tbuckley/cabot-search huggingface dataset:
Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes
Authors: Yingjuan J. Lu, Leroy W. Wheeler, Haiyan Chu, Paul J. Kleindl, Michael Pugh, Fei You, Satish Rao, Gabriela Garcia, Henry Y. Wu, Andre P. da Cunha, Richard Johnson, Elaine Westrick, Vicky Cross, Alex Lloyd, Christina Dircksen, Patrick J. Klein, Iontcho R. Vlahov, Philip S. Low, Christopher P. Leamon
Journal: Cell Reports Medicine (2021)

Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1β release by FRβ+ monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development.
P39.04 Thymic Epithelial Tumors: The Importance of Invasive Investigation to Adequate Diagnosis
Authors: P.A. Schulze, L. Hinrichsen, R. Paulino, T. Menegaz, M.T. Tsukazan, J. Rios, J.A. Figueiredo Pinto
Journal: Journal of Thoracic Oncology (2021)
P45.15 Clinical Outcomes, Long-Term Survival and Toleration With Sequential Therapy of First-Line Crizotinib Followed by Alectinib in ALK+ NSCLC
Authors: Z. Zou, P. Xing, X. Hao, C. Zhang, K. Ma, L. Shan, X. Song, J. Li
Journal: Journal of Thoracic Oncology (2021)
Abstract 15113: Association Between Financial Burden, Quality of Life and Mental Health Among Those With Atherosclerotic Cardiovascular Disease in the United States
Authors: Amarnath Annapureddy, Javier Valero-Elizondo, Shiwani Mahajan, Anshul Saxena, Rohan Khera, Gowtham Grandhi, Erica S Spatz, Rachel Dreyer, Nihar Desai, Harlan M Krumholz, Khurram Nasir
Journal: Circulation (2018)

Introduction: Emerging evidence suggest a substantial proportion of those with atherosclerotic cardiovascular disease (ASCVD) experience financial hardship from cumulative out-of-pocket healthcare ...
Imaging brain cortisol regulation in PTSD with a target for 11β-hydroxysteroid dehydrogenase type 1
Authors: Shivani Bhatt, Ansel T. Hillmer, Aleksandra Rusowicz, Nabeel Nabulsi, David Matuskey, Gustavo A. Angarita, Soheila Najafzadeh, Michael Kapinos, Steven M. Southwick, John H. Krystal, Richard E. Carson, Yiyun Huang, Kelly P. Cosgrove
Journal: Journal of Clinical Investigation (2021)

BACKGROUNDInvestigations of stress dysregulation in posttraumatic stress disorder (PTSD) have focused on peripheral cortisol, but none have examined cortisol in the human brain. This study used positron emission tomography (PET) to image 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-producing enzyme, as a putative brain cortisol marker in PTSD.METHODSSixteen individuals with PTSD and 17 healthy, trauma-exposed controls (TCs) underwent PET imaging with [18F]AS2471907, a radioligand for 11β-HSD1.RESULTSPrefrontal-limbic 11β-HSD1 availability, estimated as [18F]AS2471907 volume of distribution (VT), was significantly higher in the PTSD group compared with the TC group (β = 1.16, P = 0.0057). Lower prefrontal-limbic 11β-HSD1 availability was related to greater overall PTSD severity (R2 = 0.27, P = 0.038) in the PTSD group. 11β-HSD1 availability was not related to plasma cortisol levels (R2 = 0.026, P = 0.37). In a PTSD subset (n = 10), higher 11β-HSD1 availability was associated with higher availability of translocator protein (TSPO), a microglial marker (β = 4.40, P = 0.039).CONCLUSIONHigher brain cortisol-producing 11β-HSD1 in the PTSD group may represent a resilience-promoting neuroadaptation resulting in lower PTSD symptoms. Along with preliminary associations between 11β-HSD1 and TSPO, corroborating previous evidence of immune suppression in PTSD, these findings collectively challenge previous hypotheses of the deleterious effects of both excessive brain glucocorticoid and brain immune signaling in PTSD.FUNDINGBrain and Behavior Research Foundation Independent Investigator Grant, National Institute of Mental Health grants F30MH116607 and R01MH110674, the Veterans Affairs National Center for PTSD, the Gustavus and Louise Pfeiffer Foundation Fellowship, Clinical and Translational Science Awards grant UL1 TR000142 from the NIH National Center for Advancing Translational Science.
Abstract 230: Differential Effects of Prehospital Hypotension and Injury Severity in Isolated vs. Multisystem Major Traumatic Brain Injury
Authors: Daniel W Spaite, Chengcheng Hu, Bentley J Bobrow, Bruce J Barnhart, Vatsal Chikani, Joshua B Gaither, Kurt R Denninghoff, Amber D Rice, Samuel M Keim
Journal: Circulation (2018)

