tbuckley/cabot-search huggingface dataset:
Abstract IA019: Organoids to model endometrial cancer subtypes
Authors: David G. Huntsman
Journal: Clinical Cancer Research (2021)

Abstract Before the Cancer Genome Atlas and other genomic studies, endometrial cancer had no reproducible biologic or clinical structure. The molecular classification of endometrial cancer is reproducible, potentially clinically useful and, in the same way that recognition of subtypes led to more effective ovarian cancer research, should enable researchers to have greater impact through more focused studies. Some mutations found in endometrial cancer are subtype specific such as MMR mutations in the MRD subtype or PPP2R1a mutations in the tp53 mutation/copy number high subtype while others such as ARID1a are seen in multiple subtypes. Although the frequency of clear cell cancer is much higher in endometriosis associated ovarian cancers that eutopic endometrial cancers, both sites have similar tumors and these are distinct from those that occur from the similar appearing epithelium of the fallopian tube. This points to the importance of interactions between cell context, mutation and also microenvironment in the development of these cancers. To study these processes we have developed an organoid model system using normal endometrial epithelium. In initial experiments we used Notch inhibitors to force ciliated differentiation and single cell RNA seq to compare ciliated to secretory cell expression profiles. From these data novel markers for ciliated differentiation were obtained. When deployed against endometrial carcinoma tissue microarrays these markers revealed that many cancers are replete with ciliated like cells. Perhaps not surprisingly, as this is a form of differentiation, the presence of these cells was associated with an improved survival as did expression of a secretory cell marker MST. To model uterine cancers we have mutated the organoids with commonly found mutations. ARID1a loss in combination with PIK3CA mutation in this model leads to a morphologic shift towards clear cell cancer and consistent expression changes including loss of RBP1. The key experiments to determine how stromal interactions shape the oncogenic impact of these mutations are ongoing. Citation Format: David G. Huntsman. Organoids to model endometrial cancer subtypes [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA019.
Non-invasive vagus nerve stimulation for rheumatoid arthritis: a proof-of-concept study
Authors: Sara Marsal, Héctor Corominas, Juan José de Agustín, Carolina Pérez-García, María López-Lasanta, Helena Borrell, Delia Reina, Raimón Sanmartí, Javier Narváez, Clara Franco-Jarava, Charles Peterfy, José Antonio Narváez, Vivek Sharma, Konstantinos Alataris, Mark C Genovese, Matthew C Baker
Journal: The Lancet Rheumatology (2021)
Abstract 1054: Widely Used Endothelial Progenitor Cell Assays Define Different Classes of Circulating Progenitor Cells
Authors: Thomas J Povsic, Stacie Ulanch, Katherine Lambeth, Francine Kelly, Eric D Peterson
Journal: Circulation (2007)

