tbuckley/cabot-search huggingface dataset:
Abstract B27: MT1-MMP targeting in melanoma brain metastasis
Authors: Julia Escandon, Varsha Thakur, Barbara Bedogni
Journal: Cancer Research (2020)

Abstract Background: Melanoma brain metastases contribute to morbidity and mortality of melanoma, and the treatment is limited due to its accessibility for drugs and also for surgical approaches. Radiotherapy is a widely used approach for disseminated metastatic foci in the brain. However, there is a gap in therapeutics since there are few to no alternatives to melanoma brain metastasis after the radiotherapy dose has been maximized. MT1-MMP is a metalloproteinase that has shown a direct correlation with metastasis and whose inhibition slows down the occurrence of metastasis and tumor growth. By microarray analysis, it has been found that inhibition of MT1-MMP downregulates the expression of DNA-damage response genes. Objective/Hypothesis: We hypothesize that the inhibition of MT1-MMP in combination with radiotherapy will enhance the tumor cell killing efficacy by means of preventing cells from responding to the DNA damage that is caused by radiation. Further, we hypothesize that the Integrin beta 1 pathway downstream of MT1-MMP is the mediator in the downregulation of DNA-damage response genes. Methods: We utilized melanoma cell lines, A375, WM-266-4-Luciferase, and K457, in which we introduced shMT1-MMP lentivirus with control shGFP. Cell culture assays compared the response of shMT1-MMP cells and shGFP cells in the presence of radiotherapy and the assays included comet assay, foci of gammaH2AX staining, clonogenic assay, and evaluation of radiotherapy response by Western blot. Furthermore, a nude mouse model was utilized in which WM-266-4-luciferase shMT1-MMP and control shGFP cells were inoculated by stereotactic injection. In vivo imaging system (IVIS) was utilized to follow up the tumors. Results: Ongoing experiments aim to look at the response of shMT1-MMP cells to radiotherapy compared to shGFP cells by DNA damage evaluation assays (Comet assay, gammaH2AX foci, DNA-damage response proteins by Western blot), downstream signaling of Integrin beta 1 pathway, and the survival of nude mice in shMT1-MMP inoculated tumors and their response to radiotherapy. Impact: This project has the potential to advance the current treatment of melanoma brain metastasis and also has the potential of advancing the understanding of the DNA-damage response in melanoma. Citation Format: Julia Escandon, Varsha Thakur, Barbara Bedogni. MT1-MMP targeting in melanoma brain metastasis [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B27.
PCSK9 and LRP5 in macrophage lipid internalization and inflammation
Authors: Lina Badimon, Aureli Luquero, Javier Crespo, Esther Peña, Maria Borrell-Pages
Journal: Cardiovascular Research (2020)

Atherosclerosis, the leading cause of cardiovascular diseases, is driven by high blood cholesterol levels and chronic inflammation. Low-density lipoprotein receptors (LDLR) play a critical role in regulating blood cholesterol levels by binding to and clearing LDLs from the circulation. The disruption of the interaction between proprotein convertase subtilisin/kexin 9 (PCSK9) and LDLR reduces blood cholesterol levels. It is not well known whether other members of the LDLR superfamily may be targets of PCSK9. The aim of this work was to determine if LDLR-related protein 5 (LRP5) is a PCSK9 target and to study the role of PCSK9 and LRP5 in foam cell formation and lipid accumulation.Primary cultures of human inflammatory cells (monocytes and macrophages) were silenced for LRP5 or PCSK9 and challenged with LDLs. We first show that LRP5 is needed for macrophage lipid uptake since LRP5-silenced macrophages show less intracellular CE accumulation. In macrophages, internalization of LRP5-bound LDL is already highly evident after 5 h of LDL incubation and lasts up to 24 h; however, in the absence of both LRP5 and PCSK9, there is a strong reduction of CE accumulation indicating a role for both proteins in lipid uptake. Immunoprecipitation experiments show that LRP5 forms a complex with PCSK9 in lipid-loaded macrophages. Finally, PCSK9 participates in TLR4/NFkB signalling; a decreased TLR4 protein expression levels and a decreased nuclear translocation of NFκB were detected in PCSK9 silenced cells after lipid loading, indicating a downregulation of the TLR4/NFκB pathway.Our results show that both LRP5 and PCSK9 participate in lipid uptake in macrophages. In the absence of LRP5, there is a reduced release of PCSK9 indicating that LRP5 also participates in the mechanism of release of soluble PCSK9. Furthermore, PCSK9 up-regulates TLR4/NFκB favouring inflammation.
Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults
Authors: Evan J. Anderson, Nadine G. Rouphael, Alicia T. Widge, Lisa A. Jackson, Paul C. Roberts, Mamodikoe Makhene, James D. Chappell, Mark R. Denison, Laura J. Stevens, Andrea J. Pruijssers, Adrian B. McDermott, Britta Flach, Bob C. Lin, Nicole A. Doria-Rose, Sijy O’Dell, Stephen D. Schmidt, Kizzmekia S. Corbett, Phillip A. Swanson, Marcelino Padilla, Kathy M. Neuzil, Hamilton Bennett, Brett Leav, Mat Makowski, Jim Albert, Kaitlyn Cross, Venkata Viswanadh Edara, Katharine Floyd, Mehul S. Suthar, David R. Martinez, Ralph Baric, Wendy Buchanan, Catherine J. Luke, Varun K. Phadke, Christina A. Rostad, Julie E. Ledgerwood, Barney S. Graham, John H. Beigel
Journal: New England Journal of Medicine (2020)

Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and death from coronavirus disease 2019 (Covid-19) have been associated with an older age. We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 μg or 100 μg of vaccine administered 28 days apart. Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-μg dose, the anti-S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-μg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells. In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, which supports the use of the 100-μg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461.).
The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes
Authors: Floris Dammeijer, Mandy van Gulijk, Evalyn E. Mulder, Melanie Lukkes, Larissa Klaase, Thierry van den Bosch, Menno van Nimwegen, Sai Ping Lau, Kitty Latupeirissa, Sjoerd Schetters, Yvette van Kooyk, Louis Boon, Antien Moyaart, Yvonne M. Mueller, Peter D. Katsikis, Alexander M. Eggermont, Heleen Vroman, Ralph Stadhouders, Rudi W. Hendriks, Jan von der Thüsen, Dirk J. Grünhagen, Cornelis Verhoef, Thorbald van Hall, Joachim G. Aerts
Journal: Cancer Cell (2020)
Phase 2 trial to assess lebrikizumab in patients with idiopathic pulmonary fibrosis
Authors: Toby M. Maher, Ulrich Costabel, Marilyn K. Glassberg, Yasuhiro Kondoh, Takashi Ogura, Mary Beth Scholand, David Kardatzke, Monet Howard, Julie Olsson, Margaret Neighbors, Paula Belloni, Jeffrey J. Swigris
Journal: European Respiratory Journal (2020)

This phase 2, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of lebrikizumab, an interleukin (IL)-13 monoclonal antibody, alone or with background pirfenidone therapy, in patients with idiopathic pulmonary fibrosis (IPF). Patients with IPF aged ≥40 years with forced vital capacity (FVC) of 40%–100% predicted and diffusing capacity for carbon monoxide of 25%–90% predicted and who were treatment-naïve (cohort A) or receiving pirfenidone (2403 mg·day −1 ; cohort B) were randomised 1:1 to receive lebrikizumab 250 mg or placebo subcutaneously every 4 weeks. The primary endpoint was annualised rate of FVC % predicted decline over 52 weeks. In cohort A, 154 patients were randomised to receive lebrikizumab (n=78) or placebo (n=76). In cohort B, 351 patients receiving pirfenidone were randomised to receive lebrikizumab (n=174) or placebo (n=177). Baseline demographics were balanced across treatment arms in both cohorts. The primary endpoint (annualised rate of FVC % predicted decline) was not met in cohort A (lebrikizumab versus placebo, −5.2% versus −6.2%; p=0.456) or cohort B (lebrikizumab versus placebo, −5.5% versus −6.0%; p=0.557). In cohort B, a non-statistically significant imbalance in mortality favouring combination therapy was observed (hazard ratio 0.42 (95% CI 0.17–1.04)). Pharmacodynamic biomarkers indicated lebrikizumab activity. The safety profile was consistent with that in previous studies of lebrikizumab and pirfenidone as monotherapies. Lebrikizumab alone or with pirfenidone was not associated with reduced FVC % predicted decline over 52 weeks despite evidence of pharmacodynamic activity. Lebrikizumab was well tolerated with a favourable safety profile. These findings suggest that blocking IL-13 may not be sufficient to achieve a lung function benefit in patients with IPF.
Haplotype-resolved genome analyses of a heterozygous diploid potato
Authors: Qian Zhou, Dié Tang, Wu Huang, Zhongmin Yang, Yu Zhang, John P. Hamilton, Richard G. F. Visser, Christian W. B. Bachem, C. Robin Buell, Zhonghua Zhang, Chunzhi Zhang, Sanwen Huang
Journal: Nature Genetics (2020)