Background: In hospital-based studies, hypotension (HT, SBP &lt;90) is more likely to occur in multisystem traumatic brain injury (MTBI) than isolated (ITBI). However, there are few EMS studies on this issue. Hypothesis: Prehospital HT is associated with differential effects in MTBI and ITBI and these effects are influenced by the severity of primary brain injury. Methods: Inclusion: TBI cases in the EPIC Study (NIH 1R01NS071049) before TBI guideline implementation (1/07-3/14). ITBI: Major TBI cases (CDC Barell Matrix Type 1) that had no injury with ICD9-based Regional Severity Score [RSS (AIS equivalent)] ≥3 in any other body region. MTBI: Type 1 TBI plus at least one non-head region injury with RSS ≥3. Results: Included were 13,435 cases [Excl: age &lt;10 (5.9%), missing data (6.2%)]. 10,374 (77.2%) were ITBI, 3061 (22.8%) MTBI. Mortality: ITBI: 7.7% (797/10,374), MTBI: 19.2% (587/3061, p&lt;0.0001). Prehospital HT occurred 3.5 times more often in MTBI (14.8%, 453/3061 vs 4.2%, 437/10,374; p&lt;0.0001). Among HT cases, 40.8% (185/453) with MTBI died vs 30.9% with ITBI (135/437; p&lt;0.0001). In the hypotensive moderate/severe TBI cohort (RSS-Head 3/4), MTBI mortality was 2.4 times higher (17.2%, 40/232) than ITBI (7.1%, 17/240, p = 0.001). However, in the hypotensive very/extremely severe TBI group (RSS-Head 5/6), mortality was almost identical in MTBI (73.4%, 141/192) and ITBI (72.1%, 116/161, p = 0.864). Conclusion: Among major TBI patients with prehospital HT, those with MTBI were much more likely to die than those with ITBI. However, this association varied dramatically with TBI severity. In mod/severe TBI cases with HT, MTBI mortality was 2.4 times higher than in ITBI. In contrast, in very/extremely severe TBI with HT, there was no identifiable mortality difference. Thus, in cases with substantial potential to survive the primary brain injury (mod/severe), outcome is markedly worse in patients with multisystem injuries. However, in very/extremely severe TBI, non-head region injuries have no apparent association with mortality. This may be because the TBI is the primary factor leading to death in these cases. The main EPIC study is evaluating whether this severity-based difference in “effect” has implications for TBI guideline treatment effectiveness.
Social support and unmet needs among older trans and gender non-conforming people during the COVID-19 ‘lockdown’ in the UK
Authors: Michael Toze, Sue Westwood, Trish Hafford-Letchfield
Journal: International Journal of Transgender Health (2021)

