tbuckley/cabot-search huggingface dataset:
Defibrotide Inhibits Antiphospholipid Antibody–Mediated Neutrophil Extracellular Trap Formation and Venous Thrombosis
Authors: Ramadan A. Ali, Shanea K. Estes, Alex A. Gandhi, Srilakshmi Yalavarthi, Claire K. Hoy, Hui Shi, Yu Zuo, Doruk Erkan, Jason S. Knight
Journal: Arthritis & Rheumatology (2021)

Defibrotide is a heterogenous mixture of polyanionic oligonucleotides currently approved for treatment of transplant-associated venoocclusive disease. While defibrotide has a known role in limiting endothelial cell activation, some studies have also demonstrated anti-leukocyte properties. In a recent study, we found that neutrophil extracellular traps (NETs) play a role in the thrombotic complications of antiphospholipid syndrome (APS). In the present study, we investigated the hypothesis that defibrotide might act to mitigate APS-relevant NET formation in vitro and in mouse models.
Inhibition of the CDK9–cyclin T1 protein–protein interaction as a new approach against triple-negative breast cancer
Authors: Sha-Sha Cheng, Yuan-Qing Qu, Jia Wu, Guan-Jun Yang, Hao Liu, Wanhe Wang, Qi Huang, Feng Chen, Guodong Li, Chun-Yuen Wong, Vincent Kam Wai Wong, Dik-Lung Ma, Chung-Hang Leung
Journal: Acta Pharmaceutica Sinica B (2021)

Cyclin-dependent kinase 9 (CDK9) activity is correlated with worse outcomes of triple-negative breast cancer (TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein–protein interaction (PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CˆN ligand and tested their activity against the CDK9–cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9–cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9–cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.
TCT-316 Impact of Geographic Variation on the Safety and Efficacy of the Supreme Biodegradable Polymer Sirolimus-Eluting Stent: Results From the PIONEER III Clinical Trial in North America, Europe, and Japan
Authors: Philippe Garot, Martin Leon, Shigeru Saito, Andreas Baumbach, Dean Kereiakes, Stephan Windecker, Cody Pietras, Ovidiu Dressler, Melek Issever, Michael Curtis, Barry Bertolet, James Zidar, Pieter Smits, Victor Alfonso Jimenez Diaz, Brent Mclaurin, Angel Cequier, Sjoerd Hofma, Nabil Dib, Akihiko Takahashi, Tsunekazu Kakuta, Atsushi Hirohata, Alexandra Lansky
Journal: Journal of the American College of Cardiology (2021)
TCT-193 The Correlation and Relative Prognostic Value of FFR and Pd/Pa of Nonculprit Lesions in STEMI
Authors: Zsolt Piroth, Gabor Fulop, Bianca Boxma–de Klerk, Elmir Omerovic, Peter Andreka, Geza Fontos, Franz-Josef Neumann, Gert Richardt, Mohammad Abdelghani, Pieter Smits
Journal: Journal of the American College of Cardiology (2021)
TCT-118 Propensity-Adjusted Population-Based Analysis of Impella in Patients Undergoing High-Risk PCI From a Large-Scale Claims Dataset
Authors: Alexandra Lansky, Daniela Tirziu, Cody Pietras, Jeffrey Moses, E. Magnus Ohman, William O'Neill, Cindy Grines, Keith Needham, Mercedes Ekono, David Gregory, Helen Parise
Journal: Journal of the American College of Cardiology (2021)
TCT-451 Thirty-Day Outcomes After Next-Day Discharge in Transcatheter Aortic Valve Replacement: Analysis of the STS/ACC TVT Registry
Authors: Wayne Batchelor, Carlos Sanchez, Paul Sorajja, James Harvey, Benjamin Galper, Annapoorna Kini, Patricia Keegan, Kendra Grubb, Ruth Eisenberg, Toby Rogers
Journal: Journal of the American College of Cardiology (2021)
Development of Cellular Pathology
Authors: W BOYD
Journal: JAMA (1963)