Introduction: Interest in the assessment of circulating endogenous progenitor cells (EPCs) is growing as evidence of their role in vascular repair mounts. Multiple measures of EPCs have been described, but there has been limited study of the comparability of these assays. Methods: We sought to determine the correlation between and reproducibility of alternative EPC assay methodologies. The precision of each EPC assay was determined by comparing EPC numbers in duplicate samples. Temporal stability of EPCs was assessed in samples obtained 24 hours apart from healthy volunteers. We then assessed the correlation of EPCs identified using the two most commonly used culture techniques: endothelial cell outgrowth and colony forming unit outgrowth (CFUs) (n=110), as well as EPCs based on cell surface marker expression (CD133, CD34, and VEGFR-2) and aldehyde dehydrogenase (ALDH) activity (n=77) in patients with suspected coronary disease. Results: EPC enumeration based on flow cytometry (FACS) based techniques was more precise (r 2 = 0.84 vs. 0.70) and temporally stable (r 2 = 0.82 vs. 0.21) than culture assays. There was limited correlation in EPC numbers determined using the two common culture based assays, either with each other (p=NS) or with EPCs enumerated based on CD34/CD133 expression (p=NS); however, endothelial CFUs correlated with VEGFR-2 (p&lt;0.0001, Spearman r = 0.60) and CD34/VEGFR-2 (p&lt;0.05, Spearman r = 0.31) expressing cells. EPCs defined by expression of CD133, CD34 and CD133/CD34 correlated with each other (CD133 + vs. CD34 + cells, p&lt;0.05, r = 0.27; CD34 + vs. CD133 + CD34 + cells, p&lt;0.0001, r 2 = 0.52) and with ALDH br cells (ALDH br vs. CD133 + CD34 + cells, p&lt;0.05, r 2 = 0.27), but not with VEGFR-2 + cells (p=NS). Conclusion: Identification of EPCs using flow cytometry can be performed more precisely and reliably than using culture techniques. EPCs can be broadly grouped into two classes: VEGFR-2 expressing cells which are correlated with the numbers of endothelial CFUs, and cells identified based on expression of CD133/CD34 or ALDH activity. These observations underscore the need for better assay standardization and a more precise definition of EPCs in cellular therapy research.
A neuronal blood marker is associated with mortality in old age
Authors: Stephan A. Kaeser, Benoit Lehallier, Mikael Thinggaard, Lisa M. Häsler, Anja Apel, Carina Bergmann, Daniela Berdnik, Bernard Jeune, Kaare Christensen, Sebastian Grönke, Linda Partridge, Tony Wyss-Coray, Jonas Mengel-From, Mathias Jucker
Journal: Nature Aging (2021)
Sulfonated cryogel scaffolds for focal delivery in ex-vivo brain tissue cultures
Authors: Dimitri Eigel, Romy Schuster, Max J. Männel, Julian Thiele, Martyna J. Panasiuk, Laura C. Andreae, Carmine Varricchio, Andrea Brancale, Petra B. Welzel, Wieland B. Huttner, Carsten Werner, Ben Newland, Katherine R. Long
Journal: Biomaterials (2021)
Oxygen supplementation during exercise improves leg muscle fatigue in chronic fibrotic interstitial lung disease
Authors: Mathieu Marillier, Anne-Catherine Bernard, Samuel Verges, Onofre Moran-Mendoza, Denis E O'Donnell, José Alberto Neder
Journal: Thorax (2021)

Background Exercise-induced hypoxaemia is a hallmark of chronic fibrotic interstitial lung disease ( f -ILD). It remains unclear whether patients’ severe hypoxaemia may exaggerate locomotor muscle fatigue and, if so, to what extent oxygen (O 2 ) supplementation can ameliorate these abnormalities. Methods Fifteen patients (12 males, 9 with idiopathic pulmonary fibrosis) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) while breathing medical air. Fifteen age-matched and sex-matched controls cycled up to patients’ Tlim. Patients repeated the exercise test on supplemental O 2 (42%±7%) for the same duration. Near-infrared spectroscopy assessed vastus lateralis oxyhaemoglobin concentration ((HbO 2 )). Pre-exercise to postexercise variation in twitch force (∆Tw) induced by femoral nerve magnetic stimulation quantified muscle fatigue. Results Patients showed severe hypoxaemia (lowest O 2 saturation by pulse oximetry=80.0%±7.6%) which was associated with a blunted increase in muscle (HbO 2) during exercise vs controls (+1.3±0.3 µmol vs +4.4±0.4 µmol, respectively; p&lt;0.001). Despite exercising at work rates ∼ one-third lower than controls (42±13 W vs 66±13 W), ∆Tw was greater in patients (∆Tw/external work performed by the leg muscles=−0.59±0.21 %/kJ vs −0.25±0.19 %/kJ; p&lt;0.001). Reversal of exertional hypoxaemia with supplemental O 2 was associated with a significant increase in muscle (HbO 2) , leading to a reduced decrease in ∆Tw in patients (−0.33±0.19 %/kJ; p&lt;0.001 vs air). Supplemental O 2 significantly improved leg discomfort (p=0.005). Conclusion O 2 supplementation during exercise improves leg muscle oxygenation and fatigue in f -ILD. Lessening peripheral muscle fatigue to enhance exercise tolerance is a neglected therapeutic target that deserves clinical attention in this patient population.
Death by Massive Hemorrhage in Robert Frost’s “Out, Out–”
Authors: Rosalyn Buckland, Michael K. Abernethy
Journal: JAMA (2021)

This Arts and Medicine feature uses poet Robert Frost’s poem “Out, Out–”, about the tragic death of a boy in the premodern era from a work injury and hemorrhagic shock, to discuss the stakes of developing a more effective public health response to traumatic injury.
Angus Howard Weir Bain
Authors: Lawrence Bain, Sophie Dear, Catherine Clifford, Janet Cole
Journal: BMJ (2021)

