tbuckley/cabot-search huggingface dataset:
Multimodal Imaging in a Patient With Alzheimer Disease and Parkinsonism Because of a Presenilin-1 Mutation
Authors: Jia-Ying Lu, Yi-Min Sun, Tzu-Chen Yen, Chuan-Tao Zuo, Jian Wang
Journal: Clinical Nuclear Medicine (2021)

Abstract A correct clinical diagnosis of motor dysfunction accompanied by cognitive impairment remains challenging. Recent advances in molecular imaging biomarkers hold promise to overcome this issue. A 37-year-old woman presenting with parkinsonism and cognitive impairment underwent both multimodal neuroimaging and genetic testing. Her main findings on PET included diffuse tau accumulation in the cerebral cortex and left putamen, increased cerebellar amyloid deposits, asymmetrically reduced dopamine transporter binding, and mild hypermetabolism in the putamen. Genetic analysis revealed the presence of a presenilin-1 mutation (C.1157T&gt;G). These findings suggested a diagnosis of early-onset autosomal dominant Alzheimer disease accompanied by parkinsonism.
Targeted Deep Sequencing of Bladder Tumors Reveals Novel Associations between Cancer Gene Mutations and Mutational Signatures with Major Risk Factors
Authors: Stella Koutros, Nina Rao, Lee E. Moore, Michael L. Nickerson, Donghyuk Lee, Bin Zhu, Larissa A. Pardo, Dalsu Baris, Molly Schwenn, Alison Johnson, Kristine Jones, Montserrat Garcia-Closas, Ludmila Prokunina-Olsson, Debra T. Silverman, Nathaniel Rothman, Michael Dean
Journal: Clinical Cancer Research (2021)

Exome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle-invasive bladder cancer with detailed risk factor information.
Drosophila primary microRNA-8 encodes a microRNA-encoded peptide acting in parallel of miR-8
Authors: Audrey Montigny, Patrizia Tavormina, Carine Duboe, Hélène San Clémente, Marielle Aguilar, Philippe Valenti, Dominique Lauressergues, Jean-Philippe Combier, Serge Plaza
Journal: Genome biology (2021)

Abstract Background Recent genome-wide studies of many species reveal the existence of a myriad of RNAs differing in size, coding potential and function. Among these are the long non-coding RNAs, some of them producing functional small peptides via the translation of short ORFs. It now appears that any kind of RNA presumably has a potential to encode small peptides. Accordingly, our team recently discovered that plant primary transcripts of microRNAs ( pri-miRs ) produce small regulatory peptides (miPEPs) involved in auto-regulatory feedback loops enhancing their cognate microRNA expression which in turn controls plant development. Here we investigate whether this regulatory feedback loop is present in Drosophila melanogaster . Results We perform a survey of ribosome profiling data and reveal that many pri-miRNAs exhibit ribosome translation marks. Focusing on miR-8, we show that pri-miR-8 can produce a miPEP-8. Functional assays performed in Drosophila reveal that miPEP-8 affects development when overexpressed or knocked down. Combining genetic and molecular approaches as well as genome-wide transcriptomic analyses, we show that miR-8 expression is independent of miPEP-8 activity and that miPEP-8 acts in parallel to miR-8 to regulate the expression of hundreds of genes. Conclusion Taken together, these results reveal that several Drosophila pri-miRs exhibit translation potential. Contrasting with the mechanism described in plants, these data shed light on the function of yet undescribed primary-microRNA -encoded peptides in Drosophila and their regulatory potential on genome expression.
Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial
Authors: Steven G. Kelsen, Ioana O. Agache, Weily Soong, Elliot Israel, Geoffrey L. Chupp, Dorothy S. Cheung, Wiebke Theess, Xiaoying Yang, Tracy L. Staton, David F. Choy, Alice Fong, Ajit Dash, Michael Dolton, Rajita Pappu, Christopher E. Brightling
Journal: Journal of Allergy and Clinical Immunology (2021)

