tbuckley/cabot-search huggingface dataset:
Intratumoral CXCL13<sup>+</sup>CD8<sup>+</sup>T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma
Authors: Siyuan Dai, Han Zeng, Zhaopei Liu, Kaifeng Jin, Wenbin Jiang, Zewei Wang, Zhiyuan Lin, Ying Xiong, Jiajun Wang, Yuan Chang, Qi Bai, Yu Xia, Li Liu, Yu Zhu, Le Xu, Yang Qu, Jianming Guo, Jiejie Xu
Journal: Journal for ImmunoTherapy of Cancer (2021)

Chemokine (C-X-C motif) ligand 13 (CXCL13) was known as a selective chemotaxis for B cells, a product of follicular helper CD4+T cells (TFH) and a contributor to tertiary lymphoid structures (TLS). Although secretion and function of CXCL13 produced by TFH have been deeply explored, the immune function and prognostic significance of CXCL13 secreted by CD8+T cells still remain unrevealed. This study aims to investigate the clinical merit of CXCL13+CD8+T cells in clear cell renal cell carcinoma (ccRCC).We analyzed prognostic value and immune contexture that associated with CXCL13+CD8+T cells infiltration level in a total of 755 patients from Zhongshan Hospital cohort (n=223) and The Cancer Genome Atlas cohort (n=532). In vitro analyses were conducted on 42 samples of resected tumor tissue from Zhongshan Hospital in order to detect the immune status of CXCL13+CD8+T cells and total CD8+T cells. Immunohistochemistry (IHC) and flow cytometry were applied to characterize immune cells and portray the tumor microenvironment (TME) in ccRCC.Intratumoral CXCL13+CD8+T cells abundance was associated with inferior overall survival and disease-free survival. CXCL13+CD8+T cells possessed higher level of immune checkpoints like programmed cell-death protein 1 (PD-1), T-cell immunoglobulin mucin 3 (Tim-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), higher Ki-67 expression and lower tumor necrosis factor α (TNF-α), interferon γ (IFN-γ) expression. Total CD8+T cells in high-level CXCL13+CD8+T cells infiltration subgroup exhibited elevated exhausted markers (PD-1, Tim-3, TIGIT) and descended activated markers (TNF-α, IFN-γ) without quantity variance. Furthermore, the abundance of intratumoral CXCL13+CD8+T cell was correlated with immunoevasive TME accompanied by increased T helper 2 cells, tumor-associated macrophages, Foxp3+ regulatory T cells, TLS and decreased natural killer cells, GZMB+ cells.Intratumoral CXCL13+CD8+T cells infiltration indicated inferior clinical outcome in patients with ccRCC. CXCL13+CD8+T cells possessed increased exhausted markers, decreased effector molecules and better proliferation ability. CXCL13+CD8+T cells abundance impaired total CD8+T cells' immune function. Intratumoral CXCL13+CD8+T cells abundance was associated with immunoevasive contexture. The abundance of CXCL13+CD8+T cells was an independent prognosticator and a potential immunotherapeutic target marker for ccRCC treatment.
Authors’ response: Excess all-cause mortality during second wave of COVID-19 – the Polish perspective
Authors: Lasse S Vestergaard, Sarah K Nørgaard, Jens Nielsen, Tyra G Krause, Kåre Mølbak
Journal: Eurosurveillance (2021)

Preview this article: Authors' response: Excess all-cause mortality during second wave of COVID-19 – the Polish perspective, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/26/7/eurosurv-26-7-4-1.gif
Abstract SP094: DCIS - Con
Authors: S McLaughlin
Journal: Cancer Research (2021)