Although from the very beginning Rudolf Virchow, the father of cellular pathology, laid emphasis on disturbance of function, for many years the attention of pathologists was concentrated on the changes in structure produced by disease. The structures involved were the nucleus and cytoplasm. Now that the infinite complexity of cellular structure has been revealed by the electron microscope and cytochemical technique, attention has again been focused on disturbance of function, which alone is responsible for the symptoms of the sick person who seeks help from the doctor.
Allergens from rye pollen (<i>Secale cereale</i>)
Authors: M. T. Montero, E. Alonso, T. Sainz
Journal: Allergy (1992)

Rye pollen was incubated for 30 min and proteins extracted at this time were collected as extract A (EA). The same pollen grains were resuspended in buffer and incubated for 18.5 h. Proteins extracted in this period were designated extract B (EB), Both extracts were subfractionated by DEAE ion‐exchange chromatography and allergen presence in peaks detected by the dot‐immnunobinding technique. The results reveal that unretained proteins (peaks 1 and 2) and proteins eluted at 0.2 M NaCl from extract B contain the highest proportion of allergens, SDS‐PAGE of chromatographic peaks showed that peak 2 from extract B contains a highly purified 28 kDa band. On the skin of allergic patients this band gave a stronger positive prick test than for the crude extract.
Amyloid and Tau in Alzheimer’s Disease: Biomarkers or Molecular Targets for Therapy? Are We Shooting the Messenger?
Authors: Anand Kumar, Charles B. Nemeroff, Joseph J. Cooper, Alik Widge, Carolyn Rodriguez, Linda Carpenter, William M. McDonald
Journal: American Journal of Psychiatry (2021)

Alzheimer's disease is a neuropsychiatric disorder with devastating clinical and socioeconomic consequences. Since the original description of the neuropathological correlates of the disorder, neuritic plaques and neurofibrillary tangles have been presumed to be critical to the underlying pathophysiology of the illness. The authors review the clinical and neuropathological origins of Alzheimer's disease and trace the evolution of modern biomarkers from their historical roots. They describe how technological innovations such as neuroimaging and biochemical assays have been used to measure and quantify key proteins and lipids in the brain, cerebrospinal fluid, and blood and advance their role as biomarkers of Alzheimer's disease. Together with genomics, these approaches have led to the development of a thematic and focused science in the area of degenerative disorders. The authors conclude by drawing distinctions between legitimate biomarkers of disease and molecular targets for therapeutic intervention and discuss future approaches to this complex neurobehavioral illness.
Non-coding RNAs: key regulators of reprogramming, pluripotency, and cardiac cell specification with therapeutic perspective for heart regeneration
Authors: Hannah J Hunkler, Sonja Groß, Thomas Thum, Christian Bär
Journal: Cardiovascular Research (2021)

Abstract Myocardial infarction causes a massive loss of cardiomyocytes (CMs), which can lead to heart failure accompanied by fibrosis, stiffening of the heart, and loss of function. Heart failure causes high mortality rates and is a huge socioeconomic burden, which, based on diets and lifestyle in the developed world, is expected to increase further in the next years. At present, the only curative treatment for heart failure is heart transplantation associated with a number of limitations such as donor organ availability and transplant rejection among others. Thus, the development of cellular reprogramming and defined differentiation protocols provide exciting new possibilities for cell therapy approaches and which opened up a new era in regenerative medicine. Consequently, tremendous research efforts were undertaken to gain a detailed molecular understanding of the reprogramming processes and the in vitro differentiation of pluripotent stem cells into functional CMs for transplantation into the patient’s injured heart. In the last decade, non-coding RNAs, particularly microRNAs, long non-coding RNAs, and circular RNAs emerged as critical regulators of gene expression that were shown to fine-tune cellular processes both on the transcriptional and the post-transcriptional level. Unsurprisingly, also cellular reprogramming, pluripotency, and cardiac differentiation and maturation are regulated by non-coding RNAs. In here, we review the current knowledge on non-coding RNAs in these processes and highlight how their modulation may enhance the quality and quantity of stem cells and their derivatives for safe and efficient clinical application in patients with heart failure. In addition, we summarize the clinical cell therapy efforts undertaken thus far.
Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study
Authors: Michael Wang, Radhakrishnan Ramchandren, Robert Chen, Lionel Karlin, Geoffrey Chong, Wojciech Jurczak, Ka Lung Wu, Mark Bishton, Graham P. Collins, Paul Eliadis, Frédéric Peyrade, Yihua Lee, Karl Eckert, Jutta K. Neuenburg, Constantine S. Tam
Journal: Journal of Hematology & Oncology (2021)

