tbuckley/cabot-search huggingface dataset:
Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke
Authors: Matthias Endres, Maria A. Moro, Christian H. Nolte, Claudia Dames, Marion S. Buckwalter, Andreas Meisel
Journal: Circulation Research (2022)

Inflammation and immune mechanisms are crucially involved in the pathophysiology of the development, acute damage cascades, and chronic course after ischemic stroke. Atherosclerosis is an inflammatory disease, and, in addition to classical risk factors, maladaptive immune mechanisms lead to an increased risk of stroke. Accordingly, individuals with signs of inflammation or corresponding biomarkers have an increased risk of stroke. Anti-inflammatory drugs, such as IL (interleukin)-1β blockers, methotrexate, or colchicine, represent attractive treatment strategies to prevent vascular events and stroke. Lately, the COVID-19 pandemic shows a clear association between SARS-CoV2 infections and increased risk of cerebrovascular events. Furthermore, mechanisms of both innate and adaptive immune systems influence cerebral damage cascades after ischemic stroke. Neutrophils, monocytes, and microglia, as well as T and B lymphocytes each play complex interdependent roles that synergize to remove dead tissue but also can cause bystander injury to intact brain cells and generate maladaptive chronic inflammation. Chronic systemic inflammation and comorbid infections may unfavorably influence both outcome after stroke and recurrence risk for further stroke. In addition, stroke triggers specific immune depression, which in turn can promote infections. Recent research is now increasingly addressing the question of the extent to which immune mechanisms may influence long-term outcome after stroke and, in particular, cause specific complications such as poststroke dementia or even poststroke depression.
A T-cell independent universal cellular therapy strategy through antigen depletion
Authors: Dan Li, Wenbing Wang, Shufeng Xie, Maolin Ge, Ruiheng Wang, Qiongyu Xu, Yan Sun, Jiang Zhu, Han Liu
Journal: Theranostics (2022)

Rationale: T cell therapeutic strategy using CD19-targeting chimeric antigen receptor (CAR) is a revolutionary, novel, and successful treatment for B-cell malignancies. However, the dependency on T-cell mediated cytotoxicity restricts CAR-T therapy as a patient-specific individualized therapy with severe side effects, such as cytokine release syndrome (CRS). Whether a non-T-cell based universal cellular therapy can substitute CAR-T therapy is largely unknown. Methods: Various artificial antigen-recognizing cells were prepared to determine whether non-T-cell-derived CD19-scFv bearing effector cells could cause target cell death. A universal strategy for CRS-free cellular therapeutics was proposed, utilizing artificial antigen-recognizing cells (AARC), which can be manufactured universally and routinely as "off-the-shelf" mesenchymal stromal cells (MSCs) or other types of non-autologous cells expressing anergic CARs. Results: We demonstrated that T-lymphocytic and non-lymphocytic cells could cause CD19 internalization and subsequent depletion when armed with a CD19-recognizing moiety. This CD19 antigen depletion could efficiently induce T-cell independent apoptosis in target cancer cells whose survival depends on CD19 expression, suggesting that CD19 antigen depletion constitutes a crucial tumor destroying mechanism for CD19-CAR-T, especially for its long-term efficacy. Conclusion: Our results uncovered an unrecognized CAR-T cytotoxicity and antigen loss mechanism and provided new insights into a shift from unique patient-specific autologous therapeutics to universal and standardized allogeneic treatment.
Establishment of Patient-Derived Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response
Authors: Mayra Yebra, Shruti Bhargava, Avi Kumar, Adam M. Burgoyne, Chih-Min Tang, Hyunho Yoon, Sudeep Banerjee, Joseph Aguilera, Thekla Cordes, Vipul Sheth, Sangkyu Noh, Rowan Ustoy, Sam Li, Sunil J. Advani, Christopher L. Corless, Michael C. Heinrich, Razelle Kurzrock, Scott M. Lippman, Paul T. Fanta, Olivier Harismendy, Christian Metallo, Jason K. Sicklick
Journal: Clinical Cancer Research (2021)