The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics.This study evaluated astegolimab efficacy and safety in patients with severe asthma.This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured ∼30 patients who were eosinophil-high (≥300 cells/μL) and ∼95 patients who were eosinophil-low (<300 cells/μL) per arm.Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups.Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.
Opportunities and Challenges for the Next Phase of Enhanced Recovery After Surgery
Authors: Olle Ljungqvist, Hans D. de Boer, Angie Balfour, William J. Fawcett, Dileep N. Lobo, Gregg Nelson, Michael J. Scott, Thomas W. Wainwright, Nicolas Demartines
Journal: JAMA Surgery (2021)

Enhanced Recovery After Surgery (ERAS) is a global surgical quality improvement initiative now firmly entrenched within the field of perioperative care. Although ERAS is associated with significant clinical outcome improvements and cost savings in numerous surgical specialties, several opportunities and challenges deserve further discussion.Uptake and implementation of ERAS Society guidelines, together with ERAS-related research, have increased exponentially since the inception of the ERAS movement. Opportunities to further improve patient outcomes include addressing frailty, optimizing nutrition, prehabilitation, correcting preoperative anemia, and improving uptake of ERAS worldwide, including in low- and middle-income countries. Challenges facing enhanced recovery today include implementation, carbohydrate loading, reversal of neuromuscular blockade, and bowel preparation. The COVID-19 pandemic poses both a challenge and an opportunity for ERAS.To date, ERAS has achieved significant benefit for patients and health systems; however, improvements are still needed, particularly in the areas of patient optimization and systematic implementation. During this time of global crisis, the ERAS method of delivering care is required to take surgery and anesthesia to the next level and bring improvements in outcomes to both patients and health systems.
Long-Term Outcomes of Patients With Late Presentation of ST-Segment Elevation Myocardial Infarction
Authors: Kyung Hoon Cho, Xiongyi Han, Joon Ho Ahn, Dae Young Hyun, Min Chul Kim, Doo Sun Sim, Young Joon Hong, Ju Han Kim, Youngkeun Ahn, Jin Yong Hwang, Seok Kyu Oh, Kwang Soo Cha, Cheol Ung Choi, Kyung-Kuk Hwang, Hyeon Cheol Gwon, Myung Ho Jeong
Journal: Journal of the American College of Cardiology (2021)
A pain killer without analgesic tolerance designed by co-targeting PSD-95-nNOS interaction and α2-containning GABA<sub>A</sub>Rs
Authors: Jun Li, Lin Zhang, Chu Xu, Ying-Ying Shen, Yu-Hui Lin, Yu Zhang, Hai-Yin Wu, Lei Chang, Ying-Dong Zhang, Rong Chen, Zheng-Ping Zhang, Chun-Xia Luo, Fei Li, Dong-Ya Zhu
Journal: Theranostics (2021)