Abstract Ductal carcinoma in situ (DCIS) represents a collection of biologically heterogenous pre-invasive breast lesions some with the potential for progression to invasive cancer. Widespread adoption of screening mammography has increased the diagnosis of DCIS and may contribute to overdiagnosis identifying some conditions that may never impact one’s overall health. Unfortunately, clinicians treating DCIS patients currently lack robust biomarkers stratifying DCIS patients into those at high or low risk for invasive progression. Further, variations in pathologic assessment and grade, intra-lesional DCIS heterogeneity, and discordance in pathologic interpretations between pathologists make it challenging for providers to further identify appropriate low risk DCIS patients for active surveillance. Guideline concordant care including excision and potentially radiation and anti-estrogen therapies should remain as the standard of care and provides a definitive treatment endpoint which patients desire. Existing evidence documents a significant upstage rate of DCIS to invasive disease at surgical excision including a small, but important population benefiting from adjuvant systemic therapy. Finally, patient anxiety and documented poor adherence rates to endocrine therapy preclude active surveillance and after all the morbidity of surgical excision is low. Citation Format: S McLaughlin. DCIS - Con [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP094.
Dot1l Reverses the Abnormal Self-Renewal Conferred on HSPCs through Cohesin Haploinsufficiency By Diminishing Expression of Hoxa7 and Hoxa9
Authors: Joseph B Fisher, Cary Stelloh, Emily Kristine Phillips, Katelyn Heimbruch, Alison E Meyer, Kirthi Pulakanti, Maureen McNulty, Aaron D Viny, Ross L. Levine, John D. Crispino, Sridhar Rao
Journal: Blood (2017)
How will we find the elephant in the room? : In response to: The elephant in the room: What matters cognitively in cumulative technological culture
Authors: Wybo Houkes, Krist Vaesen
Journal: Behavioral and Brain Sciences (2020)

We argue that Osirak's and Reynaud's technological-reasoning hypothesis raises conceptual and methodological challenges. Interrelations between technical potential and expertise leave it unclear exactly what the technical-reasoning hypothesis encompasses. We submit that it is compatible with a range of hypotheses that are difficult to differentiate empirically.
Participatory Research for Environmental Justice: A Critical Interpretive Synthesis
Authors: Leona F. Davis, Mónica D. Ramírez-Andreotta
Journal: Environmental Health Perspectives (2021)

BACKGROUND: Environmental health risks are disproportionately colocated with communities in poverty and communities of color.In some cases, participatory research projects have effectively addressed structural causes of health risk in environmental justice (EJ) communities.However, many such projects fail to catalyze change at a structural level.OBJECTIVES: This review employs Critical Interpretive Synthesis (CIS) to theorize specific elements of participatory research for environmental health that effectively prompt structural change in EJ communities.METHODS: Academic database search was used to identify peer-reviewed literature describing participatory research with EJ communities to address environmental health.Synthetic constructs were developed iteratively related to study characteristics, design elements, and outcomes; and data were extracted for included records.Statistical analyses were performed to assess correlations between study design elements and structural change outcomes.Through critical, comparative, and contextual analyses of the "structural change" case study group and "nonstructural change" group, informed by relevant theoretical literature, a synthesizing argument was generated.RESULTS: From 505 total records identified, eligibility screening produced 232 case study articles, representing 154 case studies, and 55 theoretical articles for synthesis.Twenty-six case studies resulted in a structural change outcome.The synthesizing argument states that participatory research with EJ communities may be more likely to result in structural change when a) community members hold formal leadership roles; b) project design includes decision-makers and policy goals; and c) long term partnerships are sustained through multiple funding mechanisms.The assumption of EJ community benefit through research participation is critically examined.
Aberrant AZIN2 and polyamine metabolism precipitates tau neuropathology
Authors: Leslie A. Sandusky-Beltran, Andrii Kovalenko, Devon S. Placides, Kevin Ratnasamy, Chao Ma, Jerry B. Hunt, Huimin Liang, John Ivan T. Calahatian, Camilla Michalski, Margaret Fahnestock, Laura J. Blair, April L. Darling, Jeremy D. Baker, Sarah N. Fontaine, Chad A. Dickey, Joshua J. Gamsby, Kevin R. Nash, Erin Abner, Maj-Linda B. Selenica, Daniel C. Lee
Journal: Journal of Clinical Investigation (2021)

Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell's response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer's disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD.
Population subgroup differences in the use of a COVID-19 chatbot
Authors: Laura C. Schubel, Deliya B. Wesley, Ethan Booker, John Lock, Raj M. Ratwani
Journal: npj Digital Medicine (2021)