Abstract Potato ( Solanum tuberosum L.) is the most important tuber crop worldwide. Efforts are underway to transform the crop from a clonally propagated tetraploid into a seed-propagated, inbred-line-based hybrid, but this process requires a better understanding of potato genome. Here, we report the 1.67-Gb haplotype-resolved assembly of a diploid potato, RH89-039-16, using a combination of multiple sequencing strategies, including circular consensus sequencing. Comparison of the two haplotypes revealed ~2.1% intragenomic diversity, including 22,134 predicted deleterious mutations in 10,642 annotated genes. In 20,583 pairs of allelic genes, 16.6% and 30.8% exhibited differential expression and methylation between alleles, respectively. Deleterious mutations and differentially expressed alleles were dispersed throughout both haplotypes, complicating strategies to eradicate deleterious alleles or stack beneficial alleles via meiotic recombination. This study offers a holistic view of the genome organization of a clonally propagated diploid species and provides insights into technological evolution in resolving complex genomes.
Abstract A26: Humanized mouse model: A model to understand mechanisms of immune non-responsiveness to immune checkpoint inhibitors in melanoma
Authors: Rajasekharan Somasundaram, Anastasia Samarkina, Thomas Connelly, Robin Choi, Hedy Choi, Kar Muthumani, Xiaowei Xu, Klaus Kaestner, Meenhard Herlyn
Journal: Cancer Research (2020)

Abstract Immune checkpoint inhibitor therapy (anti-CTLA4 or anti-PD1 antibodies) is rapidly emerging as a front-line treatment option for many solid tumors. However, only a third of melanoma patients respond to immune checkpoint blockade. Currently available mouse xenograft and transgenic models have many shortcomings and are unable to address the basis of therapy resistance and immune nonresponsiveness that are observed in patients. Thus, there is an urgent need to establish an in vivo model with a human immune microenvironment that can address issues of therapy resistance. Our laboratory has developed a novel humanized mouse melanoma model. Immunodeficient NSG mice were reconstituted with human CD34+ cells and after 8-12 weeks, mice are fully reconstituted with human innate (monocyte/myeloid lineage cells, dendritic cells and NK cells) and adaptive (T and B cells) immune cells. Humanized mice were then challenged with HLA-matched melanoma cells, and the functional ability of human immune cells to restrict tumor growth was monitored. Delayed tumor growth was observed in humanized mice, indicating in vivo sensitization of human immune cells to melanoma. This was confirmed by in vitro demonstration of human lymphocytes from tumor-bearing mice showing enhanced cytokine expression after stimulation with melanoma antigen peptides. In therapy studies, tumor-bearing humanized mice treated with anti-PD-1 showed restricted tumor growth. Anti-PD-1 therapy resulted in enhanced infiltration of T cells that correlated with tumor response. MassCyTOF studies were performed using a panel of immune markers to understand the mechanism of therapy nonresponsiveness in some tumors. Downmodulation of HLA-class I molecules and increased presence of FOXP3+ cells in the tumor region were seen. Our results suggest that humanized mouse melanoma model can be explored further to understand the causes of therapy resistance and immune nonresponsiveness. Citation Format: Rajasekharan Somasundaram, Anastasia Samarkina, Thomas Connelly, Robin Choi, Hedy Choi, Kar Muthumani, Xiaowei Xu, Klaus Kaestner, Meenhard Herlyn. Humanized mouse model: A model to understand mechanisms of immune non-responsiveness to immune checkpoint inhibitors in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A26.
Clinical Activity and Safety of the Anti–Programmed Death 1 Monoclonal Antibody Dostarlimab for Patients With Recurrent or Advanced Mismatch Repair–Deficient Endometrial Cancer
Authors: Ana Oaknin, Anna V. Tinker, Lucy Gilbert, Vanessa Samouëlian, Cara Mathews, Jubilee Brown, Maria-Pilar Barretina-Ginesta, Victor Moreno, Adriano Gravina, Cyril Abdeddaim, Susana Banerjee, Wei Guo, Hadi Danaee, Ellie Im, Renaud Sabatier
Journal: JAMA Oncology (2020)

