckert, Dirk Schlüter
Journal: Cellular and Molecular Immunology (2020)

Abstract Dendritic cells (DCs) are indispensable for defense against pathogens but may also contribute to immunopathology. Activation of DCs upon the sensing of pathogens by Toll-like receptors (TLRs) is largely mediated by pattern recognition receptor/nuclear factor-κB (NF-κB) signaling and depends on the appropriate ubiquitination of the respective signaling molecules. However, the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely understood. Here, we reveal that the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide challenge. Stimulation of DCs with the TLR11/12 ligand T. gondii profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-κB activation in OTUB1-competent cells, resulting in elevated interleukin-6 (IL-6), IL-12, and tumor necrosis factor (TNF) production, which was also observed upon the specific stimulation of TLR2, TLR3, TLR7, and TLR9. Mechanistically, OTUB1 promoted NF-κB activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13, resulting in increased K63-linked ubiquitination of IRAK1 (IL-1 receptor-associated kinase 1) and TRAF6 (TNF receptor-associated factor 6). Consequently, DC-specific deletion of OTUB1 impaired the production of cytokines, in particular IL-12, by DCs over the first 2 days of T. gondii infection, resulting in the diminished production of protective interferon-γ (IFN-γ) by natural killer cells, impaired control of parasite replication, and, finally, death from chronic T. encephalitis , all of which could be prevented by low-dose IL-12 treatment in the first 3 days of infection. In contrast, impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced immunopathology. Collectively, these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.
Enhanced lysosome escape mediated by 1,2-dicarboxylic-cyclohexene anhydride-modified poly-l-lysine dendrimer as a gene delivery system
Authors: Jianmin Shen, Jing Chen, Jingbo Ma, Linlan Fan, Xiaoli Zhang, Ting Yue, Yaping Yan, Yuhang Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2020)

Antisense oligodeoxynucleotide (ASODN) can directly interfere a series of biological events of the target RNA derived from tumor cells through Watson-Crick base pairing, in turn, plays antitumor therapeutic roles. In the study, a novel HIF-1α ASODN-loaded nanocomposite was formulated to efficiently deliver gene to the target RNA. The physicochemical properties of nanocomposite were characterized using TEM, FTIR, DLS and zeta potentials. The mean diameter of resulting GEL-DGL-FA-ASODN-DCA nanocomposite was about 170-192 nm, and according to the agarose gel retardation assay, the loading amount of ASODN accounted for 166.7 mg/g. The results of cellular uptake showed that the nanocomposite could specifically target to HepG2 and Hela cells. The cytotoxicity assay demonstrated that the toxicity of vectors was greatly reduced by using DCA to reversibly block the cationic DGL. The subcellular distribution images clearly displayed the lysosomal escape ability of the DCA-modified nanocomposite. In vitro exploration of molecular mechanism indicated that the nanocomposite could inhibit mRNA expression and HIF-1α protein translation at different levels. In vivo optical images and quantitative assay testified that the formulation accumulated preferentially in the tumor tissue. In vivo antitumor efficacy research confirmed that this nanocomposite had significant antitumor activity and the tumor inhibitory rate was 77.99%. These results manifested that the GEL-DGL-FA-ASODN-DCA nanocomposite was promising in gene therapeutics for antitumor by interacting directly with target RNA.
Models of Palliative Care Delivery for Patients With Cancer
Authors: David Hui, Eduardo Bruera
Journal: Journal of Clinical Oncology (2020)

Palliative care has evolved over the past five decades as an interprofessional specialty to improve quality of life and quality of care for patients with cancer and their families. Existing evidence supports that timely involvement of specialist palliative care teams can enhance the care delivered by oncology teams. This review provides a state-of-the-science synopsis of the literature that supports each of the five clinical models of specialist palliative care delivery, including outpatient clinics, inpatient consultation teams, acute palliative care units, community-based palliative care, and hospice care. The roles of embedded clinics, nurse-led models, telehealth interventions, and primary palliative care also will be discussed. Outpatient clinics represent the key point of entry for timely access to palliative care. In this setting, patient care can be enhanced longitudinally through impeccable symptom management, monitoring, education, and advance care planning. Inpatient consultation teams provide expert symptom management and facilitate discharge planning for acutely symptomatic hospitalized patients. Patients with the highest level of distress and complexity may benefit from an admission to acute palliative care units. In contrast, community-based palliative care and hospice care are more appropriate for patients with a poor performance status and low to moderate symptom burden. Each of these five models of specialist palliative care serve a different patient population along the disease continuum and complement one another to provide comprehensive supportive care. Additional research is needed to define the standards for palliative care interventions and to refine the models to further improve access to quality palliative care.
Modeling Acquired Resistance to the Second-Generation Androgen Receptor Antagonist Enzalutamide in the TRAMP Model of Prostate Cancer
Authors: Marianna Cerasuolo, Federica Maccarinelli, Daniela Coltrini, Ali Mokhtar Mahmoud, Viviana Marolda, Gaia Cristina Ghedini, Sara Rezzola, Arianna Giacomini, Luca Triggiani, Magdalena Kostrzewa, Roberta Verde, Debora Paris, Dominique Melck, Marco Presta, Alessia Ligresti, Roberto Ronca
Journal: Cancer Research (2020)

Enzalutamide (MDV3100) is a potent second-generation androgen receptor antagonist approved for the treatment of castration-resistant prostate cancer (CRPC) in chemotherapy-naïve as well as in patients previously exposed to chemotherapy. However, resistance to enzalutamide and enzalutamide withdrawal syndrome have been reported. Thus, reliable and integrated preclinical models are required to elucidate the mechanisms of resistance and to assess therapeutic settings that may delay or prevent the onset of resistance. In this study, the prostate cancer multistage murine model TRAMP and TRAMP-derived cells have been used to extensively characterize in vitro and in vivo the response and resistance to enzalutamide. The therapeutic profile as well as the resistance onset were characterized and a multiscale stochastic mathematical model was proposed to link the in vitro and in vivo evolution of prostate cancer. The model showed that all therapeutic strategies that use enzalutamide result in the onset of resistance. The model also showed that combination therapies can delay the onset of resistance to enzalutamide, and in the best scenario, can eliminate the disease. These results set the basis for the exploitation of this "TRAMP-based platform" to test novel therapeutic approaches and build further mathematical models of combination therapies to treat prostate cancer and CRPC.Significance: Merging mathematical modeling with experimental data, this study presents the "TRAMP-based platform" as a novel experimental tool to study the in vitro and in vivo evolution of prostate cancer resistance to enzalutamide.
初回選択チエノピリジン抗血小板薬(チクロピジン対クロピドグレル)投与下の薬物溶出ステントの初期確定ステント血栓症:後向き非ランダム化試験
Authors: Ishikawa Tetsuya, Nakano Yosuke, Endoh Akira, Kubota Takeyuki, Suzuki Teruhiko, Nakata Kotaro, Imai Kamon, Mochizuki Seibu, Yoshimura Michihiro, Mutoh Makoto
Journal: Circulation (2009)
Coronavirus: global stocks of protective gear are depleted, with demand at “100 times” normal level, WHO warns
Authors: Elisabeth Mahase
Journal: BMJ (2020)

The demand for personal protective equipment such as masks and respirators is 100 times the normal level, and costs have skyrocketed to around 20 times their usual price, the World Health Organization has reported.

WHO warned of “severe disruption” in the market for personal protective equipment and said that worldwide stocks were “now insufficient” to meet demand. The warning came from WHO’s director general, Tedros Adhanom Ghebreyesus, during his opening remarks at a …