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase (SDH) subunits (A-D) comprising less than 7.5% (i.e., 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH-mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any SDH-mutant tumors, including GIST, has limited molecular characterization and drug discovery.We describe methods for establishing novel patient-derived SDH-mutant (mSDH) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of patients with mSDH GIST.Molecular and metabolic characterization of our patient-derived mSDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our mSDH GIST models. Translating our in vitro discovery to the clinic, a cohort of patients with SDH-mutant GIST treated with temozolomide (n = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST.We report the first methods to establish patient-derived mSDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with mSDH GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.See related commentary by Blakely et al., p. 3.
Quality and Safety in Healthcare, Part LXXIX
Authors: Jay A. Harolds, Laura B. Miller
Journal: Clinical Nuclear Medicine (2020)

Abstract Most executives new to a health care organization should have introductory and development programs during their first year, which should include networking opportunities, special projects to improve skills, independent or assigned course work, multiple types of assessments, and periodic discussions regarding expectations about their work and their progress in achieving them. It is preferable for the organization and the new executive to have information from outside sources about how a person in that position can achieve success and the reasons for turnover in the position. This is discussed in this article, using the chief nursing officer as the example.
61P Updated efficacy and ctDNA analysis of patients with TRK fusion lung cancer treated with larotrectinib
Authors: V. Moreno, J.J. Lin, D.S.W. Tan, U.N. Lassen, S. Leyvraz, Y. Liu, J. Patel, L. Rosen, B. Solomon, M. Rudolph, R. Norenberg, A. Schulz, M. Fellous, N. Brega, L. Shen, S. Kummar, A. Drilon
Journal: Annals of Oncology (2022)
Theranostic nanoparticles for the management of thrombosis
Authors: Peije Russell, Christoph Eugen Hagemeyer, Lars Esser, Nicolas Hans Voelcker
Journal: Theranostics (2022)

Acute thrombosis and thromboembolisms are one of the leading causes of mortality and morbidity in both developed and developing countries, placing a huge burden on health and economic systems.Early diagnosis is critical but currently limited in accuracy and hampered by a narrow time frame, where the short therapeutic window also severely restricts treatment options.Additionally, clinically used antithrombotics and thrombolytics suffer from severe side effects and are limited in efficacy by a short half-life and susceptibility to degradation.The use of systems containing both diagnostic and therapeutic moieties, known as theranostics, can potentially improve patient outcomes by increasing the precision and efficacy of diagnosis and treatment, enabling personalised and precision medicine.Leveraging nanomedicine may further improve treatment by improving the system's pharmacokinetic properties including controlled drug delivery.This review provides an overview of the development of such theranostic nanoparticle systems, with a focus on approaches that may be utilised to usher this field towards clinical use.
Abstract MP39: Association Of Race And Ethnicity On The Management Of Acute Non-st Elevation Myocardial Infarction
Authors: Tarryn Tertulien, Stephen T Broughton, Gretchen Swabe, Utibe Essien, Jared W Magnani
Journal: Circulation (2022)