Overactivation of N-methyl-D-aspartate receptor (NMDAR) in the spinal cord dorsal horn (SDH) in the setting of injury represents a key mechanism of neuropathic pain. However, directly blocking NMDAR or its downstream signaling, interaction between postsynaptic density-95 (PSD-95) and neuronal nitric oxide synthase (nNOS), causes analgesic tolerance, mainly due to GABAergic disinhibition. The aim of this study is to explore the possibility of preventing analgesic tolerance through co-targeting NMDAR downstream signaling and γ-aminobutyric acid type A receptors (GABAARs). Methods: Mechanical/thermal hyperalgesia were quantified to assess analgesic effects. Miniature postsynaptic currents were tested by patch-clamp recording to evaluate synaptic transmission in the SDH. GABA-evoked currents were tested on HEK293 cells expressing different subtypes of recombinant GABAARs to assess the selectivity of (+)-borneol and ZL006-05. The expression of α2 and α3 subunits of GABAARs and BDNF, and nNOS-PSD-95 complex levels were analyzed by western blotting and coimmunoprecipitation respectively. Open field test, rotarod test and Morris water maze task were conducted to evaluate the side-effect of ZL006-05. Results: (+)-Borneol selectively potentiated α2- and α3-containing GABAARs and prevented the disinhibition of laminae I excitatory neurons in the SDH and analgesic tolerance caused by chronic use of ZL006, a nNOS-PSD-95 blocker. A dual-target compound ZL006-05 produced by linking ZL006 and (+)-borneol through an ester bond blocked nNOS-PSD-95 interaction and potentiated α2-containing GABAAR selectively. Chronic use of ZL006-05 did not produce analgesic tolerance and unwanted side effects. Conclusion: By targeting nNOS-PSD-95 interaction and α2-containing GABAAR simultaneously, chronic use of ZL006-05 can avoid analgesic tolerance and unwanted side effects. Therefore, we offer a novel candidate drug without analgesic tolerance for treating neuropathic pain.
Familial thrombocytopenia due to a complex structural variant resulting in a <i>WAC-ANKRD26</i> fusion transcript
Authors: Lara Wahlster, Jeffrey M. Verboon, Leif S. Ludwig, Susan C. Black, Wendy Luo, Kopal Garg, Richard A. Voit, Ryan L. Collins, Kiran Garimella, Maura Costello, Katherine R. Chao, Julia K. Goodrich, Stephanie P. DiTroia, Anne O’Donnell-Luria, Michael E. Talkowski, Alan D. Michelson, Alan B. Cantor, Vijay G. Sankaran
Journal: The Journal of Experimental Medicine (2021)

Advances in genome sequencing have resulted in the identification of the causes for numerous rare diseases. However, many cases remain unsolved with standard molecular analyses. We describe a family presenting with a phenotype resembling inherited thrombocytopenia 2 (THC2). THC2 is generally caused by single nucleotide variants that prevent silencing of ANKRD26 expression during hematopoietic differentiation. Short-read whole-exome and genome sequencing approaches were unable to identify a causal variant in this family. Using long-read whole-genome sequencing, a large complex structural variant involving a paired-duplication inversion was identified. Through functional studies, we show that this structural variant results in a pathogenic gain-of-function WAC-ANKRD26 fusion transcript. Our findings illustrate how complex structural variants that may be missed by conventional genome sequencing approaches can cause human disease.
Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189
Authors: D. Rodríguez-Abreu, S.F. Powell, M.J. Hochmair, S. Gadgeel, E. Esteban, E. Felip, G. Speranza, F. De Angelis, M. Dómine, S.Y. Cheng, H.G. Bischoff, N. Peled, M. Reck, R. Hui, E.B. Garon, M. Boyer, T. Kurata, J. Yang, M.C. Pietanza, F. Souza, M.C. Garassino
Journal: Annals of Oncology (2021)
<i>Notes from the Field</i>: Multistate Outbreak of <i>Escherichia coli</i> O26 Infections Linked to Raw Flour — United States, 2019
Authors: Michael Vasser, Jonathan Barkley, Adam Miller, Ellen Gee, Katherine Purcell, Morgan N. Schroeder, Colin Basler, Karen P. Neil
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