Angus Howard Weir Bain was the son and brother of general practitioners. He was educated at Epsom College. On qualifying he completed national service as a captain in the Royal Army Medical Corps in Egypt. He did house physician and house surgeon roles in Grimsby and Epsom, …
Preclinical Modeling of Surgery and Steroid Therapy for Glioblastoma Reveals Changes in Immunophenotype that are Associated with Tumor Growth and Outcome
Authors: Balint Otvos, Tyler J. Alban, Matthew M. Grabowski, Defne Bayik, Erin E. Mulkearns-Hubert, Tomas Radivoyevitch, Anja Rabljenovic, Sarah Johnson, Charlie Androjna, Alireza M. Mohammadi, Gene H. Barnett, Manmeet S. Ahluwalia, Michael A. Vogelbaum, Peter E. Fecci, Justin D. Lathia
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Glioblastoma (GBM) immunotherapy clinical trials are generally initiated after standard-of-care treatment—including surgical resection, perioperative high-dose steroid therapy, chemotherapy, and radiation treatment—has either begun or failed. However, the impact of these interventions on the antitumoral immune response is not well studied. While discoveries regarding the impact of chemotherapy and radiation on immune response have been made and translated into clinical trial design, the impact of surgical resection and steroids on the antitumor immune response has yet to be determined. Experimental Design: We developed a murine model integrating tumor resection and steroid treatment and used flow cytometry to analyze systemic and local immune changes. These mouse model findings were validated in a cohort of 95 patients with primary GBM. Results: Using our murine resection model, we observed a systemic reduction in lymphocytes corresponding to increased tumor volume and decreased circulating lymphocytes that was masked by dexamethasone treatment. The reduction in circulating T cells was due to reduced CCR7 expression, resulting in T-cell sequestration in lymphoid organs and the bone marrow. We confirmed these findings in a cohort of patients with primary GBM and found that prior to steroid treatment, circulating lymphocytes inversely correlated with tumor volume. Finally, we demonstrated that peripheral lymphocyte content varies with progression-free survival and overall survival, independent of tumor volume, steroid use, or molecular profiles. Conclusions: These data reveal that prior to intervention, increased tumor volume corresponds with reduced systemic immune function and that peripheral lymphocyte counts are prognostic when steroid treatment is taken into account.
Staphylococcus aureus Carriage and Differential Cell Counts in Nasal Lavages of Ragweed-Induced Allergic Rhinitis Using Nasal Allergen Challenge
Authors: Sophia Linton, Rashi Ramchandani, Alyssa Burrows, Jenny Thiele, Lisa Steacy, Prameet Sheth, Anne Ellis
Journal: Journal of Allergy and Clinical Immunology (2021)
Monogenic diabetes: a gateway to precision medicine in diabetes
Authors: Haichen Zhang, Kevin Colclough, Anna L. Gloyn, Toni I. Pollin
Journal: Journal of Clinical Investigation (2021)

Monogenic diabetes refers to diabetes mellitus (DM) caused by a mutation in a single gene and accounts for approximately 1%-5% of diabetes. Correct diagnosis is clinically critical for certain types of monogenic diabetes, since the appropriate treatment is determined by the etiology of the disease (e.g., oral sulfonylurea treatment of HNF1A/HNF4A-diabetes vs. insulin injections in type 1 diabetes). However, achieving a correct diagnosis requires genetic testing, and the overlapping of the clinical features of monogenic diabetes with those of type 1 and type 2 diabetes has frequently led to misdiagnosis. Improvements in sequencing technology are increasing opportunities to diagnose monogenic diabetes, but challenges remain. In this Review, we describe the types of monogenic diabetes, including common and uncommon types of maturity-onset diabetes of the young, multiple causes of neonatal DM, and syndromic diabetes such as Wolfram syndrome and lipodystrophy. We also review methods of prioritizing patients undergoing genetic testing, and highlight existing challenges facing sequence data interpretation that can be addressed by forming collaborations of expertise and by pooling cases.
Covid-19: volunteers cannot be outsourced
Authors: David Barer
Journal: BMJ (2021)

A spokesperson from the Department of Health and Social Care said that there were no delays in accrediting volunteers to help with the covid-19 vaccination programme.1 Evidently NHS staff have time to vaccinate 30 million people in a few weeks without our help. I worry that the real reason for the stonewalling is that unpaid volunteers cannot be outsourced to private companies.