Previous research has suggested that older trans and gender non-conforming (TGNC) people may face particular challenges related to stigma, social exclusion and discrimination in later life. However, direct data on social support and needs in older TGNC population both internationally and within the UK is limited due to the small, dispersed nature of this population, and the absence of specific data collection on aging TGNC populations. During the UK COVID-19 lockdown in summer 2020, older people and those with long-term health conditions were advised to adopt particular precautions.This study aimed to explore older TGNC people's social support networks, key concerns and unmet needs during the COVID-19 'lockdown'.A UK cross-sectional survey of LGBT + people aged 60+ (n = 375) was undertaken during the lockdown. This paper analyses responses from the subset (n = 38) of TGNC participants.The majority of TGNC respondents described diverse social networks, often centered around friends and non-kin social networks, although partners and adult children were also significant for some. In most cases, those with existing strong networks continued to maintain social connections during lockdown, albeit with some regrets about loss of activities and face-to-face connection. However, a minority of respondents had experienced greater challenges prior to lockdown, and may have been at increased vulnerability during the pandemic, for example indicating that they had no-one to call on for practical support in an emergency. When asked about unmet needs and challenges, social isolation was repeatedly raised as the most frequent concern. Several respondents also mentioned issues specifically affecting TGNC communities, including access to gender affirming care and a perceived rise in social intolerance.Health and social care providers should be aware of the diversity of support networks within TGNC communities. There may also be benefits in community sector interventions to help older TGNC build and maintain strong social networks.
<i>AQP1</i> Promoter Variant, Water Transport, and Outcomes in Peritoneal Dialysis
Authors: Johann Morelle, Céline Marechal, Zanzhe Yu, Huguette Debaix, Tanguy Corre, Mark Lambie, Marion Verduijn, Friedo Dekker, Philippe Bovy, Pieter Evenepoel, Bert Bammens, Rafael Selgas, Maria A. Bajo, Annemieke M. Coester, Amadou Sow, Nicolas Hautem, Dirk G. Struijk, Raymond T. Krediet, Jean-Luc Balligand, Eric Goffin, Ralph Crott, Pierre Ripoche, Simon Davies, Olivier Devuyst
Journal: New England Journal of Medicine (2021)

Variability in ultrafiltration influences prescriptions and outcomes in patients with kidney failure who are treated with peritoneal dialysis. Variants in AQP1, the gene that encodes the archetypal water channel aquaporin-1, may contribute to that variability.We gathered clinical and genetic data from 1851 patients treated with peritoneal dialysis in seven cohorts to determine whether AQP1 variants were associated with peritoneal ultrafiltration and with a risk of the composite of death or technique failure (i.e., transfer to hemodialysis). We performed studies in cells, mouse models, and samples obtained from humans to characterize an AQP1 variant and investigate mitigation strategies.The common AQP1 promoter variant rs2075574 was associated with peritoneal ultrafiltration. Carriers of the TT genotype at rs2075574 (10 to 16% of patients) had a lower mean (±SD) net ultrafiltration level than carriers of the CC genotype (35 to 47% of patients), both in the discovery phase (506±237 ml vs. 626±283 ml, P = 0.007) and in the validation phase (368±603 ml vs. 563±641 ml, P = 0.003). After a mean follow-up of 944 days, 139 of 898 patients (15%) had died and 280 (31%) had been transferred to hemodialysis. TT carriers had a higher risk of the composite of death or technique failure than CC carriers (adjusted hazard ratio, 1.70; 95% confidence interval [CI], 1.24 to 2.33; P = 0.001), as well as a higher risk of death from any cause (24% vs. 15%, P = 0.03). In mechanistic studies, the rs2075574 risk variant was associated with decreases in AQP1 promoter activity, aquaporin-1 expression, and glucose-driven osmotic water transport. The use of a colloid osmotic agent mitigated the effects of the risk variant.A common variant in AQP1 was associated with decreased ultrafiltration and an increased risk of death or technique failure among patients treated with peritoneal dialysis. (Funded by the Swiss National Science Foundation and others.).
T cells step up after SARS-CoV-2 vaccination with B cell depletion
Authors: Thomas Berger, Barbara Kornek
Journal: Nature Reviews Neurology (2021)

