tbuckley/cabot-search huggingface dataset:
Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice
Authors: Yu Pan, Shirong Cao, Jiaqi Tang, Juan P. Arroyo, Andrew S. Terker, Yinqiu Wang, Aolei Niu, Xiaofeng Fan, Suwan Wang, Yahua Zhang, Ming Jiang, David H. Wasserman, Ming-Zhi Zhang, Raymond C. Harris
Journal: Journal of Clinical Investigation (2022)

Obesity-associated complications are causing increasing morbidity and mortality worldwide. Expansion of adipose tissue in obesity leads to a state of low-grade chronic inflammation and dysregulated metabolism, resulting in insulin resistance and metabolic syndrome. Adipose tissue macrophages (ATMs) accumulate in obesity and are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction. Macrophages are rich sources of cyclooxygenase (COX), the rate limiting enzyme for prostaglandin E2 (PGE2) production. When mice were fed a high-fat diet (HFD), ATMs increased expression of COX-2. Selective myeloid cell COX-2 deletion resulted in increased monocyte recruitment and proliferation of ATMs, leading to increased proinflammatory ATMs with decreased phagocytic ability. There were increased weight gain and adiposity, decreased peripheral insulin sensitivity and glucose utilization, increased adipose tissue inflammation and fibrosis, and abnormal adipose tissue angiogenesis. HFD pair-feeding led to similar increases in body weight, but mice with selective myeloid cell COX-2 still exhibited decreased peripheral insulin sensitivity and glucose utilization. Selective myeloid deletion of the macrophage PGE2 receptor subtype, EP4, produced a similar phenotype, and a selective EP4 agonist ameliorated the metabolic abnormalities seen with ATM COX-2 deletion. Therefore, these studies demonstrated that an ATM COX-2/PGE2/EP4 axis plays an important role in inhibiting adipose tissue dysfunction.
Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1
Authors: Sanjeev Sethi, Benjamin Madden, Marta Casal Moura, Samih H. Nasr, Nattawat Klomjit, LouAnn Gross, Vivian Negron, M. Cristine Charlesworth, Mariam P. Alexander, Nelson Leung, Ulrich Specks, Fernando C. Fervenza, Mark Haas
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement Hematopoietic stem cell transplant (HSCT) is a treatment for certain hematologic malignancies and immune disorders. A complication of HSCT is membranous nephropathy (MN), which results from antibodies targeting an antigen in the glomerular basement membrane (GBM). The antigen in most cases of HSCT-associated MN is not known. Laser microdissection and mass spectrometry identified a novel protein, protocadherin FAT1 (FAT1), in HSCT-associated MN. Kidney biopsy specimens showed granular staining for FAT1 along the GBM in HSCT-associated MN. Antibodies to FAT1 were detected in serum and in kidney biopsy tissue in HSCT-associated MN, but not in controls. FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents the majority of MN associated with HSCT. Background Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown. Methods We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli from 250 patients with PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence (IF) microscopy studies to localize the novel antigen. Western blot analyses using serum and IgG eluted from frozen biopsy specimen to detect binding of IgG to new 'antigen'. Results MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in nine patients with PLA2R-negative MN. In all nine patients, MN developed after allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in five patients known to have allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all five patients by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean±SD, 20.9±10.1). All 14 patients were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy specimens showed IgG (2 to 3+) with mild C3 (0 to 1+) along the GBM; IgG4 was the dominant IgG subclass. IHC after protease digestion and confocal IF confirmed granular FAT1 deposits along the GBM. Lastly, Western blot analyses detected anti-FAT1 IgG and IgG4 in the eluate obtained from pooled frozen kidney biopsy tissue and in the serum of those with FAT1-asssociated MN, but not from those with PLA2R-associated MN. Conclusions FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT.
Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs
Authors: Tsunaki Hongu, Maren Pein, Jacob Insua-Rodríguez, Ewgenija Gutjahr, Greta Mattavelli, Jasmin Meier, Kristin Decker, Arnaud Descot, Matthias Bozza, Richard Harbottle, Andreas Trumpp, Hans-Peter Sinn, Angela Riedel, Thordur Oskarsson
Journal: Nature Cancer (2022)

Abstract Disseminated cancer cells frequently lodge near vasculature in secondary organs. However, our understanding of the cellular crosstalk invoked at perivascular sites is still rudimentary. Here, we identify intercellular machinery governing formation of a pro-metastatic vascular niche during breast cancer colonization in the lung. We show that specific secreted factors, induced in metastasis-associated endothelial cells (ECs), promote metastasis in mice by enhancing stem cell properties and the viability of cancer cells. Perivascular macrophages, activated via tenascin C (TNC) stimulation of Toll-like receptor 4 (TLR4), were shown to be crucial in niche activation by secreting nitric oxide (NO) and tumor necrosis factor (TNF) to induce EC-mediated production of niche components. Notably, this mechanism was independent of vascular endothelial growth factor (VEGF), a key regulator of EC behavior and angiogenesis. However, targeting both macrophage-mediated vascular niche activation and VEGF-regulated angiogenesis resulted in added potency to curb lung metastasis in mice. Together, our findings provide mechanistic insights into the formation of vascular niches in metastasis.
Evidence should inform more than prescribing decisions
Authors: Fiona Cowdell
Journal: British Journal of Dermatology (2022)

