tbuckley/cabot-search huggingface dataset:
Systems-Level Immunomonitoring from Acute to Recovery Phase of Severe COVID-19
Authors: Lucie Rodriguez, Pirkka T. Pekkarinen, Tadepally Lakshmikanth, Ziyang Tan, Camila Rosat Consiglio, Christian Pou, Yang Chen, Constantin Habimana Mugabo, Ngoc Anh Nguyen, Kirsten Nowlan, Tomas Strandin, Lev Levanov, Jaromir Mikes, Jun Wang, Anu Kantele, Jussi Hepojoki, Olli Vapalahti, Santtu Heinonen, Eliisa Kekäläinen, Petter Brodin
Journal: Cell Reports Medicine (2020)

HighlightsImmunomonitoring from acute to recovery phase COVID-19An IFNγ-eosinophil axis precedes lung hyperinflammationBasophils modulate SARS-CoV-2 IgG responsesA shared trajectory of immunological recovery in COVID-19SummarySevere disease of SARS-CoV-2 is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5–7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Given that every patient is captured at different stages of infection, longitudinal monitoring of the immune response is critical and systems-level analyses are required to capture cellular interactions. Here, we report on a systems-level blood immunomonitoring study of 37 adult patients diagnosed with COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNγ-eosinophil axis activated before lung hyperinflammation and changes in cell-cell co-regulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.Graphical abstract
Trends in Outcomes for Marginal Allografts in Liver Transplant
Authors: Theodore Zhang, Jordan Dunson, Fasiha Kanwal, Nhu Thao Nguyen Galvan, John M. Vierling, Christine O’Mahony, John A. Goss, Abbas Rana
Journal: JAMA Surgery (2020)

Investigating outcomes after marginal allograft transplant is essential in determining appropriate and more aggressive use of these allografts.
Efficacy of Maintenance Olaparib for Patients With Newly Diagnosed Advanced Ovarian Cancer With a BRCA Mutation: Subgroup Analysis Findings From the SOLO1 Trial
Authors: Paul DiSilvestro, Nicoletta Colombo, Giovanni Scambia, Byoung-Gie Kim, Ana Oaknin, Michael Friedlander, Alla Lisyanskaya, Anne Floquet, Alexandra Leary, Gabe S. Sonke, Charlie Gourley, Susana Banerjee, Amit Oza, Antonio González-Martín, Carol A. Aghajanian, William H. Bradley, Cara A. Mathews, Joyce Liu, Elizabeth S. Lowe, Ralph Bloomfield, Kathleen N. Moore
Journal: Journal of Clinical Oncology (2020)

In SOLO1, maintenance olaparib (300 mg twice daily) significantly improved progression-free survival (PFS) for patients with newly diagnosed
Tomisaku Kawasaki: identified and named Kawasaki disease
Authors: Barbara Kermode-Scott
Journal: BMJ (2020)

Photo credit: Tsubara Kawasaki

Not many physicians have a disease named after them. Tomisaku (“Tomi”) Kawasaki, who has died at the age of 95, was one of the few. Kawasaki disease, a rare inflammatory autoimmune disorder found in young children, is his namesake.1 In recent months, this syndrome has been in the global media spotlight as paediatricians discuss its similarity to the complications of covid-19 in children.

“Kawasaki was an icon in the paediatric world,” Jane Burns, professor and director of the Kawasaki Disease Research Centre at the University of California San Diego School of Medicine, told The BMJ . “Dr K was an amazing cheerleader and advocate for research on the condition that bears his name. Despite his rock star status, he was humble and generous with his time to physicians and parents alike. He was clearly motivated by a deep love of all children.”