Detailed immunological analysis in a new study provides insight into the mechanisms of immune responses after SARS-CoV-2 vaccination in people who are receiving B cell-depleting therapy for multiple sclerosis. The findings have implications for clinical practice, but more questions about SARS-CoV-2 vaccination and immunosuppression remain.
MA12.07 Oncological Procedures and Risk Assessment of COVID-19 in Thoracic Cancer Patients: A Picture From an Italian Cancer Center
Authors: M. Bungaro, V. Bertaglia, M. Audisio, E. Parlagreco, C. Pisano, V. Cetoretta, I. Persano, F. Jacobs, C. Baratelli, L. Consito, M.L. Reale, F. Tabbò, P. Bironzo, G. Scagliotti, S. Novello
Journal: Journal of Thoracic Oncology (2021)
Host-directed therapy, an untapped opportunity for antimalarial intervention
Authors: Ling Wei, Jack Adderley, Didier Leroy, David H. Drewry, Danny W. Wilson, Alexis Kaushansky, Christian Doerig
Journal: Cell Reports Medicine (2021)

Host-directed therapy (HDT) is gaining traction as a strategy to combat infectious diseases caused by viruses and intracellular bacteria, but its implementation in the context of parasitic diseases has received less attention. Here, we provide a brief overview of this field and advocate HDT as a promising strategy for antimalarial intervention based on untapped targets. HDT provides a basis from which repurposed drugs could be rapidly deployed and is likely to strongly limit the emergence of resistance. This strategy can be applied to any intracellular pathogen and is particularly well placed in situations in which rapid identification of treatments is needed, such as emerging infections and pandemics, as starkly illustrated by the current COVID-19 crisis.
Carfilzomib maintenance in newly diagnosed non-transplant eligible multiple myeloma
Authors: Arthur Bobin, Maéva Kyheng, Stéphanie Guidez, Cécile Gruchet-Merouze, Valentine Richez, Alain Duhamel, Lionel Karlin, Brigitte Kolb, Mourad Tiab, Carla Araujo, Nathalie Meuleman, Jean-Valère Malfuson, Pascal Bourquard, Pascal Lenain, Aurore Perrot, Murielle Roussel, Arnaud Jaccard, Marie-Odile Petillon, Karim Belhadj-Merzoug, Marie-Lorraine Chretien, Jean Fontan, Philippe Rodon, Anna Schmitt, Fritz Offner, Laurent Voillat, Sophie Cereja, Frédérique Kuhnowski, Sophie Rigaudeau, Olivier Decaux, Catherine Humbrecht-Kraut, Jamile Frayfer, Olivier Fitoussi, Damien Roos-Weil, Jean Claude Eisenmann, Véronique Dorvaux, Eric G. Voog, Philippe Moreau, Hervé Avet-Loiseau, Cyrille Hulin, Thierry Facon, Xavier Leleu
Journal: Leukemia (2021)
Remarkably Low<i>KIR</i>and<i>HLA</i>Diversity in Amerindians Reveals Signatures of Strong Purifying Selection Shaping the Centromeric<i>KIR</i>Region
Authors: Luciana de Brito Vargas, Marcia H Beltrame, Brenda Ho, Wesley M Marin, Ravi Dandekar, Gonzalo Montero-Martín, Marcelo A Fernández-Viña, A Magdalena Hurtado, Kim R Hill, Luiza T Tsuneto, Mara H Hutz, Francisco M Salzano, Maria Luiza Petzl-Erler, Jill A Hollenbach, Danillo G Augusto
Journal: Molecular Biology and Evolution (2021)