Deficient mismatch mutation repair mechanisms may sensitize endometrial cancers to anti-programmed death 1 (PD-1) therapies. Dostarlimab (TSR-042) is an investigational anti-PD-1 antibody that binds with high affinity to the PD-1 receptor.To assess the antitumor activity and safety of dostarlimab for patients with deficient mismatch repair endometrial cancer.This ongoing, open-label, single-group, multicenter study began part 1 on March 7, 2016, and began enrolling patients with deficient mismatch mutation repair endometrial cancer on May 8, 2017. Median follow-up was 11.2 months (range, 0.03 [ongoing] to 22.11 [ongoing] months; based on radiological assessments). Statistical analysis was performed July 8 to August 9, 2019.Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, treatment discontinuation, or withdrawal.The primary end point was objective response rate and duration of response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1.As of the data cutoff, 104 women (median age, 64.0 years [range, 38-80 years]) with deficient mismatch mutation repair endometrial cancers were enrolled and treated with dostarlimab. Of these, 71 had measurable disease at baseline and at 6 months or more of follow-up and were included in the analysis. There was a confirmed response in 30 patients (objective response rate, 42.3%; 95% CI, 30.6%-54.6%); 9 patients (12.7%) had a confirmed complete response, and 21 patients (29.6%) had a confirmed partial response. Responses were durable; the median duration of response was not reached (median follow-up was 11.2 months). The estimated likelihood of maintaining a response was 96.4% at 6 months and 76.8% at 12 months. Anemia (3 of 104 [2.9%]), colitis (2 of 104 [1.9%]), and diarrhea (2 of 104 [1.9%]) were the most common grade 3 or higher treatment-related adverse events.In this nonrandomized trial, dostarlimab was associated with clinically meaningful and durable antitumor activity with an acceptable safety profile for patients with deficient mismatch mutation repair endometrial cancers after prior platinum-based chemotherapy.ClinicalTrials.gov identifier: NCT02715284.
MommiNet-v2: Mammographic multi-view mass identification networks
Authors: Zhicheng Yang, Zhenjie Cao, Yanbo Zhang, Yuxing Tang, Xiaohui Lin, Rushan Ouyang, Mingxiang Wu, Mei Han, Jing Xiao, Lingyun Huang, Shibin Wu, Peng Chang, Jie Ma
Journal: Medical Image Analysis (2021)

Many existing approaches for mammogram analysis are based on single view. Some recent DNN-based multi-view approaches can perform either bilateral or ipsilateral analysis, while in practice, radiologists use both to achieve the best clinical outcome. MommiNet is the first DNN-based tri-view mass identification approach, which can simultaneously perform bilateral and ipsilateral analysis of mammographic images, and in turn, can fully emulate the radiologists' reading practice. In this paper, we present MommiNet-v2, with improved network architecture and performance. Novel high-resolution network (HRNet)-based architectures are proposed to learn the symmetry and geometry constraints, to fully aggregate the information from all views for accurate mass detection. A multi-task learning scheme is adopted to incorporate both Breast Imaging-Reporting and Data System (BI-RADS) and biopsy information to train a mass malignancy classification network. Extensive experiments have been conducted on the public DDSM (Digital Database for Screening Mammography) dataset and our in-house dataset, and state-of-the-art results have been achieved in terms of mass detection accuracy. Satisfactory mass malignancy classification result has also been obtained on our in-house dataset.
Managing Aortic Stenosis in the Age of COVID-19
Authors: Thoralf M. Sundt
Journal: JAMA Network Open (2020)

Richard Ro, MD; Sahil Khera, MD, MPH; Gilbert H. L. Tang, MD, MSc, MBA; Parasuram Krishnamoorthy, MD; Samin K. Sharma, MD; Annapoorna Kini, MD; Stamatios Lerakis, MD, PhD
Abstract PR05: Unique lipid metabolite profiling in BRAFV600E inhibitor drug-resistant melanoma and their potential as drug target
Authors: Meng-Ting Chang, Jia-Hua Feng, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur
Journal: Cancer Research (2020)

