tbuckley/cabot-search huggingface dataset:
Expanding the allergen repertoire of salmon and catfish
Authors: Thimo Ruethers, Aya C. Taki, Shaymaviswanathan Karnaneedi, Shuai Nie, Tanja Kalic, Danyi Dai, Sakda Daduang, Michael Leeming, Nicholas A. Williamson, Heimo Breiteneder, Sam S. Mehr, Sandip D. Kamath, Dianne E. Campbell, Andreas L. Lopata
Journal: Allergy (2020)

Abstract Background Diagnostic tests for fish allergy are hampered by the large number of under‐investigated fish species. Four salmon allergens are well‐characterized and registered with the WHO/IUIS while no catfish allergens have been described so far. In 2008, freshwater‐cultured catfish production surpassed that of salmon, the globally most‐cultured marine species. We aimed to identify, quantify, and compare all IgE‐binding proteins in salmon and catfish. Methods Seventy‐seven pediatric patients with clinically confirmed fish allergy underwent skin prick tests to salmon and catfish. The allergen repertoire of raw and heated protein extracts was evaluated by immunoblotting using five allergen‐specific antibodies and patients' serum followed by mass spectrometric analyses. Results Raw and heated extracts from catfish displayed a higher frequency of IgE‐binding compared to those from salmon (77% vs 70% and 64% vs 53%, respectively). The major fish allergen parvalbumin demonstrated the highest IgE‐binding capacity (10%‐49%), followed by triosephosphate isomerase (TPI; 19%‐34%) in raw and tropomyosin (6%‐32%) in heated extracts. Six previously unidentified fish allergens, including TPI, were registered with the WHO/IUIS. Creatine kinase from salmon and catfish was detected by IgE from 14% and 10% of patients, respectively. Catfish L‐lactate dehydrogenase, glyceraldehyde‐3‐phosphate dehydrogenase, pyruvate kinase, and glucose‐6‐phosphate isomerase showed IgE‐binding for 6%‐13% of patients. In salmon, these proteins could not be separated successfully. Conclusions We detail the allergen repertoire of two highly farmed fish species. IgE‐binding to fish tropomyosins and TPIs was demonstrated for the first time in a large patient cohort. Tropomyosins, in addition to parvalbumins, should be considered for urgently needed improved fish allergy diagnostics.
Cardiorespiratory considerations for return-to-play in elite athletes after COVID-19 infection: a practical guide for sport and exercise medicine physicians
Authors: Mathew G Wilson, James H Hull, John Rogers, Noel Pollock, Miranda Dodd, Jemma Haines, Sally Harris, Mike Loosemore, Aneil Malhotra, Guido Pieles, Anand Shah, Lesley Taylor, Aashish Vyas, Fares S Haddad, Sanjay Sharma
Journal: British Journal of Sports Medicine (2020)

SARS-CoV-2 is the causative virus responsible for the COVID-19 pandemic. This pandemic has necessitated that all professional and elite sport is either suspended, postponed or cancelled altogether to minimise the risk of viral spread. As infection rates drop and quarantine restrictions are lifted, the question how athletes can safely resume competitive sport is being asked. Given the rapidly evolving knowledge base about the virus and changing governmental and public health recommendations, a precise answer to this question is fraught with complexity and nuance. Without robust data to inform policy, return-to-play (RTP) decisions are especially difficult for elite athletes on the suspicion that the COVID-19 virus could result in significant cardiorespiratory compromise in a minority of afflicted athletes. There are now consistent reports of athletes reporting persistent and residual symptoms many weeks to months after initial COVID-19 infection. These symptoms include cough, tachycardia and extreme fatigue. To support safe RTP, we provide sport and exercise medicine physicians with practical recommendations on how to exclude cardiorespiratory complications of COVID-19 in elite athletes who place high demand on their cardiorespiratory system. As new evidence emerges, guidance for a safe RTP should be updated.
Abstract 4191: Characterization of a novel anti-glucose transporter inhibitor as a pan-anticancer therapeutic <i>in vitro</i> and <i>in vivo</i>
Authors: Pratik Shriwas, Stephen Bergmeier, Xiaozhuo Chen
Journal: Cancer Research (2020)