The killer-cell immunoglobulin-like receptors (KIR) recognize human leukocyte antigen (HLA) molecules to regulate the cytotoxic and inflammatory responses of natural killer cells. KIR genes are encoded by a rapidly evolving gene family on chromosome 19 and present an unusual variation of presence and absence of genes and high allelic diversity. Although many studies have associated KIR polymorphism with susceptibility to several diseases over the last decades, the high-resolution allele-level haplotypes have only recently started to be described in populations. Here, we use a highly innovative custom next-generation sequencing method that provides a state-of-art characterization of KIR and HLA diversity in 706 individuals from eight unique South American populations: five Amerindian populations from Brazil (three Guarani and two Kaingang); one Amerindian population from Paraguay (Aché); and two urban populations from Southern Brazil (European and Japanese descendants from Curitiba). For the first time, we describe complete high-resolution KIR haplotypes in South American populations, exploring copy number, linkage disequilibrium, and KIR-HLA interactions. We show that all Amerindians analyzed to date exhibit the lowest numbers of KIR-HLA interactions among all described worldwide populations, and that 83-97% of their KIR-HLA interactions rely on a few HLA-C molecules. Using multiple approaches, we found signatures of strong purifying selection on the KIR centromeric region, which codes for the strongest NK cell educator receptors, possibly driven by the limited HLA diversity in these populations. Our study expands the current knowledge of KIR genetic diversity in populations to understand KIR-HLA coevolution and its impact on human health and survival.
Persistence of infectious SARS‐CoV‐2 particles for up to 37 days in patients with mild COVID‐19
Authors: Tobias Zahn, Ines Mhedhbi, Sascha Hein, Jan Raupach, Csaba Miskey, Younes Husria, Kathrin Bayanga, Detlef Bartel, Stefan Vieths, Zoltan Ivics, Doris Oberle, Brigitte Keller‐Stanislawski, Marie‐Luise Herrlein, Thorsten Jürgen Maier, Eberhard Hildt
Journal: Allergy (2021)

Abstract Background People suffering from COVID‐19 are typically considered non‐infectious 14 days after diagnosis if symptoms have disappeared for at least 48 h. We describe three patients who independently acquired their infection. These three patients experienced mild COVID‐19 and completely recovered symptomatically within 10 days, but remained PCR‐positive in deep pharyngeal samples for at least 38 days. We attempted to isolate virus from pharyngeal swabs to investigate whether these patients still carried infectious virus. Methods Infectious virus was amplified in Vero E6 cells and characterized by electron microscopy and WGS. The immune response was investigated by ELISA and peptide arrays. Results In all three cases, infectious and replication‐competent virus was isolated and amplified in Vero E6 cells. Virus replication was detected by RT‐PCR and immunofluorescence microscopy. Electron microscopy confirmed the formation of intact SARS‐CoV‐2 particles. For a more detailed analysis, all three isolates were characterized by whole‐genome sequencing (WGS). The sequence data revealed that the isolates belonged to the 20A or 20C clade, and two mutations in ORF8 were identified among other mutations that could be relevant for establishing a long‐term infection. Characterization of the humoral immune response in comparison to patients that had fully recovered from mild COVID‐19 revealed a lack of antibodies binding to sequential epitopes of the receptor‐binding domain (RBD) for the long‐term infected patients. Conclusion Thus, a small portion of COVID‐19 patients displays long‐term infectivity and termination of quarantine periods after 14 days, without PCR‐based testing, should be reconsidered critically.
A novel proof-of-concept study assessing the lightening effects and safety of malassezin for treatment of facial hyperpigmentation
Authors: Pearl E. Grimes, Jag Bhawan, Michael D. Howell, Seemal Desai, Edna Coryell, Rama Nashawati, Michael Einziger, Ann Marie Simpson, Alex Yaroshinsky, Tim Mc Craw
Journal: Journal of the American Academy of Dermatology (2021)
SPDEF suppresses head and neck squamous cell carcinoma progression by transcriptionally activating NR4A1
Authors: Yanting Wang, Xianyue Ren, Weiyu Li, Ruoyan Cao, Suyang Liu, Laibo Jiang, Bin Cheng, Juan Xia
Journal: International Journal of Oral Science (2021)