Kawasaki was the youngest of seven brothers and sisters. His parents named him Tomisaku, meaning to make a fortune, in the hope that he …
First case of osteosarcoma in a dinosaur: a multimodal diagnosis
Authors: Seper Ekhtiari, Kentaro Chiba, Snezana Popovic, Rhianne Crowther, Gregory Wohl, Andy Kin On Wong, Darren H Tanke, Danielle M Dufault, Olivia D Geen, Naveen Parasu, Mark A Crowther, David C Evans
Journal: The Lancet Oncology (2020)
IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe–/– mice
Authors: Jing Wang, Xiang Cheng, Mei-Xiang Xiang, Mervi Alanne-Kinnunen, Jian-An Wang, Han Chen, Aina He, Xinghui Sun, Yan Lin, Ting-Ting Tang, Xin Tu, Sara Sjöberg, Galina K. Sukhova, Yu-Hua Liao, Daniel H. Conrad, Lunyin Yu, Toshiaki Kawakami, Petri T. Kovanen, Peter Libby, Guo-Ping Shi
Journal: Journal of Clinical Investigation (2018)
Combining BRAF inhibition with oncolytic herpes simplex virus enhances the immune-mediated antitumor therapy of BRAF-mutant thyroid cancer
Authors: Eva Crespo-Rodriguez, Katharina Bergerhoff, Galabina Bozhanova, Shane Foo, Emmanuel C Patin, Harriet Whittock, Richard Buus, Syed Haider, Gareth Muirhead, Khin Thway, Kate Newbold, Robert S Coffin, Richard G Vile, Dae Kim, Martin McLaughlin, Alan A Melcher, Kevin J Harrington, Malin Pedersen
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background The aggressive clinical behavior of poorly differentiated and anaplastic thyroid cancers (PDTC and ATC) has proven challenging to treat, and survival beyond a few months from diagnosis is rare. Although 30%–60% of these tumors contain mutations in the BRAF gene, inhibitors designed specifically to target oncogenic BRAF have shown limited and only short-lasting therapeutic benefits as single agents, thus highlighting the need for improved treatment strategies, including novel combinations. Methods Using a BRAF V600E -driven mouse model of ATC, we investigated the therapeutic efficacy of the combination of BRAF inhibition and oncolytic herpes simplex virus (oHSV). Analyses of samples from tumor-bearing mice were performed to immunologically characterize the effects of different treatments. These immune data were used to inform the incorporation of immune checkpoint inhibitors into triple combination therapies. Results We characterized the immune landscape in vivo following BRAF inhibitor treatment and detected only modest immune changes. We, therefore, hypothesized that the addition of oncolytic virotherapy to BRAF inhibition in thyroid cancer would create a more favorable tumor immune microenvironment, boost the inflammatory status of tumors and improve BRAF inhibitor therapy. First, we showed that thyroid cancer cells were susceptible to infection with oHSV and that this process was associated with activation of the immune tumor microenvironment in vivo. Next, we showed improved therapeutic responses when combining oHSV and BRAF inhibition in vivo, although no synergistic effects were seen in vitro, further confirming that the dominant effect of oHSV in this context was likely immune-mediated. Importantly, both gene and protein expression data revealed an increase in activation of T cells and natural killer (NK) cells in the tumor in combination-treated samples. The benefit of combination oHSV and BRAF inhibitor therapy was abrogated when T cells or NK cells were depleted in vivo. In addition, we showed upregulation of PD-L1 and CTLA-4 following combined treatment and demonstrated that blockade of the PD-1/PD-L1 axis or CTLA-4 further improved combination therapy. Conclusions The combination of oHSV and BRAF inhibition significantly improved survival in a mouse model of ATC by enhancing immune-mediated antitumor effects, and triple combination therapies, including either PD-1 or CTLA-4 blockade, further improved therapy.
A Randomized Clinical Trial of Fecal Microbiota Transplant for Alcohol Use Disorder
Authors: Jasmohan S. Bajaj, Edith A. Gavis, Andrew Fagan, James B. Wade, Leroy R. Thacker, Michael Fuchs, Samarth Patel, Brian Davis, Jill Meador, Puneet Puri, Masoumeh Sikaroodi, Patrick M. Gillevet
Journal: Hepatology (2020)