Abstract COVID-19 chatbots are widely used to screen for symptoms and disseminate information about the virus, yet little is known about the population subgroups that interact with this technology and the specific features that are used. An analysis of 1,000,740 patients invited to use a COVID-19 chatbot, 69,451 (6.94%) of which agreed to participate, shows differences in chatbot feature use by gender, race, and age. These results can inform future public health COVID-19 symptom screening and information dissemination strategies.
Abstract 14851: Inflammation in the Perivascular Adipose Tissue is Associated With Coronary Artery Disease: An Autopsy Study
Authors: Daniela S Farias, Carlos A Pasqualucci, Aline Nishizawa, Luiz F Silva, Fernanda M Campos, Karen C Silva, Anderson Cuelho, Renata E Leite, Renata E Ferretti-Rebustini, Lea T Grinberg, José M Farfel, Wilson Jacob-Filho, Claudia K Suemoto
Journal: Circulation (2015)

Introduction: Inflammation of the perivascular adipose tissue (PAT) has been associated with coronary artery disease (CAD); however, lymphocyte B in PAT has not been previously investigated, neither the presence of inflammation in acute CAD. Hypothesis: The number of macrophages, T and B lymphocytes in PAT are greater in CAD than in controls. Methods: We collected whole hearts and abdominal subcutaneous adipose tissue (SAT) from individuals ≥ 30 years-old. Coronary artery atherosclerosis were evaluated using morphometric methods to determine the level of obstruction and the presence of unstable plaques (e.g. ulceration, hemorrhage, or thrombotic occlusion). Samples of PAT next to the atheromatous plaque and SAT were stained using immunochemistry: macrophages (CD68), T lymphocytes (CD3) and B lymphocytes (CD20) and quantified in 20 random fields. The number of inflammatory cells was compared among controls, chronic CAD, and acute CAD in PAT and in SAT. Results: We evaluated 49 participants (controls n=12; chronic CAD n=27, and acute CAD n=10). Compared to controls, the number of B lymphocytes was greater in participants with CAD in PAT [acute CAD: 7.7 (IQR 3.8-17.3); chronic CAD: 5.8 (IQR 1.9-9.6); controls: 1.9 (IQR 0-4.8); p=0.01]. In SAT, macrophages was greater in CAD groups [chronic CAD: 175 (IQR 94-326); and acute CAD: 138 (IQR 15-277)] than in controls [65 (ITQ 28-110); p=0.02]; and also for T lymphocytes [chronic CAD: 45 (IQR 25-75); acute CAD: 40 (IQR 25-56)]; controls [13 (IQR 8-38) p=0.03]. In paired analysis, we found more macrophages in the PAT than in the SAT in all groups [controls:PAT-288 (IQR 98-597); SAT-65 (IQR 28-110) p=0.02]; [chronic CAD: PAT-505 (IQR 434-987); SAT-175 (IQR 94-326) p&lt;0.0001]; [acute CAD: PAT-496 (IQR 200-743); SAT-104 (IQR 15-277) p=0.007]. B lymphocytes in CAD were larger in the PAT than in the SAT, respectively [chronic: 5,8 (IQR 1,9-9,6) vs. 1,9 (IQR 1,9-7,2) p=0.04]; [acute: 7,7 (IQR 1,9-17,3) vs. 1,0 (IQR 0-2,9) p=0.03]. Conclusions: We found an association between inflammation in the PAT and CAD mediated by humoral response. Besides, we detected inflammation in SAT in CAD groups mediated through T lymphocytes and macrophages, suggesting a systemic response in individuals with CAD that is more intense in PAT than in SAT.
Male Sex Is Associated With Higher Rates of Liver‐Related Mortality in Primary Biliary Cholangitis and Cirrhosis
Authors: Binu V. John, Gabriella Aitcheson, Kaley B. Schwartz, Nidah S. Khakoo, Bassam Dahman, Yangyang Deng, David Goldberg, Paul Martin, Tamar H. Taddei, Cynthia Levy, David E. Kaplan
Journal: Hepatology (2021)