Background: Whether differences in acute coronary syndrome (ACS) management are explained or attenuated by social risk factors has important implications for the development of interventions to address health inequities. We examined the associations between (1) race and ethnicity and (2) annual household income with the management of non-ST elevation Myocardial Infarction (NSTEMI). Hypothesis: We hypothesized we would identify racial and ethnic differences in the acute management of NSTEMI and that annual household income would attenuate such differences. Methods: We employed administrative claims of commercially insured and Medicare Advantage beneficiaries (Optum’s de-identified Clinformatics® Data Mart Database) to examine the rates of coronary angiography and percutaneous coronary intervention (PCI) by race and ethnicity as well as the contributions of social risk factors, particularly annual household income, toward racial and ethnic differences. Race and ethnicity were categorized as Asian, Black, Hispanic, or White. Covariates included demographics (age, sex); conditions compromising the Elixhauser Comorbidity Index; and social risk factors (annual household income, educational attainment). Results: We identified 87,094 individuals (age 73.8±11.6 years; 55.6% male; 2.6% Asian, 13.4% Black, 11.2% Hispanic, 72.7% White) with NSTEMI events from 2017 to 2019. The overall incidence rate for coronary angiography was 555 per 1,000 individuals (95% Confidence Interval [CI] 550-560) and for PCI was 297 per 1,000 (95% CI 293-300). Individuals of Black race were 7% less likely to undergo coronary angiography (95% CI 1.02-1.12) and 17% less likely to undergo PCI (95% CI 1.11-1.23) than those of White race. Hispanic individuals were 13% less likely (95% CI 1.08-1.19) to undergo coronary angiography and 18% less likely to undergo PCI (95% CI 1.12-1.24) than White individuals. Higher annual household income attenuated differences in the receipt of PCI for Asian and Black individuals but not those of Hispanic ethnicity. Conclusion: We identified significant racial and ethnic differences in the management of individuals presenting with NSTEMI that were marginally attenuated by higher household income. Our findings demonstrate continued evidence of health inequities in contemporary ACS treatment.
Abstract P060: The Association Of Lean Mass With Type 2 Diabetes: The Coronary Artery Risk Development In Young Adults (CARDIA) Study
Authors: Robert Booker, Shaina Alexandria, Michael Bancks, Lisa Chow, Cora E Lewis, Pamela Schreiner, Mandy Wong, Mercedes R Carnethon
Journal: Circulation (2022)

Introduction: Body mass index (BMI) does not capture tissue composition and thus is unable to assess the contribution of each tissue type to cardiometabolic health. This limitation of BMI may explain the paradoxical association of BMI-weight status with mortality for those with type 2 diabetes (T2D), and merits investigation of individual tissues. We assessed the relationship between body composition and incident T2D and assessed for differences by BMI-weight status. We hypothesized that greater lean mass (LM) would be associated with lower risk for T2D for all BMI groups. Methods: Black and White participants from CARDIA without T2D in 2005-06 (baseline) were included in this longitudinal analysis ( N =2,473). LM and fat mass (FM) were assessed via dual-energy X-ray absorptiometry. Incident T2D was defined using American Diabetes Association cut points for fasting and post-load glucose, glycated hemoglobin, and diabetes medication use. We used Cox proportional hazards regression to estimate hazard ratios (HR) for incident T2D over 10 years according to 1-standard deviation (SD) increment in LM (1 SD=1g) and assessed for potential effect measure modification (EMM) of this association by weight status. We assessed a secondary exposure, LM:FM ratio, in relation to incident T2D. Results: Mean baseline age was 45.2±3.6 years (57% White and 57% female). The cumulative incidence of T2D was 7.2% (178 events, total person years=21,421.7). Before and after adjustment, neither LM nor LM:FM were significantly associated with T2D (Table), and we did not observe evidence for EMM by weight status for any association. Conclusions: LM in middle adulthood does not appear to be associated with T2D risk. Whether incorporation of data for other tissue depots is informative to T2D risk merits evaluation.
The Darwin Prospective Melioidosis Study: a 30-year prospective, observational investigation
Authors: Bart J Currie, Mark Mayo, Linda M Ward, Mirjam Kaestli, Ella M Meumann, Jessica R Webb, Celeste Woerle, Robert W Baird, Ric N Price, Catherine S Marshall, Anna P Ralph, Emma Spencer, Jane Davies, Sarah E Huffam, Sonja Janson, Sarah Lynar, Peter Markey, Vicki L Krause, Nicholas M Anstey
Journal: The Lancet Infectious Diseases (2021)
Intrahepatic microbes govern liver immunity by programming NKT cells
Authors: Joshua C. Leinwand, Bidisha Paul, Ruonan Chen, Fangxi Xu, Maria A. Sierra, Madan M. Paluru, Sumant Nanduri, Carolina G. Alcantara, Sorin A.A. Shadaloey, Fan Yang, Salma A. Adam, Qianhao Li, Michelle Bandel, Inderdeep Gakhal, Lara Appiah, Yuqi Guo, Mridula Vardhan, Zia Flaminio, Emilie R. Grodman, Ari Mermelstein, Wei Wang, Brian Diskin, Berk Aykut, Mohammad Khan, Gregor Werba, Smruti Pushalkar, Mia McKinstry, Zachary Kluger, Jaimie J. Park, Brandon Hsieh, Kristen Dancel-Manning, Feng-Xia Liang, James S. Park, Anjana Saxena, Xin Li, Neil D. Theise, Deepak Saxena, George Miller
Journal: Journal of Clinical Investigation (2022)