Alcohol use disorder (AUD) is associated with microbial alterations that worsen with cirrhosis. Fecal microbiota transplant (FMT) could be a promising approach.In this phase 1, double-blind, randomized clinical trial, patients with AUD-related cirrhosis with problem drinking (AUDIT-10 > 8) were randomized 1:1 into receiving one placebo or FMT enema from a donor enriched in Lachnospiraceae and Ruminococcaceae. Six-month safety was the primary outcome. Alcohol craving questionnaire, alcohol consumption (urinary ethylglucuronide/creatinine), quality of life, cognition, serum IL-6 and lipopolysaccharide-binding protein, plasma/stool short-chain fatty acids (SCFAs), and stool microbiota were tested at baseline and day 15. A 6-month follow-up with serious adverse event (SAE) analysis was performed. Twenty patients with AUD-related cirrhosis (65 ± 6.4 years, all men, Model for End-Stage Liver Disease 8.9 ± 2.7) with similar demographics, cirrhosis, and AUD severity were included. Craving reduced significantly in 90% of FMT versus 30% in placebo at day 15 (P = 0.02) with lower urinary ethylglucuronide/creatinine (P = 0.03) and improved cognition and psychosocial quality of life. There was reduction in serum IL-6 and lipopolysaccharide-binding protein and increased butyrate/isobutyrate compared with baseline in FMT but not placebo. Microbial diversity increased with higher Ruminococcaceae and other SCFAs, producing taxa following FMT but not placebo, which were linked with SCFA levels. At 6 months, patients with any SAEs (8 vs. 2, P = 0.02), AUD-related SAEs (7 vs. 1, P = 0.02), and SAEs/patient (median [interquartile range], 1.5 [1.25] vs. 0 [0.25] in FMT, P = 0.02) were higher in placebo versus FMT.This phase 1 trial shows that FMT is safe and associated with short-term reduction in alcohol craving and consumption with favorable microbial changes versus placebo in patients with alcohol-associated cirrhosis with alcohol misuse. There was also a reduction in AUD-related events over 6 months in patients assigned to FMT.
Prognostic value of transbronchial lung cryobiopsy for the multidisciplinary diagnosis of idiopathic pulmonary fibrosis: a retrospective validation study
Authors: Sara Tomassetti, Claudia Ravaglia, Athol U Wells, Alberto Cavazza, Thomas V Colby, Giulio Rossi, Brett Ley, Jay H Ryu, Silvia Puglisi, Antonella Arcadu, Martina Marchi, Fabio Sultani, Sabrina Martinello, Luca Donati, Carlo Gurioli, Christian Gurioli, Paola Tantalocco, Jurgen Hetzel, Alessandra Dubini, Sara Piciucchi, Catherine Klersy, Federico Lavorini, Venerino Poletti
Journal: The Lancet Respiratory Medicine (2020)
Dabrafenib and Trametinib in Patients With Tumors With <i>BRAF<sup>V600E</sup></i> Mutations: Results of the NCI-MATCH Trial Subprotocol H
Authors: April K. S. Salama, Shuli Li, Erin R. Macrae, Jong-In Park, Edith P. Mitchell, James A. Zwiebel, Helen X. Chen, Robert J. Gray, Lisa M. McShane, Larry V. Rubinstein, David Patton, P. Mickey Williams, Stanley R. Hamilton, Deborah K. Armstrong, Barbara A. Conley, Carlos L. Arteaga, Lyndsay N. Harris, Peter J. O’Dwyer, Alice P. Chen, Keith T. Flaherty
Journal: Journal of Clinical Oncology (2020)