Abstract Cancer has surpassed cardiovascular diseases as the top killer in many US counties. Opportunistic uptake of extracellular nutrients has recently been named as an emerging hallmark of cancer metabolism. Glucose is a key nutrient taken in by cancer cells for satisfying their high energy and biosynthesis needs. Drastic upregulation of glucose uptake and metabolism, a phenomenon called the Warburg effect, is prevalent among cancers. Cancer cells overexpress specific glucose transporters (GLUTS), particularly GLUT1, on their cell surface for uptaking glucose via facilitated diffusion. Considering the addiction of cancer cells to glucose and their sensitivity and vulnerability to changes in glucose supply, Gluts, have been recognized as an attractive anticancer target. Previously, our first-generation GLUT-inhibitor, WZB117, had been characterized in vitro and in vivo as an anticancer therapeutic. In this study, DRB18, a novel and proprietary lead inhibitor of glucose transporters, is characterized in vitro and in vivo by bioassays. DRB18 inhibits growth and proliferation in about 90% of the 60 different cancer cell lines in 9 major cancer types. It shows IC50 values in high nM range in some cell lines in several different cancer types. DRB18 treatment leads to significant changes in glucose-based metabolism in A549 lung cancer cells, including cell death via ER/oxidative stress and necrosis. The docking and Seahorse studies reveal the surprising contributions of macropinocytosis in DRB18 internalization, ultimately leading to better GLUT1 binding and increase in potency in killing cancer cells. DRB18 (10mg/kg) treatment thrice a week significantly reduces growth in Xenograft A549 tumors. Comprehensive in vitro and in vivo metabolomics analysis would be presented to better describe anti-glucose metabolism of activity of DRB18. Further, GLUT1-KO A549 (A549glut1ko) cell lines, in which Glut1 gene has been knocked out, were generated using CRISPR-Cas9 system for further studying GLUT1's roles in A549 cells. Immunoblotting analysis revealed the upregulation of other GLUTs after GLUT1 is knocked out, strongly suggesting the need for a pan-GLUT inhibitor for better inhibition of tumor growth. Citation Format: Pratik Shriwas, Stephen Bergmeier, Xiaozhuo Chen. Characterization of a novel anti-glucose transporter inhibitor as a pan-anticancer therapeutic in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4191.
Abstract 126: Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth in <i>PTEN</i>-null TNBC model
Authors: Yuliang Sun, Xiaoqian Lin, Jennifer Aske, Casey Williams, Mark Abramovitz, Brian Leyland-Jones
Journal: Cancer Research (2020)

Abstract Background: The combination of a poly ADP ribose polymerase (PARP) inhibitor with a DNA-damaging agent has shown promise in treating triple-negative breast cancer (TNBC); but not all patients respond to this combination. The Src protein kinase modulates multiple cancer cell properties and plays a key role in tumorigenic processes. However, Src inhibitors as single agents have shown limited effects in solid tumors. In this study, we examined the antitumor effects of the Src inhibitor dasatinib, the PARP inhibitor veliparib, and the DNA-damaging agent carboplatin in PTEN-null TNBC cells in vitro and tumors in vivo to try to identify the combination with the most clinical potential. Methods: The PTEN-null TNBC cell line, MDA-MB-468, was used in this study. For in vitro studies, proliferation, cellular apoptosis, and 3D on-top clonogenic growth were measured, tube formation assays and western blot analysis were performed. For in vivo studies, a xenograft model was used to examine treatment responses, and immunohistochemical analysis was performed. Results: Interestingly, treatment with the combination of veliparib plus carboplatin led to an increase in Src phosphorylation of MDA-MB-468 cells. Importantly, addition of dasatinib attenuated Src overexpression induced by veliparib plus carboplatin and further increased the activation of caspase 3 and PARP, thereby enhancing the antitumor efficacy of veliparib plus carboplatin. In an MDA-MB-468 xenograft model, the triple combination of dasatinib with veliparib plus carboplatin showed greater tumor growth inhibitory effects compared with single agents or double combinations. No systemic toxicity was observed in mice treated with the triple combination. Conclusion: Here, we provide novel evidence that veliparib combined with carboplatin drives Src activation in the preclinical model tested. Moreover, we provide provocative in vitro and in vivo data highlighting the potential for increasing therapeutic efficacy by combining dasatinib with veliparib and carboplatin in PTEN-null TNBC. Citation Format: Yuliang Sun, Xiaoqian Lin, Jennifer Aske, Casey Williams, Mark Abramovitz, Brian Leyland-Jones. Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth in PTEN-null TNBC model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 126.
Reply: Survival in Crohn’s disease-associated small bowel adenocarcinoma
Authors: Jordan E Axelrad, Ola Olén, Michael C Sachs, Rune Erichsen, Lars Pedersen, Jonas Halfvarson, Johan Askling, Anders Ekbom, Henrik Toft Sørensen, Jonas F Ludvigsson
Journal: Gut (2020)