Ibrutinib plus venetoclax, given with an ibrutinib lead-in, has shown encouraging clinical activity in early phase studies in mantle cell lymphoma (MCL). The ongoing phase 3 SYMPATICO study evaluates the safety and efficacy of concurrently administered, once-daily, all-oral ibrutinib plus venetoclax in patients with relapsed/refractory MCL. A safety run-in (SRI) cohort was conducted to inform whether an ibrutinib lead-in should be implemented for the randomized portion. Patients received concurrent ibrutinib 560 mg continuously plus venetoclax in a 5-week ramp-up to venetoclax 400 mg for up to 2 years. The primary endpoint was occurrence of tumor lysis syndrome (TLS) and dose-limiting toxicities (DLTs). The SRI cohort enrolled 21 patients; six and 15 were in low- or increased-risk categories for TLS, respectively. During the 5-week venetoclax ramp-up, three patients had DLTs, and one patient at increased risk for TLS had a laboratory TLS; no additional TLS events occurred during follow-up. With a median follow-up of 31 months, the overall response rate was 81% (17/21); 62% (13/21) of patients had a complete response. SRI data informed that the randomized portion should proceed with concurrent ibrutinib plus venetoclax, with no ibrutinib lead-in. Ibrutinib plus venetoclax demonstrated promising efficacy; no new safety signals were observed.Trial registration: ClinicalTrials.gov, NCT03112174. Registered 13 April 2017, https://clinicaltrials.gov/ct2/show/NCT03112174 .
Reply
Authors: Ellen G. Driever, William Bernal, Ton Lisman
Journal: Hepatology (2021)

Introduction:The negative impact of haemophilia on social participation is well established in previous studies, however, the impact of Von Willebrand disease (VWD) on social participation has not been studied. Aim:To compare the social participation of a large cohort of VWD patients in the Netherlands with the general Dutch population.In addition, to identify factors associated with social participation in VWD.Methods: Patients participating in the "Willebrand in the Netherlands" study completed an extensive questionnaire on educational level, absenteeism from school or work, and occupational disabilities.Results: Seven-hundred and eighty-eight VWD patients were included (mean age 38.9 years, 59.5% females), of whom 136 children < 16 years.Adult patients with type 3 VWD more often had a low educational level (52.9%) compared to type 1 (40.2%),type 2 VWD (36.8%) and the general population (36.4%) (p = .005).Moreover, in patients aged ≥16 years the days lost from school and/or work in the year prior to study
Development and validation of the food allergy severity score
Authors: Montserrat Fernández‐Rivas, Ismael Gómez García, Alejandro Gonzalo‐Fernández, Manuel Fuentes Ferrer, Sabine Dölle‐Bierke, Guadalupe Marco‐Martín, Barbara K. Ballmer‐Weber, Riccardo Asero, Simona Belohlavkova, Kirsten Beyer, Frédéric de Blay, Michael Clausen, Mareen R. Datema, Ruta Dubakiene, Kate E. C. Grimshaw, Karin Hoffmann‐Sommergruber, Jonathan O’B Hourihane, Monika Jedrzejczak‐Czechowicz, André C. Knulst, Tanya Kralimarkova, Thuy‐My Le, Nikolaos G. Papadopoulos, Todor A. Popov, Lars K. Poulsen, Ashok Purohit, Suranjith L. Seneviratne, Angela Simpson, Atanasios Sinaniotis, Mirjana Turkalji, Sonia Vázquez‐Cortés, Rosialzira N. Vera‐Berrios, Antonella Muraro, Margitta Worm, Graham Roberts, Ronald van Ree, Cristina Fernández‐Pérez, Paul J. Turner, Elizabeth N. Clare Mills
Journal: Allergy (2021)