On February 20, 2019, PulseNet, the molecular subtyping network for foodborne disease surveillance, identified six Shiga toxin-producing Escherichia coli (STEC) O26:H11 infections with the same pulsed-field gel electrophoresis (PFGE) pattern combination.This PFGE pattern combination matched that of infections from a July 2018 outbreak that was associated with ground beef.In response, CDC initiated an investigation with federal, state, and local partners to identify the outbreak source and implement prevention measures.CDC defined a case as STEC O26 infection with an isolate matching the outbreak strain by PFGE or related by core genome multilocus sequence typing scheme (cgMLST), with dates of illness onset during December 11, 2018-May 21, 2019.Investigators initially hypothesized that ground beef was the outbreak cause because of the PFGE match to the July 2018 outbreak and because in early interviews, patients commonly reported eating ground beef and leafy greens.Investigators used cgMLST to compare the genetic sequences of isolates from both outbreaks and determined that they fell into separate genetic clades (differing by 6-11 alleles), suggesting that something other than ground beef caused the illness in 2019.CDC noted that one patient consumed raw cookie dough and that most patients were young adult females, similar to demographic distributions of past flour-associated STEC outbreaks (1-3).Investigators developed a supplemental questionnaire focusing on beef, leafy greens, and flour exposures.Twenty-one cases were reported from nine states (Figure).The median age of patients was 24 years (range = 7-86 years); 71% were female.Three patients were hospitalized, and none died.Among 13 patients asked about flour exposures, six reported eating, licking, or tasting raw homemade dough or batter during the week before illness onset.Three patients reported eating raw dough or batter made with the same grocery store brand of all-purpose flour, including a patient who reported eating raw dough at a bakery in Rhode Island.Overall, of 18 patients with store information, 11 reported shopping at this same grocery store chain.The Rhode Island Department of Health visited the bakery reported by the patient and collected flour for testing.On
Airspace dimension assessment with nanoparticles as a proposed biomarker for emphysema
Authors: H Laura Aaltonen, Madeleine Petersson Sjögren, Jonas K F Jakobsson, Hanna Nicklasson, Sandra Diaz, Francisco Sánchez Montiel, Sophia Zackrisson, Veronica Ideböhn, Gunnar Engström, Jakob Löndahl, Per Wollmer
Journal: Thorax (2021)

Airspace dimension assessment with nanoparticles (AiDA) is a novel method to measure distal airspace radius non-invasively. In this study, AiDA radii were measured in 618 individuals from the population-based Swedish CArdiopulmonary BioImaging Study, SCAPIS. Subjects with emphysema detected by computed tomography were compared to non-emphysematous subjects. The 47 individuals with mainly mild-to-moderate visually detected emphysema had significantly larger AiDA radii, compared with non-emphysematous subjects (326±48 µm vs 291±36 µm); OR for emphysema per 10 µm: 1.22 (1.13-1.30, p<0.0001). Emphysema according to CT densitometry was similarly associated with larger radii compared with non-emphysematous CT examinations (316±41 µm vs 291 µm±26 µm); OR per 10 µm: 1.16 (1.08-1.24, p<0.0001). The results are in line with comparable studies. The results show that AiDA is a potential biomarker for emphysema in individuals in the general population.
Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: interim results of a randomised, placebo-controlled, phase 1–2, dose-ranging study
Authors: Paul A Goepfert, Bo Fu, Anne-Laure Chabanon, Matthew I Bonaparte, Matthew G Davis, Brandon J Essink, Ian Frank, Owen Haney, Helene Janosczyk, Michael C Keefer, Marguerite Koutsoukos, Murray A Kimmel, Roger Masotti, Stephen J Savarino, Lode Schuerman, Howard Schwartz, Lawrence D Sher, Jon Smith, Fernanda Tavares-Da-Silva, Sanjay Gurunathan, Carlos A DiazGranados, Guy de Bruyn
Journal: The Lancet Infectious Diseases (2021)
Altering the Microbiome Inhibits Tumorigenesis in a Mouse Model of Oviductal High-Grade Serous Carcinoma
Authors: Lixing Chen, Yali Zhai, Yisheng Wang, Eric R. Fearon, Gabriel Núñez, Naohiro Inohara, Kathleen R. Cho
Journal: Cancer Research (2021)