Abstract SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF) plays dual roles in the initiation and development of human malignancies. However, the biological role of SPDEF in head and neck squamous cell carcinoma (HNSCC) remains unclear. In this study, the expression level of SPDEF and its correlation with the clinical parameters of patients with HNSCC were determined using TCGA-HNSC, GSE65858, and our own clinical cohorts. CCK8, colony formation, cell cycle analysis, and a xenograft tumor growth model were used to determine the molecular functions of SPDEF in HNSCC. ChIP-qPCR, dual luciferase reporter assay, and rescue experiments were conducted to explore the potential molecular mechanism of SPDEF in HNSCC. Compared with normal epithelial tissues, SPDEF was significantly downregulated in HNSCC tissues. Patients with HNSCC with low SPDEF mRNA levels exhibited poor clinical outcomes. Restoring SPDEF inhibited HNSCC cell viability and colony formation and induced G0/G1 cell cycle arrest, while silencing SPDEF promoted cell proliferation in vitro. The xenograft tumor growth model showed that tumors with SPDEF overexpression had slower growth rates, smaller volumes, and lower weights. SPDEF could directly bind to the promoter region of NR4A1 and promoted its transcription, inducing the suppression of AKT, MAPK, and NF-κB signaling pathways. Moreover, silencing NR4A1 blocked the suppressive effect of SPDEF in HNSCC cells. Here, we demonstrate that SPDEF acts as a tumor suppressor by transcriptionally activating NR4A1 in HNSCC. Our findings provide novel insights into the molecular mechanism of SPDEF in tumorigenesis and a novel potential therapeutic target for HNSCC.
P47.17 Capmatinib vs Docetaxel in Pretreated Patients With MET Exon 14 Skipping–mutated Stage IIIB/IIIC or IV NSCLC (GeoMETry-III)
Authors: P. Souquet, S. Kim, B. Solomon, J. Vansteenkiste, M. Carbini, S. Kenny, S. Glaser, A. Chassot Agostinho, J. Wolf
Journal: Journal of Thoracic Oncology (2021)
<i>Mycobacterium porcinum</i> Skin and Soft Tissue Infections After Vaccinations — Indiana, Kentucky, and Ohio, September 2018–February 2019
Authors: Erin F. Blau, Andrea Flinchum, Kathryn L. Gaub, Kathleen P. Hartnett, Michael Curran, Virginia K. Allen, Allison Napier, Elisabeth M. Hesse, Anne M. Hause, Rachel Cathey, Christine Feaster, Marika Mohr, Sietske de Fijter, Sarah Mitchell, Heather A. Moulton-Meissner, Isaac Benowitz, Kevin B. Spicer, Douglas A. Thoroughman
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

During December 2018-February 2019, a multistate investigation identified 101 patients with vaccination-associated adverse events among an estimated 940 persons in Kentucky, Indiana, and Ohio who had received influenza; hepatitis A; pneumococcal; or tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines at the workplace during September 11-November 28, 2018. These vaccines had been administered by staff members of a third-party health care company contracted by 24 businesses. Company A provided multiple vaccine types during workplace vaccination events across 54 locations in these adjoining states. Injection-site wound isolates from patients yielded Mycobacterium porcinum, a nontuberculous mycobacteria (NTM) species in the Mycobacterium fortuitum group; subtyping using pulsed-field gel electrophoresis of all 28 available isolates identified two closely related clusters. Site visits to company A and interviews with staff members identified inadequate hand hygiene, improper vaccine storage and handling, lack of appropriate medical record documentation, and lack of reporting to the Vaccine Adverse Event Reporting System (VAERS). Vaccination-associated adverse events can be prevented by training health care workers responsible for handling or administering vaccines in safe vaccine handling, administration, and storage practices, timely reporting of any suspected vaccination-associated adverse events to VAERS, and notifying public health authorities of any adverse event clusters.