The authors would like to thank Giuffrida and colleagues for their interest in our manuscript, ‘Inflammatory Bowel Disease and Risk of Small Bowel Cancer: A binational population-based cohort study from Denmark and Sweden’.1 2 In contrast to previous studies focused on small bowel adenocarcinoma death with short follow-up time, we provide an age-adjusted composite risk of death due to multiple small bowel cancer subtypes, including adenocarcinoma, neuroendocrine tumours and sarcoma, with over 20 years of follow-up.3–6 We adjusted for cancer heredity and in sensitivity analyses, excluded patients with coeliac disease in …
Debates Around the Role of School Closures in the Coronavirus 2019 Pandemic
Authors: Ping-I Lin, Yi-Chia Chen
Journal: JAMA Pediatrics (2020)

To the Editor: We read with great interest the article by Esposito and Principi, 1 who expressed skepticism as to whether school closure is an effective measure in mitigating the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).It was interesting to read that Taiwan successfully slowed the spread of SARS-CoV-2 without school closure.Additionally, they highlighted that school closure had no significant effect on the spread of SARS-CoV-2 in China.Other countries, such Japan, Israel, Denmark, and Norway, also closed their schools in an attempt to mitigate the spread of SARS-CoV-2.Interestingly, Denmark and Norway reopened their schools in April 2020 and have continued to see a decline in the number of new infections as of May 2020. 2 Denmark was one of the first countries to close schools and enforced school closure on March 11, 2020, with 262 confirmed coronavirus cases.After several weeks of closure, the Danish government reopened schools for young children on April 15, 2020. 2 In this period, the number of cases rose by 6249 to 6511 cases over a period of 35 days.As of May 25, 2020, the number of cases in Denmark stands at 11 360, a rise of 4849 cases in 40 days. 3 Thus, in a longer period with schools reopened, Denmark has seen fewer new cases of SARS-CoV-2 infection than when schools were closed.Norway was another country to close all educational institutions early, doing so on March 12, 2020, with 489 total confirmed cases. 3,4 Norway began reopening kindergartens on April 20, 2020, and junior schools on April 27. 5 Between March 12 and April 27, there was a rise of 7016 cases to a total of 7505.Since reopening primary schools, there have been just 804 new cases in Norway between April 27, 2020, and May 25, 2020, over 29 days. 3 As in Denmark, Norway has seen a huge decrease in the number of new cases while schools reopen.The reopening of schools is extremely important because children depend on schools for normal social and intellectual development.The decrease in new cases in Denmark and Norway as their schools reopen is a very encouraging sign.However, it would be nonetheless prudent to continuously monitor the number of new cases as schools reopen across the world.
Abstract 1047: Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors
Authors: Adam C. Palmer, Peter K. Sorger, Benjamin Izar
Journal: Cancer Research (2020)