PURPOSE BRAF V600 mutations are commonly found in melanoma and thyroid cancers and to a lesser degree in other tumor types. Subprotocol H (EAY131-H) of the NCI-MATCH platform trial sought to investigate the selective BRAF inhibitor dabrafenib and the MEK1/2 inhibitor trametinib in patients with solid tumors, lymphomas, or multiple myeloma whose tumors harbored a BRAF V600 mutation. PATIENTS AND METHODS EAY131-H is an open-label, single-arm study. Patients with melanoma, thyroid, or colorectal cancer were excluded; patients with non–small-cell lung cancer were later excluded in an amendment. Patients received dabrafenib 150 mg twice per day and trametinib 2 mg per day continuously until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival (PFS), 6-month PFS, and overall survival. RESULTS Thirty-five patients were enrolled, and 29 were included in the primary efficacy analysis as prespecified in the protocol. Median age was 59 years, and 45% of the patients had received ≥ 3 lines of therapy. The confirmed ORR was 38% (90% CI, 22.9% to 54.9%) with P &lt; .0001 against a null rate of 5%, and PFS was 11.4 months (90% CI, 8.4 to 16.3 months); responses were seen in 7 distinct tumor types. Seven patients had a duration of response of &gt; 12 months, including 4 patients with a duration of response of &gt; 24 months. An additional 8 patients had a PFS &gt; 6 months. The median overall survival was 28.6 months. Reported adverse events were comparable to those noted in previously reported profiles of dabrafenib and trametinib. CONCLUSION This study met its primary end point, with an ORR of 38% ( P &lt; .0001) in this mixed histology, pretreated cohort. This promising activity warrants additional investigations in BRAF V600 -mutated tumors outside of currently approved indications.
Hereditary diffuse gastric cancer: updated clinical practice guidelines
Authors: Vanessa R Blair, Maybelle McLeod, Fátima Carneiro, Daniel G Coit, Johanna L D'Addario, Jolanda M van Dieren, Kirsty L Harris, Nicoline Hoogerbrugge, Carla Oliveira, Rachel S van der Post, Julie Arnold, Patrick R Benusiglio, Tanya M Bisseling, Alex Boussioutas, Annemieke Cats, Amanda Charlton, Karen E Chelcun Schreiber, Jeremy L Davis, Massimiliano di Pietro, Rebecca C Fitzgerald, James M Ford, Kimberley Gamet, Irene Gullo, Richard H Hardwick, David G Huntsman, Pardeep Kaurah, Sonia S Kupfer, Andrew Latchford, Paul F Mansfield, Takeshi Nakajima, Susan Parry, Jeremy Rossaak, Haruhiko Sugimura, Magali Svrcek, Marc Tischkowitz, Toshikazu Ushijima, Hidetaka Yamada, Han-Kwang Yang, Adrian Claydon, Joana Figueiredo, Karyn Paringatai, Raquel Seruca, Nicola Bougen-Zhukov, Tom Brew, Simone Busija, Patricia Carneiro, Lynn DeGregorio, Helen Fisher, Erin Gardner, Tanis D Godwin, Katharine N Holm, Bostjan Humar, Caroline J Lintott, Elizabeth C Monroe, Mark D Muller, Enrique Norero, Yasmin Nouri, Joana Paredes, João M Sanches, Emily Schulpen, Ana S Ribeiro, Andrew Sporle, James Whitworth, Liying Zhang, Anthony E Reeve, Parry Guilford
Journal: The Lancet Oncology (2020)
Drug suppliers are told to replenish stockpiles for Brexit and further pandemic this winter
Authors: Matthew Limb
Journal: BMJ (2020)

The UK government has urged medicine suppliers to stockpile six weeks’ worth of drugs as a “buffer” against disruption when the Brexit transition period ends on 31 December this year.

A letter from the Department of Health and Social Care, published on 3 August, acknowledged that global supply chains were under “significant pressure, exacerbated by recent events with covid-19.”1 It said that companies should make stockpiling a key part of contingency plans and should “plan for all scenarios,” including any reduced traffic flow at short strait crossings such as between Dover and Calais.

Mark Dayan, policy analyst and head of public affairs at the Nuffield Trust, said that the letter was a significant development by ministers. “This indicates that they are scaling up for disruption to medicine supplies in the same way …
Abstract IA11: Overcoming immune evasion in pediatric brain tumors
Authors: Alexandra Garancher, Hiromichi Suzuki, Svasti Haricharan, Meher B. Masihi, Jessica M. Rusert, Paula S. Norris, Florent Carrette, Megan M. Romero, Sorana A. Morrissy, Patryk Skowron, Florence M.G. Cavalli, Hamza Farooq, Vijay Ramaswamy, Alaide Morcavallo, Jacob J. Henderson, James M. Olson, Yoon-Jae Cho, Xiao-Nan Li, Louis Chesler, Marco A. Marra, Oren J. Becher, Linda M. Bradley, Carl F. Ware, Michael D. Taylor, Robert J. Wechsler-Reya
Journal: Cancer Research (2020)