The heterogeneity and lack of validation of existing severity scores for food allergic reactions limit standardization of case management and research advances. We aimed to develop and validate a severity score for food allergic reactions.Following a multidisciplinary experts consensus, it was decided to develop a food allergy severity score (FASS) with ordinal (oFASS) and numerical (nFASS) formats. oFASS with 3 and 5 grades were generated through expert consensus, and nFASS by mathematical modeling. Evaluation was performed in the EuroPrevall outpatient clinic cohort (8232 food reactions) by logistic regression with request of emergency care and medications used as outcomes. Discrimination, classification, and calibration were calculated. Bootstrapping internal validation was followed by external validation (logistic regression) in 5 cohorts (3622 food reactions). Correlation of nFASS with the severity classification done by expert allergy clinicians by Best-Worst Scaling of 32 food reactions was calculated.oFASS and nFASS map consistently, with nFASS having greater granularity. With the outcomes emergency care, adrenaline and critical medical treatment, oFASS and nFASS had a good discrimination (receiver operating characteristic area under the curve [ROC-AUC]>0.80), classification (sensitivity 0.87-0.92, specificity 0.73-0.78), and calibration. Bootstrapping over ROC-AUC showed negligible biases (1.0 × 10-6 -1.23 × 10-3 ). In external validation, nFASS performed best with higher ROC-AUC. nFASS was strongly correlated (R 0.89) to best-worst scoring of 334 expert clinicians.FASS is a validated and reliable method to measure severity of food allergic reactions. The ordinal and numerical versions that map onto each other are suitable for use by different stakeholders in different settings.
Childhood stunting in relation to the pre- and postnatal environment during the first 2 years of life: The MAL-ED longitudinal birth cohort study
Journal: PLoS Medicine (2017)

Stunting is the most prevalent manifestation of childhood malnutrition. To characterize factors that contribute to stunting in resource-poor settings, we studied a priori selected biological and social factors collected longitudinally in a cohort of newborns.We enrolled 1,868 children across 7 resource-poor settings in Bangladesh, Brazil, India, Nepal, Peru, South Africa, and Tanzania shortly after birth and followed them for 24 months between 2 November 2009 and 28 February 2014. We collected longitudinal anthropometry, sociodemographic factors, maternal-reported illnesses, and antibiotic use; child feeding practices; dietary intake starting at 9 months; and longitudinal blood, urine, and stool samples to investigate non-diarrheal enteropathogens, micronutrients, gut inflammation and permeability, and systemic inflammation. We categorized length-for-age Z-scores into 3 groups (not stunted, ≥-1; at risk, <-1 to -2; and stunted, <-2), and used multivariable ordinal logistic regression to model the cumulative odds of being in a lower length-for-age category (at risk or stunted). A total of 1,197 children with complete longitudinal data were available for analysis. The prevalence of having a length-for-age Z-score below -1 increased from 43% (range 37%-47% across sites) shortly after birth (mean 7.7 days post-delivery, range 0 to 17 days) to 74% (16%-96%) at 24 months. The prevalence of stunting increased 3-fold during this same time period. Factors that contributed to the odds of being in a lower length-for-age category at 24 months were lower enrollment weight-for-age (interquartile cumulative odds ratio = 1.82, 95% CI 1.49-2.23), shorter maternal height (2.38, 1.89-3.01), higher number of enteropathogens in non-diarrheal stools (1.36, 1.07-1.73), lower socioeconomic status (1.75, 1.20-2.55), and lower percent of energy from protein (1.39, 1.13-1.72). Site-specific analyses suggest that reported associations were similar across settings. While loss to follow-up and missing data are inevitable, some study sites had greater loss to follow-up and more missing data than others, which may limit the generalizability of the findings.Neonatal and maternal factors were early determinants of lower length-for-age, and their contribution remained important throughout the first 24 months of life, whereas the average number of enteropathogens in non-diarrheal stools, socioeconomic status, and dietary intake became increasingly important contributors by 24 months relative to neonatal and maternal factors.
Case 33-2021: A 68-Year-Old Man with Painful Mouth Ulcers
Authors: Sook-Bin Woo, Markus Y. Wu, Nathaniel S. Treister, Philip C. Amrein, Daniela Kroshinsky, Robert P. Hasserjian
Journal: New England Journal of Medicine (2021)