Background and Aims The impact of sex on the postcirrhosis progression of primary biliary cholangitis (PBC) has not been well defined. Prior studies have suggested that men have worse outcomes but present at more advanced stages of fibrosis than women. This observation, however, has been limited by small numbers of men and even fewer patients with cirrhosis. Approach and Results We investigated the association of sex with the development of all‐cause and liver‐related mortality or transplantation, decompensation, and hepatocellular carcinoma (HCC), using competing‐risk time‐updating Cox proportional hazards models in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. In a cohort of 532 participants (418 male) with PBC‐related cirrhosis with a total follow‐up of 3,231.6 person‐years (PY) from diagnosis of compensated cirrhosis, male participants had a higher unadjusted rates of death or transplantation (8.5 vs. 3.8 per 100 PY; P &lt; 0.0001), liver‐related death or transplantation (5.5 vs. 2.7 per 100 PY; P &lt; 0.0001), decompensation (5.5 vs. 4.0 per 100 PY; P = 0.002), and HCC (0.9 vs. 0.3 per 100 PY; P &lt; 0.0001). After adjusting for confounders, male sex was associated with a higher risk of death or transplantation (adjusted hazard ratio, 1.80; 95% CI, 1.01‐3.19; P = 0.046), and liver‐related death or transplantation (subhazard ratio, 2.17; 95% CI, 1.15‐4.08; P = 0.02). A sensitivity analysis that defined ursodeoxycholic acid response as normalization of alkaline phosphatase and total bilirubin revealed similar findings. Conclusions In patients with PBC and well‐compensated cirrhosis, male sex is associated with a higher risk of both death and liver‐related death or transplantation.
Grounded procedures in mind and society
Authors: Spike W. S. Lee, Norbert Schwarz
Journal: Behavioral and Brain Sciences (2021)

Our commentators explore the operation of grounded procedures across all levels of analysis in the behavioral sciences, from mental to social, developmental, and evolutionary/functional. Building on them, we offer two integrative principles for systematic effects of grounded procedures to occur. We discuss theoretical topics at each level of analysis, address methodological recommendations, and highlight further extensions of grounded procedures.
How Can We Distinguish Sorafenib-Associated Skin Rash From Skin Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem-Cell Transplantation?
Authors: Shigeo Fuji
Journal: Journal of Clinical Oncology (2021)

Burchert et al 1 reported the result of a prospective randomized controlled trial, the SORMAIN study, which assessed the impact of sorafenib maintenance after allogeneic hematopoietic stem-cell transplantation (HSCT) for acute myeloid leukemia with FLT3-ITD mutation.They found a significant benefit of sorafenib maintenance in the probability of relapsefree survival after allogeneic HSCT, although the sample size was not large.
Correction: Acute esophageal necrosis (black esophagus) with active upper gastrointestinal bleeding: What to do?
Authors: Igor Braga Ribeiro, Gustavo de Oliveira Luz, Gabriel Mayo Vieira de Souza, Mateus Bond Boghossian, Epifânio Silvino do Monte Junior, Marcos Eduardo Lera dos Santos, Eduardo Guimarães Hourneaux de Moura
Journal: Endoscopy (2021)

Correction to:Acute esophageal necrosis (black esophagus) with active upper gastrointestinal bleeding: What to do?Endoscopy eFirstDOI: 10.1055/a-1346-8343
Gene Deconvolution Reveals Aberrant Liver Regeneration and Immune Cell Infiltration in Alcohol‐Associated Hepatitis
Authors: Adam Kim, Xiaoqin Wu, Daniela S. Allende, Laura E. Nagy
Journal: Hepatology (2021)

Background and Aims Acute liver damage causes hepatocyte stress and death, but in chronic liver disease impaired hepatocyte regeneration and immune cell infiltration prevents recovery. While the roles of both impaired liver regeneration and immune infiltration have been studied extensively in chronic liver diseases, the differential contribution of these factors is difficult to assess. Approach and Results We combined single‐cell RNA‐sequencing (RNA‐seq) data from healthy livers and peripheral immune cells to measure cell proportions in chronic liver diseases. Using bulk RNA‐seq data from patients with early alcohol‐associated hepatitis, severe AH (sAH), HCV, HCV with cirrhosis, and NAFLD, we performed gene deconvolution to predict the contribution of different cell types in each disease. Patients with sAH had the greatest change in cell composition, with increases in both periportal hepatocytes and cholangiocyte populations. Interestingly, while central vein hepatocytes were decreased, central vein endothelial cells were expanded. Endothelial cells are thought to regulate liver regeneration through WNT signaling. WNT2, important in central vein hepatocyte development, was down in sAH, while multiple other WNTs and WNT receptors were up‐regulated. Immunohistochemistry revealed up‐regulation of FZD6, a noncanonical WNT receptor, in hepatocytes in sAH. Immune cell populations also differed in disease. In sAH, a specific group of inflammatory macrophages was increased and distinct from the macrophage population in patients with HCV. Network and correlation analyses revealed that changes in the cell types in the liver were highly correlated with clinical liver function tests. Conclusions These results identify distinct changes in the liver cell populations in chronic liver disease and illustrate the power of using single‐cell RNA‐seq data from a limited number of samples in understanding multiple different diseases.
Immune checkpoint inhibitors
Authors: Guido Kroemer, Laurence Zitvogel
Journal: The Journal of Experimental Medicine (2021)