Having retired in 2019, I applied to the General Medical Council last March and am currently …
BciPy: brain–computer interface software in Python
Authors: Tab Memmott, Aziz Koçanaoğulları, Matthew Lawhead, Daniel Klee, Shiran Dudy, Melanie Fried-Oken, Barry Oken
Journal: Brain-Computer Interfaces (2021)

There are high technological and software demands associated with conducting Brain–Computer Interface (BCI) research. In order to accelerate the development and accessibility of BCIs, it is worthwhile to focus on open-source and community desired tooling. Python, a prominent computer language, has emerged as a language of choice for many research and engineering purposes. In this article, BciPy, an open-source, Python-based software for conducting BCI research is presented. It was developed with a focus on restoring communication using Event-Related Potential (ERP) spelling interfaces; however, it may be used for other non-spelling and non-ERP BCI paradigms. Major modules in this system include support for data acquisition, data queries, stimuli presentation, signal processing, signal viewing and modeling, language modeling, task building, and a simple Graphical User Interface (GUI).
RINT1 Regulates SUMOylation and the DNA Damage Response to Preserve Cellular Homeostasis in Pancreatic Cancer
Authors: Frank Arnold, Johann Gout, Heike Wiese, Stephanie E. Weissinger, Elodie Roger, Lukas Perkhofer, Karolin Walter, Jeanette Scheible, Caterina Prelli Bozzo, André Lechel, Thomas J. Ettrich, Ninel Azoitei, Li Hao, Axel Fürstberger, Ewa K. Kaminska, Konstantin M.J. Sparrer, Volker Rasche, Sebastian Wiese, Hans A. Kestler, Peter Möller, Thomas Seufferlein, Pierre-Olivier Frappart, Alexander Kleger
Journal: Cancer Research (2021)

Abstract Pancreatic ductal adenocarcinoma (PDAC) still presents with a dismal prognosis despite intense research. Better understanding of cellular homeostasis could identify druggable targets to improve therapy. Here we propose RAD50-interacting protein 1 (RINT1) as an essential mediator of cellular homeostasis in PDAC. In a cohort of resected PDAC, low RINT1 protein expression correlated significantly with better survival. Accordingly, RINT1 depletion caused severe growth defects in vitro associated with accumulation of DNA double-strand breaks (DSB), G2 cell cycle arrest, disruption of Golgi–endoplasmic reticulum homeostasis, and cell death. Time-resolved transcriptomics corroborated by quantitative proteome and interactome analyses pointed toward defective SUMOylation after RINT1 loss, impairing nucleocytoplasmic transport and DSB response. Subcutaneous xenografts confirmed tumor response by RINT1 depletion, also resulting in a survival benefit when transferred to an orthotopic model. Primary human PDAC organoids licensed RINT1 relevance for cell viability. Taken together, our data indicate that RINT1 loss affects PDAC cell fate by disturbing SUMOylation pathways. Therefore, a RINT1 interference strategy may represent a new putative therapeutic approach. Significance: These findings provide new insights into the aggressive behavior of PDAC, showing that RINT1 directly correlates with survival in patients with PDAC by disturbing the SUMOylation process, a crucial modification in carcinogenesis.
Unraveling circuits of visual perception and cognition through the superior colliculus
Authors: Michele A. Basso, Martha E. Bickford, Jianhua Cang
Journal: Neuron (2021)

The superior colliculus is a conserved sensorimotor structure that integrates visual and other sensory information to drive reflexive behaviors. Although the evidence for this is strong and compelling, a number of experiments reveal a role for the superior colliculus in behaviors usually associated with the cerebral cortex, such as attention and decision-making. Indeed, in addition to collicular outputs targeting brainstem regions controlling movements, the superior colliculus also has ascending projections linking it to forebrain structures including the basal ganglia and amygdala, highlighting the fact that the superior colliculus, with its vast inputs and outputs, can influence processing throughout the neuraxis. Today, modern molecular and genetic methods combined with sophisticated behavioral assessments have the potential to make significant breakthroughs in our understanding of the evolution and conservation of neuronal cell types and circuits in the superior colliculus that give rise to simple and complex behaviors.
Natural history of MZ B cells
Authors: David Nemazee
Journal: The Journal of Experimental Medicine (2021)