The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from that of the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically the bacteroidetes species. Targeting bacteroidetes with oral antibiotics reduced hepatic immune cells by approximately 90%, prevented antigen-presenting cell (APC) maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial/glycosphingolipid/NKT/CCL5 axis that underlies hepatic immunity.
75TiP Open-label, phase II study of tusamitamab ravtansine (SAR408701) in combination with pembrolizumab and with pembrolizumab + platinum-based chemotherapy +/− pemetrexed in patients with CEACAM5-positive nonsquamous NSCLC (CARMEN-LC05)
Authors: L. Paz-Ares, S. Parakh, J. Park, C. Rojas, F. Orlandi, R. Veillon, N. Isambert, T. Nagy, V. Muller, B. Medgyasszay, D. Rodriguez-Abreu, A. Fernandez, A. Puaud, S. Bensfia, N. Yang, A. Spira
Journal: Annals of Oncology (2022)
Clinical implementation of RNA sequencing for Mendelian disease diagnostics
Authors: Vicente A. Yépez, Mirjana Gusic, Robert Kopajtich, Christian Mertes, Nicholas H. Smith, Charlotte L. Alston, Rui Ban, Skadi Beblo, Riccardo Berutti, Holger Blessing, Elżbieta Ciara, Felix Distelmaier, Peter Freisinger, Johannes Häberle, Susan J. Hayflick, Maja Hempel, Yulia S. Itkis, Yoshihito Kishita, Thomas Klopstock, Tatiana D. Krylova, Costanza Lamperti, Dominic Lenz, Christine Makowski, Signe Mosegaard, Michaela F. Müller, Gerard Muñoz-Pujol, Agnieszka Nadel, Akira Ohtake, Yasushi Okazaki, Elena Procopio, Thomas Schwarzmayr, Joél Smet, Christian Staufner, Sarah L. Stenton, Tim M. Strom, Caterina Terrile, Frederic Tort, Rudy Van Coster, Arnaud Vanlander, Matias Wagner, Manting Xu, Fang Fang, Daniele Ghezzi, Johannes A. Mayr, Dorota Piekutowska-Abramczuk, Antonia Ribes, Agnès Rötig, Robert W. Taylor, Saskia B. Wortmann, Kei Murayama, Thomas Meitinger, Julien Gagneur, Holger Prokisch
Journal: Genome Medicine (2022)

Abstract Background Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics. Methods We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES. We also assessed through simulations how aberrant expression and mono-allelic expression tests depend on RNA-seq coverage. Results We detected on average 12,500 genes per sample including around 60% of all disease genes—a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than 1 week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions. Conclusion Together, these results show that streamlined experimental and computational processes can accelerate the implementation of RNA-seq in routine diagnostics.
99mTc-MIBI SPECT/CT and FDG PET/CT in Isolated Bilateral Renal Metastases From Adenoid Cystic Carcinoma of the Maxilla
Authors: Qian Zhao, Aisheng Dong, Huamao Ye, Changjing Zuo
Journal: Clinical Nuclear Medicine (2021)