Abstract Melanoma is the most life-threatening skin cancer in the world. Advanced melanoma is highly metastatic, commonly develops drug resistance, and causes low survival rate in patients. PLX4032 (vemurafenib), a BRAFV600E inhibitor, is used to treat patients with late-stage melanoma. It showed initial good clinical responses but relapsed due to acquired drug resistance in tumors. The mechanism of PLX4032-induced resistance in melanoma is not well characterized; in particular, whether PLX4032-induced drug resistance in BRAF mutant melanoma would alter lipid metabolism in cancer is not clear. Understanding the status and role of lipid mediators (oxylipins) in melanoma pathology may be crucial for developing effective approach to overcome drug resistance. Our laboratory has demonstrated that plant sesquiterpene lactone deoxyelephantopin (DET) and its novel derivative DETD-35 effectively suppressed human A375 BRAFV600E melanoma with acquired drug resistance to PLX4032 in vitro and in xenograft mice. In this study we aimed to identify potential biomarkers associated with the resistant melanoma cells (A375-R) in the context of bioactive lipid mediators and to investigate whether DETD-35/DET effects against drug-resistant melanoma are through regulating their dynamics and contents. MS-based metabolomics was used to comprehensively analyze the oxylipin profiles in A375 and A375-R cells, mouse A375/A375-R tumor tissues, and respective sera with vehicle, drug, or compound treatment. We observed that PLX4032-resistant A375R melanoma cells or tumors produce significant and higher amounts of CYP450 enzyme-derived oxylipins than the parental A375, which were decreased after DETD-35 or DET treatment. This study proposes a role of CYP450-derived oxylipins in PLX4032-resistant melanoma cells and its potential to be a drug target. This abstract is also being presented as Poster B03. Citation Format: Meng-Ting Chang, Jia-Hua Feng, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur. Unique lipid metabolite profiling in BRAFV600E inhibitor drug-resistant melanoma and their potential as drug target [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR05.
Assessing the 5×-Multiplier Calculation to Reduce Discharge Opioid Prescription Volumes After Inpatient Surgery
Authors: Ryan W. Day, Timothy E. Newhook, Whitney L. Dewhurst, Elsa M. Arvide, Morgan L. Bruno, Jean-Nicolas Vauthey, Ching-Wei D. Tzeng
Journal: JAMA Surgery (2020)

State-specific limits on total days and procedure-specific recommendations of discharge opioid volumes have had mixed success in mitigating postoperative opioid dissemination. 1,2ost prescribers still expose their clinician-specific bias in writing round numbers of opioid doses (eg, 30-50 pills).In the theme of patient-centered care, this study analyzed oncologic surgery discharge opioid prescriptions and 30-day refills when a novel, patient-centered prescription calculation was implemented.
The impact of COVID-19 pandemic on cancer care: A global collaborative study
Authors: A. R. Jazieh, H. Akbulut, G. Curigliano, A. Rogado, A. A. Alsharm, E. Razis, L. Y. I. Mula-Hussain, H. Errihani, A. Khattak, R. B. De Guzman, C. C. Mathias, M. O. F. Alkaiyat, H. Jradi, C. D. Rolfo
Journal: Annals of Oncology (2020)
Staphylococcus aureus second immunoglobulin-binding protein drives atopic dermatitis via IL-33
Authors: Arwa Al Kindi, Helen Williams, Kenshiro Matsuda, Abdullah M. Alkahtani, Charis Saville, Hayley Bennett, Yasmine Alshammari, Soo Y. Tan, Catherine O’Neill, Akane Tanaka, Hiroshi Matsuda, Peter D. Arkwright, Joanne L. Pennock
Journal: Journal of Allergy and Clinical Immunology (2020)
In Situ Maturation and Tissue Adaptation of Type 2 Innate Lymphoid Cell Progenitors
Authors: Patrice Zeis, Mi Lian, Xiying Fan, Josip S. Herman, Daniela C. Hernandez, Rebecca Gentek, Shlomo Elias, Cornelia Symowski, Konrad Knöpper, Nina Peltokangas, Christin Friedrich, Remi Doucet-Ladeveze, Agnieszka M. Kabat, Richard M. Locksley, David Voehringer, Marc Bajenoff, Alexander Y. Rudensky, Chiara Romagnani, Dominic Grün, Georg Gasteiger
Journal: Immunity (2020)