A 68-year-old man was admitted with painful mouth ulcers and weight loss of 6 weeks' duration. The ulcers had worsened despite treatment with acyclovir, prednisone, and colchicine. The blood eosinophil count was increased, and the patient was positive for the HLA-B51 allele. A diagnostic procedure was performed.
TCT-189 Effect of Low-Dose Intracoronary Alteplase on Global Circumferential Strain: Myocardial Strain Cardiovascular Magnetic Resonance Substudy of the T-TIME Trial
Authors: Peter McCartney, Daniel Ang, Kenneth Mangion, Annette Maznyczka, Margaret McEntegart, Hany Eteiba, John Greenwood, Douglas Muir, Saqib Chowdhary, Clare Appleby, James Cotton, Andrew Wragg, Nick Curzen, Keith Oldroyd, Richard Good, Keith Robertson, Tom Ford, Damien Collison, Lynsey Gillespie, Mark Petrie, Robin Weir, Peter Macfarlane, Ian Ford, Alex McConnachie, Colin Berry
Journal: Journal of the American College of Cardiology (2021)
New threats to visceral leishmaniasis control
Authors: Munyaradzi Makoni
Journal: The Lancet Microbe (2021)

Visceral leishmaniasis—also known as kala-azar—is a neglected tropical disease (NTD) transmitted by the bite of phlebotomine sandflies and is the deadliest parasitic killer after malaria. It threatens the poorest communities most strongly. "Visceral leishmaniasis is a fatal disease if not treated, many millions of people in endemic areas are exposed to infection, and with [frequent] occurrence of outbreaks, often associated with conflict, population displacement", says Elin Hoffmann Dahl (MSF Access Campaign, Médecins Sans Frontières, Geneva, Switzerland).
Youth-onset type 2 diabetes among First Nations young people in northern Australia: a retrospective, cross-sectional study
Authors: Angela Titmuss, Elizabeth A Davis, Vicki O'Donnell, Mark Wenitong, Louise J Maple-Brown, Aveni Haynes, Angela Titmuss, Elizabeth A Davis, Vicki O'Donnell, Mark Wenitong, Elizabeth L M Barr, John Boffa, Alex D H Brown, Christine Connors, Sumaria Corpus, James Dowler, Sian Graham, Emma Griffiths, Renae Kirkham, Christopher Lee, Elizabeth Moore, Glenn Pearson, Jonathan E Shaw, Sally Singleton, Ashim Sinha, Gwyneth White, Paul Zimmet, Louise J Maple-Brown, Aveni Haynes
Journal: The Lancet Diabetes & Endocrinology (2021)
Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn's disease: a systematic review and network meta-analysis
Authors: Siddharth Singh, M Hassan Murad, Mathurin Fumery, Rocio Sedano, Vipul Jairath, Remo Panaccione, William J Sandborn, Christopher Ma
Journal: The Lancet. Gastroenterology & hepatology (2021)
Role of the IgG4-related cholangitis autoantigen annexin A11 in cholangiocyte protection
Authors: Toni Herta, Remco Kersten, Jung-Chin Chang, Lowiek Hubers, Simei Go, Dagmar Tolenaars, Coen C. Paulusma, Michael H. Nathanson, Ronald Oude Elferink, Stan F.J. van de Graaf, Ulrich Beuers
Journal: Journal of Hepatology (2021)