Abstract Many immunotherapies act by enhancing T-cell killing of tumor cells. Cytotoxic T cells recognize antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. Our studies suggest that medulloblastomas and high-grade gliomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. Treatment with tumor necrosis factor or lymphotoxin beta receptor agonist rescues expression of Erap1, Tap1, and MHC-I on p53 mutant tumor cells. In vivo, TNF treatment prolongs survival and markedly augments the efficacy of the immune checkpoint inhibitor anti-PD-1. These studies identify p53 as a key regulator of immune evasion in vivo and suggest that TNF could be used to enhance sensitivity of p53-mutant tumors to immunotherapy. Citation Format: Alexandra Garancher, Hiromichi Suzuki, Svasti Haricharan, Meher B. Masihi, Jessica M. Rusert, Paula S. Norris, Florent Carrette, Megan M. Romero, Sorana A. Morrissy, Patryk Skowron, Florence M.G. Cavalli, Hamza Farooq, Vijay Ramaswamy, Alaide Morcavallo, Jacob J. Henderson, James M. Olson, Yoon-Jae Cho, Xiao-Nan Li, Louis Chesler, Marco A. Marra, Oren J. Becher, Linda M. Bradley, Carl F. Ware, Michael D. Taylor, Robert J. Wechsler-Reya. Overcoming immune evasion in pediatric brain tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA11.
Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency
Authors: Enrica E.K. Tan, Richard A. Hopkins, Chrissie K. Lim, Saumya S. Jamuar, Christina Ong, Koh C. Thoon, Mark J.A. Koh, Eun Mong Shin, Derrick W.Q. Lian, Madhushanee Weerasooriya, Christopher Z.W. Lee, Andreas Alvin Pumomo Soetedjo, Chang Siang Lim, Veonice B. Au, Edmond Chua, Hui Yin Lee, Leigh Ann Jones, Sharmy S. James, Nivashini Kaliaperumal, Jeffery Kwok, Ee Shien Tan, Biju Thomas, Lynn Xue Wu, Lena Ho, Anna Marie Fairhurst, Florent Ginhoux, Adrian K.K. Teo, Yong Liang Zhang, Kok Huar Ong, Weimiao Yu, Byrappa Venkatesh, Vinay Tergaonkar, Bruno Reversade, Keh Chuang Chin, Ah Moy Tan, Woei Kang Liew, John E. Connolly
Journal: Journal of Clinical Investigation (2020)

Although IKK-β has previously been shown as a negative regulator of IL-1β secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1β expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1β secretion was elevated in the patient's stimulated leukocytes, in her induced pluripotent stem cell–derived macrophages, and in murine bone marrow–derived macrophages containing the L34P mutation. The patient's hypersecretion of IL-1β correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1β release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1β secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.
Clinically Important Improvements in Risk Assessment by Adding High-Sensitivity Troponin Level to Cholesterol Guidelines
Authors: Harvey D. White
Journal: JAMA Cardiology (2020)

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Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products
Authors: Qian Wei, Jian Bai, Daojiang Yan, Xiuqi Bao, Wenting Li, Bingyu Liu, Dan Zhang, Xiangbing Qi, Dequan Yu, Youcai Hu
Journal: Acta Pharmaceutica Sinica B (2020)

Endophytic fungi are promising producers of bioactive small molecules. Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters, exhibited its strong ability to produce numbers of secondary metabolites. However, this strain mainly produce rubratoxins alone with high yield in varied culture conditions, suggested most gene clusters are silent. Efforts for mining the cryptic gene clusters in P. dangeardii, including epigenetic regulation and one-strain-many-compounds (OSMAC) approach were failed probably due to the high yield of rubratoxins. A metabolic shunting strategy by deleting the key gene for rubratoxins biosynthesis combining with optimization of culture condition successfully activated multiple silent genes encoding for other polyketide synthases (PKSs), and led to the trace compounds detectable. As a result, a total of 23 new compounds including azaphilone monomers, dimers, trimers with unprecedented polycyclic bridged heterocycle and spiral structures, as well as siderophores were identified. Some compounds showed significant cytotoxicities, anti-inflammatory or antioxidant activities. The attractive dual PKSs gene clusters for azaphilones biosynthesis were mined by bioinformatic analysis and overexpression of a pathway specific transcription factor. Our work therefor provides an efficient approach to mine the chemical diversity of endophytic fungi.