Abstract Renal metastasis from adenoid cystic carcinoma of the head and neck is uncommon. We present 99m Tc-MIBI SPECT/CT and FDG PET/CT findings in a case with isolated bilateral renal metastases from adenoid cystic carcinoma of the left maxilla. The metastatic adenoid cystic carcinomas of the kidneys showed photopenia on 99m Tc-MIBI SPECT/CT and increased FDG uptake on FDG PET/CT mimicking primary renal cell carcinoma.
Integrating Selection and Risk Assessment of Chemical Mixtures: A Novel Approach Applied to a Breast Milk Survey
Authors: Amélie Crépet, Paule Vasseur, Julien Jean, Pierre-Marie Badot, Fabrice Nesslany, Jean-Paul Vernoux, Cyril Feidt, Sakina Mhaouty-Kodja
Journal: Environmental Health Perspectives (2022)

Background: One of the main challenges of modern risk assessment is to account for combined exposure to the multitude of various substances present in food and the environment. Objective: The present work proposes a methodological approach to perform chemical risk assessment of contaminant mixtures across regulatory silos regarding an extensive range of substances and to do so when comprehensive relevant data concerning the specific effects and modes of action of the mixture components are not available. Methods: We developed a complete step-by-step approach using statistical methods to prioritize substances involved in combined exposure, and we used a component-based approach to cumulate the risk using dose additivity. The most relevant toxicological end point and the associated reference point were selected from the literature to construct a toxicological threshold for each substance. Discussion: By applying the proposed method to contaminants in breast milk, we observed that among the 19 substances comprising the selected mixture, ∑DDT, ∑PCBi, and arsenic were main joint contributors to the risk of neurodevelopmental and thyroid effects for infants. In addition, ∑PCCD/F contributed to the thyroid effect and ∑aldrin-dieldrin to the neurodevelopmental effect. Our case study on contaminants in breast milk demonstrated the importance of crossing regulatory silos when studying mixtures and the importance of identifying risk drivers to regulate the risk related to environmental contamination. Applying this method to another set of data, such as human biomonitoring or in ecotoxicology, will reinforce its relevance for risk assessment. https://doi.org/10.1289/EHP8262
Spinal brachytherapy
Authors: Gordon Mao, Nicholas Theodore
Journal: Neuro-Oncology (2022)

Brachytherapy remains an underrecognized and underutilized radiation therapy modality for the treatment of spinal tumors. This article summarizes the existing body of medical literature on the usage, indications, techniques, and outcomes of brachytherapy for the treatment of spine tumors. The disease pathology most commonly treated with brachytherapy is metastatic spine cancer, rather than primary bone tumors of the spine. Brachytherapy can be used alone, as percutaneous needle injections; however, it is more often used in conjunction with open surgery or cement vertebral body augmentation. Although the data are still relatively sparse, studies show consistent benefit from brachytherapy in terms of improvements in pain, function, local recurrence rate, and overall survival. Brachytherapy is also associated with a favorable complication profile.
Rare Presentation of Late Complications After Undiagnosed Perforated Appendicitis Mimicking Recurrent Endometrial Carcinoma on 18F-FDG PET/CT
Authors: Danijela Dejanovic, Tenna Elgaard, Annika Loft, Berit Jul Mosgaard
Journal: Clinical Nuclear Medicine (2021)

Abstract Acute appendicitis is one of the most common causes of acute abdominal pain. Undiagnosed or untreated appendicitis can lead to serious complications. The most frequent complication of acute appendicitis is perforation with subsequent formation of a localized periappendiceal abscess or diffuse bacterial peritonitis. Late occurring complications following undiagnosed appendix perforation can pose a diagnostic challenge due to uncharacteristic clinical and imaging presentation. Herein, we describe late findings of undiagnosed perforated appendicitis that on 18 F-FDG PET/CT mimicked recurrent endometrial carcinoma disease in a 67-year-old woman.
Latent Tuberculosis Infection
Authors: Maunank Shah, Susan E. Dorman
Journal: New England Journal of Medicine (2021)

Persons with risk factors for Mycobacterium tuberculosis exposure or for progression to tuberculosis disease should be tested for M. tuberculosis infection, preferably with an interferon-γ release assay. After tuberculosis disease is ruled out, those at increased risk for progression should be treated, preferably with a rifamycin-based regimen.