Studies have shown bacteria influence the initiation and progression of cancers arising in sites that harbor rich microbial communities, such as the colon. Little is known about the potential for the microbiome to influence tumorigenesis at sites considered sterile, including the upper female genital tract. The recent identification of distinct bacterial signatures associated with ovarian carcinomas suggests microbiota in the gut, vagina, or elsewhere might contribute to ovarian cancer pathogenesis. Here, we tested whether altering the microbiome affects tumorigenesis in a mouse model of high-grade serous carcinoma (HGSC) based on conditional oviduct-specific inactivation of the Brca1, Trp53, Rb1, and Nf1 tumor suppressor genes. Cohorts of control (n = 20) and antibiotic-treated (n = 23) mice were treated with tamoxifen to induce tumor formation and then monitored for 12 months. The antibiotic cocktail was administered for the first 5 months of the monitoring period in the treatment group. Antibiotic-treated mice had significantly fewer and less advanced tumors than control mice at study endpoint. Antibiotics induced changes in the composition of the intestinal and vaginal microbiota, which were durable in the fecal samples. Clustering analysis showed particular groups of microbiota are associated with the development of HGSC in this model. These findings demonstrate the microbiome influences HGSC pathogenesis in an in vivo model that closely recapitulates the human disease. Because the microbiome can modulate efficacy of cancer chemo- and immunotherapy, our genetically engineered mouse model system may prove useful for testing whether altering the microbiota can improve the heretofore poor response of HGSC to immunotherapies. SIGNIFICANCE: This study provides strong in vivo evidence for a role of the microbiome in ovarian cancer pathogenesis.
Macroautophagy in lymphatic endothelial cells inhibits T cell–mediated autoimmunity
Authors: Guillaume Harlé, Camille Kowalski, Juan Dubrot, Dale Brighouse, Gaëlle Clavel, Robert Pick, Natacha Bessis, Jennifer Niven, Christoph Scheiermann, Monique Gannagé, Stéphanie Hugues
Journal: The Journal of Experimental Medicine (2021)

Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.
A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer
Authors: Bernhard Kloesch, Vivien Ionasz, Sumit Paliwal, Natascha Hruschka, Jaime Martinez de Villarreal, Rupert Öllinger, Sebastian Mueller, Hans Peter Dienes, Martin Schindl, Elisabeth S Gruber, Judith Stift, Dietmar Herndler-Brandstetter, Gwen A Lomberk, Barbara Seidler, Dieter Saur, Roland Rad, Raul A Urrutia, Francisco X Real, Paola Martinelli
Journal: Gut (2021)

Molecular taxonomy of tumours is the foundation of personalised medicine and is becoming of paramount importance for therapeutic purposes. Four transcriptomics-based classification systems of pancreatic ductal adenocarcinoma (PDAC) exist, which consistently identified a subtype of highly aggressive PDACs with basal-like features, including ΔNp63 expression and loss of the epithelial master regulator GATA6. We investigated the precise molecular events driving PDAC progression and the emergence of the basal programme.
A highly multiplexed droplet digital PCR assay to measure the intact HIV-1 proviral reservoir
Authors: Claire N. Levy, Sean M. Hughes, Pavitra Roychoudhury, Daniel B. Reeves, Chelsea Amstuz, Haiying Zhu, Meei-Li Huang, Yulun Wei, Marta E. Bull, Noah A.J. Cassidy, Jan McClure, Lisa M. Frenkel, Mars Stone, Sonia Bakkour, Elizabeth R. Wonderlich, Michael P. Busch, Steven G. Deeks, Joshua T. Schiffer, Robert W. Coombs, Dara A. Lehman, Keith R. Jerome, Florian Hladik
Journal: Cell Reports Medicine (2021)

Quantifying the replication-competent HIV reservoir is essential for evaluating curative strategies. Viral outgrowth assays (VOAs) underestimate the reservoir because they fail to induce all replication-competent proviruses. Single- or double-region HIV DNA assays overestimate it because they fail to exclude many defective proviruses. We designed two triplex droplet digital PCR assays, each with 2 unique targets and 1 in common, and normalize the results to PCR-based T cell counts. Both HIV assays are specific, sensitive, and reproducible. Together, they estimate the number of proviruses containing all five primer-probe regions. Our 5-target results are on average 12.1-fold higher than and correlate with paired quantitative VOA (Spearman's ρ = 0.48) but estimate a markedly smaller reservoir than previous DNA assays. In patients on antiretroviral therapy, decay rates in blood CD4+ T cells are faster for intact than for defective proviruses, and intact provirus frequencies are similar in mucosal and circulating T cells.