Three papers by James Allison and Tasuku Honjo published in JEM between 1995 and 2000 crystallized seminal insights into the role of CTLA-4 and PD-1 in immunosuppression (Krummel and Allison. 1995. J. Exp. Med.https://doi.org/10.1084/jem.182.2.459; van Elsas et al. 1999. J. Exp. Med.https://doi.org/10.1084/jem.190.3.355; Freeman et al. 2000. J. Exp. Med.https://doi.org/10.1084/jem.192.7.1027). These papers laid the basis for modern cancer immunotherapy and led to a shared 2018 Nobel Prize.
Beryllium-specific CD4+ T cells induced by chemokine neoantigens perpetuate inflammation
Authors: Michael T. Falta, Jeremy C. Crawford, Alex N. Tinega, Laurie G. Landry, Frances Crawford, Douglas G. Mack, Allison K. Martin, Shaikh M. Atif, Li Li, Radleigh G. Santos, Maki Nakayama, John W. Kappler, Lisa A. Maier, Paul G. Thomas, Clemencia Pinilla, Andrew P. Fontenot
Journal: Journal of Clinical Investigation (2021)

Discovering dominant epitopes for T cells, particularly CD4+ T cells, in human immune-mediated diseases remains a significant challenge. Here, we used bronchoalveolar lavage (BAL) cells from HLA-DP2–expressing patients with chronic beryllium disease (CBD), a debilitating granulomatous lung disorder characterized by accumulations of beryllium-specific (Be-specific) CD4+ T cells in the lung. We discovered lung-resident CD4+ T cells that expressed a disease-specific public CDR3β T cell receptor motif and were specific to Be-modified self-peptides derived from C-C motif ligand 4 (CCL4) and CCL3. HLA-DP2–CCL/Be tetramer staining confirmed that these chemokine-derived peptides represented major antigenic targets in CBD. Furthermore, Be induced CCL3 and CCL4 secretion in the lungs of mice and humans. In a murine model of CBD, the addition of LPS to Be oxide exposure enhanced CCL4 and CCL3 secretion in the lung and significantly increased the number and percentage of CD4+ T cells specific for the HLA-DP2–CCL/Be epitope. Thus, we demonstrate a direct link between Be-induced innate production of chemokines and the development of a robust adaptive immune response to those same chemokines presented as Be-modified self-peptides, creating a cycle of innate and adaptive immune activation.
Molecular targets for anticancer therapies in companion animals and humans: what can we learn from each other?
Authors: Irati Beltrán Hernández, Jannes Z. Kromhout, Erik Teske, Wim E. Hennink, Sebastiaan A. van Nimwegen, Sabrina Oliveira
Journal: Theranostics (2021)

Despite clinical successes in the treatment of some early stage cancers, it is undeniable that novel and innovative approaches are needed to aid in the fight against cancer.Targeted therapies offer the desirable feature of tumor specificity while sparing healthy tissues, thereby minimizing side effects.However, the success rate of translation of these therapies from the preclinical setting to the clinic is dramatically low, highlighting an important point of necessary improvement in the drug development process in the oncology field.The practice of a comparative oncology approach can address some of the current issues, by introducing companion animals with spontaneous tumors in the linear drug development programs.In this way, animals from the veterinary clinic get access to novel/innovative therapies, otherwise inaccessible, while generating robust data to aid therapy refinement and increase translational success.In this review, we present an overview of targetable membrane proteins expressed in the most well-characterized canine and feline solid cancers, greatly resembling the counterpart human malignancies.We identified particular areas in which a closer collaboration between the human and veterinary clinic would benefit both human and veterinary patients.Considerations and challenges to implement comparative oncology in the development of anticancer targeted therapies are also discussed.