Abstract IMPORTANCE Immune Checkpoint Inhibitors (ICIs), frequently combined with other therapies, have become the standard of care for the treatment of several cancers, and hundreds of clinical trials evaluate the efficacy of novel combinations with ICI. However, it is unclear whether combination therapies truly enhance ICI activity or simply provide multiple “shots on target” for a response to occur. OBJECTIVE To assess whether ICIs in combination with other therapies result in ‘additive' or ‘synergistic' anti-tumor activity. The null hypothesis is independent drug action, where each patient's response to a combination of therapies is equal to that patient's best single-agent response. DATA SOURCES We analyzed twelve randomized-controlled clinical trials testing combinations of ICIs with other drug classes in patients with advanced cancers, including melanoma and lung, breast, gastric, kidney, and head and neck cancers. For each analysis, the clinical activity of each constituent therapy of the combination was available in the respective study population. METHODS We digitized Progression Free Survival curves for combination therapies and their constituents, and computed PFS expected for the null hypothesis of independent action by randomly sampling single-agent PFS durations (with correlation ρ=0.3±0.2 to account for cross-resistance), and assigning each simulated patient the longer of the two sampled PFS values. For each combination therapy, simulated and clinically observed PFS distributions were compared. RESULTS None of the analyzed clinical trials of ICIs in combination therapies exhibited PFS surpassing the null hypothesis of independent drug action. This suggest that there is no additive or synergistic effect in patients receiving combination therapies with ICIs. Rather, these combinations provided benefits that are largely predictable from the response probabilities of each constituent therapy. CONCLUSIONS Combining ICIs with other cancer therapies provides predictable and clinically meaningful benefit by bet-hedging: providing patients with more chances of a response to any one therapy. This implies that similar benefits may in principle result from sequential treatments or biomarker-stratified choice of treatment. This insight may be most valuable in cases where toxicity prevents full-dose combinations. Citation Format: Adam C. Palmer, Peter K. Sorger, Benjamin Izar. Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1047.
Abstract 954: Adverse immunomodulatory effects of chemotherapy on myeloid-derived suppressor cell compromise immune-checkpoint blockade efficacy
Authors: Tsz Tung Kwong, Chi Hang Wong, Jing Ying Zhou, Alfred Sze Lok Cheng, Anthony Wing Hung Chan, Stephen Lam Chan
Journal: Cancer Research (2020)

Abstract Introduction: Intrinsic immunologic composition in liver tumor microenvironment (TME) may play a role in the heterogenous response towards immune-checkpoint blockade in hepatocellular carcinoma (HCC). In some cancers, it has been shown that cytotoxic chemotherapy is synergistic with checkpoint inhibitors. In this study, we evaluated the efficacy and immunomodulation of 5-FU and anti-PD-L1 in orthotopic liver cancer mouse model. Method: The orthotopic mouse model was established with the murine HCC cell line RIL-175 through intrahepatic injection. The tumor-bearing mice was then treated with 5-FU (i.p.) 3 times per week at 20mg/kg. Anti-PD-L1(10mg/kg) was delivered (i.p.) every 5 days. Tumor growth was reflected by the luciferase intensity via in vivo imaging. Upon sacrifice, the tumor tissue, liver, spleen and blood sample were harvested, followed by subsequent immune profiling analysis using flow cytometry. Results: Based on the tumor growth rate and endpoint tumor weight, anti-PD-L1 monotherapy induced a significant tumor reduction whereas 5-FU, either alone or combined with anti-PD-L1, did not have therapeutic effect as compared to vehicle control. Proportions of immunosurveillance cells including natural killer (NK) cells, CD8+ T cells and CD4+ T cells were drastically increased in the tumor site after anti-PD-L1 single treatment, but reduced in 5-FU-treated tumor. To depict the underlying regulation by chemotherapy, immunosuppressive components were also examined. Accumulation in myeloid cells, particularly CD11b+Gr-1+Ly6G+Ly6Cint polymorphonuclear myeloid-derived suppressor cells (P-MDSCs) were found to be a contributing factor to lymphocytes depletion when treated with 5-FU, hence counteracting the anti-tumor activity by PD-L1 blockade. Conclusion: In summary, our data indicate that chemotherapeutics may impose immunosuppressive modulation in HCC TME and latently alter the therapeutic outcome against immune-checkpoint blockade. This study suggests that combination of chemotherapy with checkpoint inhibitors may not be a feasible approach for HCC. Acknowledgement: The study is supported by the Terry Fox Foundation. Key Words: Tumor microenvironment (TME), Hepatocellular carcinoma, Chemotherapy, myeloid-derived suppressor cell (MDSC), anti-PD-L1, immunotherapy Citation Format: Tsz Tung Kwong, Chi Hang Wong, Jing Ying Zhou, Alfred Sze Lok Cheng, Anthony Wing Hung Chan, Stephen Lam Chan. Adverse immunomodulatory effects of chemotherapy on myeloid-derived suppressor cell compromise immune-checkpoint blockade efficacy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 954.
Abstract 2137: A high proportion of protein phosphorylation sites identified in CPTAC breast cancer and lung adenocarcinoma may result from direct phosphorylation by CDK1
Authors: Dunrui Wang, Xiaolan Qian, Sarah Eng, Lisa Jenkins, Marian Durkin, Douglas Lowy
Journal: Cancer Research (2020)