Annexin A11 was identified as autoantigen in IgG4-related cholangitis (IRC), a B-cell driven disease. Annexin A11 modulates calcium-dependent exocytosis, a crucial mechanism for insertion of proteins into their target membranes. Human cholangiocytes form an apical 'biliary bicarbonate umbrella' regarded as defense against harmful hydrophobic bile acid influx. The bicarbonate secretory machinery comprises the chloride/bicarbonate exchanger AE2 and the chloride channel ANO1. We aimed to investigate the expression and function of annexin A11 in human cholangiocytes and a potential role of IgG1/IgG4-mediated autoreactivity against annexin A11 in the pathogenesis of IRC.
TCT-51 Complete Cerebral Protection via Left Radial Approach During Transcatheter Aortic Valve Replacement: Results From the PROTEMBO C Trial
Authors: Dariusz Jagielak, Radoslaw Targonski, Tobias Schmidt, Christian Frerker, Mohamed Abdel-Wahab, Johannes Wilde, Michael Lauterbach, Juergen Leick, Marek Grygier, Marcin Misterski, Andrejs Erglis, Inga Narbute, Adam Witkowski, Matti Adam, Derk Frank, Fernando Gatto, Nikos Werner
Journal: Journal of the American College of Cardiology (2021)
Xenoextracellular matrix-rosiglitazone complex-mediated immune evasion promotes xenogenic bioengineered root regeneration by altering M1/M2 macrophage polarization
Authors: Tingting Lan, Jie Chen, Jiayu Zhang, Fangjun Huo, Xue Han, Zhijun Zhang, Yuchan Xu, Yibing Huang, Li Liao, Li Xie, Weidong Tian, Weihua Guo
Journal: Biomaterials (2021)
TCT-42 Impact of Right Ventricle-Pulmonary Artery Coupling on Clinical Outcomes After Transcatheter and Surgical Aortic Valve Replacement: An Analysis of the PARTNER 3 Trial
Authors: Tom Cahill, Philippe Pibarot, Vasilis Babaliaros, Philipp Blanke, Marie-Annick Clavel, Pamela Douglas, Omar Khalique, Jonathon Leipsic, Raj Makkar, Erin Rogers, Mark Russo, Neil Weissman, Maria Alu, Susheel Kodali, Michael Mack, Martin Leon, Rebecca Hahn
Journal: Journal of the American College of Cardiology (2021)
Challenges in estimating numbers of vectors integrated in gene-modified cells using DNA sequence information
Authors: Frederic D. Bushman, Adrian Cantu, John Everett, Denise Sabatino, Charles Berry
Journal: Molecular Therapy (2021)

In evaluating outcomes in human gene therapy, it can be of interest to estimate the absolute numbers of vector copies integrated into the genomes of patient cells. Unfortunately, all methods for quantification of population sizes have limitations, some of which may not be fully appreciated by the field. In one approach, DNA sequencing can be used to enumerate junctions between vector and host sequences in patient specimens. However, a second technical replicate from the same DNA specimen almost always yields numerous integration sites not recovered in the first. Thus, reconstructing the full number requires mathematical modeling to infer the full population size from partial samples. Many methods have been proposed for this; the Chao1 estimator is often used for integration site data. However, complications of sampling lead to estimates that represent only a lower bound on the true number. In addition, choices of methods for quality control may have large effects on population bounds. After accounting for the number of cells sampled, a lower bound can be proposed for the number of cells harboring an integrated vector. Other methods for estimating the numbers of gene-modified cells are also described, but these too have considerable uncertainties, emphasizing that accurate population size estimation remains a challenge.