In this issue, Tull et al. (https://doi.org/10.1084/jem.20202001) and Kibler et al. (https://doi.org/10.1084/jem.20201952) track human marginal zone B cell development from early progenitors to the memory compartment, addressing changes in age and autoimmunity, the sequence of development in the gut-associated lymphoid tissue, and clonal sharing among memory cells.
Quantitative Assessment of Viral Dispersion Associated with Respiratory Support Devices in a Simulated Critical Care Environment
Authors: Hamed Avari, Ryan J. Hiebert, Agnes A. Ryzynski, Ariela Levy, Julie Nardi, Hasina Kanji-Jaffer, Peter Kiiza, Ruxandra Pinto, Simon W. Plenderleith, Robert A. Fowler, Hamza Mbareche, Samira Mubareka
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Patients with severe coronavirus disease (COVID-19) require supplemental oxygen and ventilatory support. It is unclear whether some respiratory support devices may increase the dispersion of infectious bioaerosols and thereby place healthcare workers at increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Objectives: To quantitatively compare viral dispersion from invasive and noninvasive respiratory support modalities.Methods: This study used a simulated ICU room with a breathing-patient simulator exhaling nebulized bacteriophages from the lower respiratory tract with various respiratory support modalities: invasive ventilation (through an endotracheal tube with an inflated cuff connected to a mechanical ventilator), helmet ventilation with a positive end-expiratory pressure (PEEP) valve, noninvasive bilevel positive-pressure ventilation, nonrebreather face masks, high-flow nasal oxygen (HFNO), and nasal prongs.Measurements and Main Results: Invasive ventilation and helmet ventilation with a PEEP valve were associated with the lowest bacteriophage concentrations in the air, and HFNO and nasal prongs were associated with the highest concentrations. At the intubating position, bacteriophage concentrations associated with HFNO (2.66 × 104 plaque-forming units [PFU]/L of air sampled), nasal prongs (1.60 × 104 PFU/L of air sampled), nonrebreather face masks (7.87 × 102 PFU/L of air sampled), and bilevel positive airway pressure (1.91 × 102 PFU/L of air sampled) were significantly higher than those associated with invasive ventilation (P < 0.05 for each). The difference between bacteriophage concentrations associated with helmet ventilation with a PEEP valve (4.29 × 10-1 PFU/L of air sampled) and bacteriophage concentrations associated with invasive ventilation was not statistically significant.Conclusions: These findings highlight the potential differential risk of dispersing virus among respiratory support devices and the importance of appropriate infection prevention and control practices and personal protective equipment for healthcare workers when caring for patients with transmissible respiratory viral infections such as SARS-CoV-2.
Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)
Authors: Jennifer H. Foster, Stephan D. Voss, David C. Hall, Charles G. Minard, Frank M. Balis, Keith Wilner, Stacey L. Berg, Elizabeth Fox, Peter C. Adamson, Susan M. Blaney, Brenda J. Weigel, Yael P. Mossé
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. Patients and Methods: Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the antitumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study. Results: The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count. Conclusions: Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity. See related commentary by Schulte and Eggert, p. 3507
The immune contexture of primary central nervous system diffuse large B cell lymphoma associates with patient survival and specific cell signaling
Authors: Melissa Alame, Emmanuel Cornillot, Valère Cacheux, Valérie Rigau, Valérie Costes-Martineau, Vanessa Lacheretz-Szablewski, Jacques Colinge
Journal: Theranostics (2021)

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Dupilumab Efficacy in GINA-Defined Difficult-to-Treat Type 2 Asthma Patients in the LIBERTY ASTHMA QUEST Study
Authors: Klaus Rabe, J. Mark FitzGerald, Mario Castro, Ian Pavord, Jorge Maspero, William Busse, Nadia Daizadeh, Benjamin Ortiz, Nami Pandit-Abid, Paul Rowe, Amin Nikhil, Yamo Deniz
Journal: Journal of Allergy and Clinical Immunology (2021)