Abstract Cyclin-dependent kinase 1 (CDK1) is a serine/threonine kinase that drives the G2/M phase of the cell cycle, and increased CDK1 kinase activity is a frequent feature of several tumor types. In the current study, we have used the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets to identify potential target phosphorylation sites associated with CDK1 activity in breast and lung adenocarcinoma and to experimentally study some of their biologic effects. Among the global protein phosphorylation sites detected in CPTAC, 80% and 81% of the identified phosphorylation sites in breast cancer and lung adenocarcinoma were found to correlate well with the level of an activating phosphorylation site in CDK1, t161. Positive correlations (r &amp;gt; 0.6) were present in most paired samples of tumor tissue and normal tissue. In addition, 42% and 40% of all phosphorylation sites in both of these tumor types were found to contain the minimum CDK1 consensus motif Ser/Thr-Pro (S/T-P). This result suggests that many of the sites with this motif are directly phosphorylated by CDK1, while most of the sites that lack this sequence are likely to be phosphorylated by other kinases. In both tumor types, increased phosphorylation of proteins in several signaling pathways, including those for glycolysis and the cell cycle, were found to be associated with phosphorylation of CDK1 t161. To study a possible direct effect of CDK1-dependent phosphorylation on a protein involved in cell cycle progression, we selected Epithelial Cell Transforming 2 (ECT2), which is a Rho family-specific GEF (guanine nucleotide exchange factor) with a role in G2/M. In agreement with the proteomic data, mass spectrometry analysis showed elevated ECT2 phosphorylation on T359, S367, T373, S376 and S861 in the G2/M phase that was sensitive to treatment with a CDK1 inhibitor. Biological experiments confirmed that phosphorylation of these sites enhanced the pro-oncogenic and GEF activity of ECT2. Additional experimental mechanistic analysis is needed to demonstrate whether specific phosphorylations are attributable to direct or indirect effects of CDK1. Citation Format: Dunrui Wang, Xiaolan Qian, Sarah Eng, Lisa Jenkins, Marian Durkin, Douglas Lowy. A high proportion of protein phosphorylation sites identified in CPTAC breast cancer and lung adenocarcinoma may result from direct phosphorylation by CDK1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2137.
Abstract 5613: Human interleukin 15 (IL15) humanized NCG mice support the human natural killer cells reconstitution and development
Authors: Cunxiang Ju, Mingkun Zhang, Dan Wu, Dingyu Wang, Hongyan Sun, Jin Tang, Shuai Li, Jing Zhao, Xiang Gao
Journal: Cancer Research (2020)

Abstract The potential of NK cells in cancer therapy has aroused increasing attention. While highly immune deficient mice, NCG,with null mutation on Prkdc and IL2Rγ,is ideal for human immune reconstitution, the reconstitution of human NK cells is still challenging. This is mostly because species barrier on cytokines which are necessary for the proliferation and maturation of NK cells. To this end, we established a human IL-15 (hIL-15) knock-in NCG (NCG-hIL-15), which produces hIL-15 under physiological level and pattern.NCG-hIL-15 implanted with either purified human NK cells or hematopoietic stem cells (HSCs) could give rise to a longer-term maintenance of human NK cell when compared to NCG. These long-lived NK cells retained the ability of migration, as evidenced by their wide distribution in various organs (e.g. spleen, liver, and lung). We also tested the expression profiles of killer cell immunoglobulin-like receptor (KIR) molecules, as well as the secretion of granzyme and perforin, results suggested normal activity and function of these reconstituted NK cells. Moreover, after human NK cell reconstitution, efficient tumor growth inhibition of human NK-specific agonist was shown in tumor engrafted NCG-hIL15. Taken together, NCG-hIL-15 mice is a novel mouse model for studying human NK cell biology and human NK-mediated cancer immunotherapy in vivo. Citation Format: Cunxiang Ju, Mingkun Zhang, Dan Wu, Dingyu Wang, Hongyan Sun, Jin Tang, Shuai Li, Jing Zhao, Xiang Gao. Human interleukin 15 (IL15) humanized NCG mice support the human natural killer cells reconstitution and development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5613.