Linked Article: Hewitt et al. Br J Dermatol 2022. For many years researchers have investigated optimal approaches to delivering patient-centred care. Patient-centred medicine was a term first used by Michael Balint in the late 1960s; it challenged the orthodox illness-oriented model of care and proposed seeing each patient as a unique human being.1 The notion of patient-centred care has evolved; recent reviews suggest nine core themes: (i) empathy, (ii) respect, (iii) engagement, (iv) relationship, (v) communication, (vi) shared decision making, (vii) holistic focus, (viii) individualized focus and (ix) coordinated care.2 In more recent years the focus has shifted to person-centred care, the key difference being the aim of the former is a functional life, while the latter strives to enable a meaningful life.2 Both concepts have a clear place in dermatology care where people are living with conditions such as psoriasis which impact on wellbeing and quality of life. Shared decision making is a key component of person-centred care.3 It is essential in dermatology practice,4, 5 as it provides a foundation to enable the significant and sustained self-management that must be integrated into the person’s everyday life. The ‘personal models of illness’ theory emerged in the 1990s and defines ‘personal models’ as an amalgamation of individual beliefs, emotions, knowledge, attitudes and experiences that influence behavioural responses to illness.6 Existing research mainly focuses on patients, but one study of clinician personal models in psoriasis concludes that although most participants recognized psoriasis as a complex condition they continued to treat it as a skin condition alone.7 In this issue of the BJD, Hewitt et al.8 report on a qualitative study designed to deepen understanding about how dermatologist’s personal models inform a patient-centred approach to psoriasis management with a focus on prescribing a new treatment. In this rigorous research a patient-centred approach to clinician’s care decision was not universal. One clinician offered the powerful quote: ‘Well, my patients, they actually do what I tell them to do (laughs) […] In this regard, I am conservative (laughs) and if you don’t like that, you should find someone else.’ In dermatology, as with all healthcare, we espouse the principles of evidence-based practice. In prescribing Apremilast clinicians will be adhering to evidence-based guidance. This article points to the need to give more thought to other types of equally important evidence. We know that person-centred care can improve patient satisfaction, knowledge and quality of life in other long-term conditions, for example prevention and treatment of chronic wounds.9 Extensive literature suggests shared decision making is a key component of person-centred care in dermatology.5 Now is the time to influence the personal models of those clinicians who have yet to integrate this important evidence that will improve patient experience and outcomes.
Machine perfusion in liver transplantation
Authors: Richard X. Sousa Da Silva, Achim Weber, Philipp Dutkowski, Pierre‐Alain Clavien
Journal: Hepatology (2022)

Although liver transplantation is a true success story, many patients still die awaiting an organ. The increasing need for liver grafts therefore remains an unsolved challenge to the transplant community. To address this, transplant donor criteria have been expanded and, for example, more liver grafts with significant steatosis or from donors with circulatory death are being used. These marginal grafts, however, carry an increased risk of graft-associated complications, such as primary nonfunction, delayed graft function, or late biliary injuries. Therefore, reliable assessment of graft viability before use is essential for further success. To achieve this, machine liver perfusion, a procedure developed more than 50 years ago but almost forgotten at the end of the last century, is again of great interest. We describe in this review the clinical most applied machine perfusion techniques, their mechanistic background, and a novel concept of combining immediate organ assessment during hypothermic oxygenated perfusion, followed by an extended phase of normothermic machine perfusion, with simultaneous ex situ treatment of the perfused liver. Such a new approach may allow the pool of usable livers to dramatically increase and improve outcomes for recipients.
More Research is Still Needed To Support The Real-world Generalizability of The Benefits of Lifestyle Interventions for CKD
Authors: Liuyan Huang, Fan Zhang
Journal: Journal of the American Society of Nephrology (2022)

We read with interest a randomized controlled trial by Beetham et al., published in the latest issue of JASN as part of the LANDMARK III trial.1 The results demonstrated the beneficial effects of a 3-year lifestyle intervention on physical activity, cardiorespiratory fitness, and neuromuscular fitness in patients with stage 3–4 CKD. It also highlights the importance of multidisciplinary research for such a population. However, some aspects need to be considered when interpreting the study results. First, only 160 patients who were screened received the randomization sequence, of which 79 participated in the lifestyle intervention, and restrictions of the included patients (patients with nondialysis CKD) and the higher rate of dropouts limit the generalizability of the results in the real world. Second, unlike previous studies of similar interventions,2,3 the study lacked hard endpoints, such as mortality, and restricted the cost-effectiveness findings. Finally, although the questionnaire was validated, the assessment of physical activity levels through self-report could lead to recall bias and thus overestimate actual activity. Undeniably, Beetham et al. presented this study with an extremely rigorous study design that provides further insight into the disease management of patients with CKD. Disclosures All authors have nothing to disclose. Funding None.
Potential Role of IFNγ Inhibition in Refractory Cytokine Release Syndrome Associated with CAR T-cell Therapy
Authors: Kevin O. McNerney, Amanda M. DiNofia, David T. Teachey, Stephan A. Grupp, Shannon L. Maude
Journal: Blood Cancer Discovery (2021)

Summary: Here we review the pathophysiology and management of cytokine release syndrome (CRS) secondary to immunotherapy, and potential options for CRS refractory to IL6 inhibition and glucocorticoids, for which there are no proven treatments. To illustrate, we describe a patient with B-cell acute lymphoblastic leukemia who developed refractory grade 4 CRS following CD19-directed chimeric antigen receptor T-cell therapy, treated with tocilizumab, methylprednisolone, siltuximab, and the IFNγ inhibitor emapalumab, with complete remission from leukemia for 12 months. See related article by Bailey et al., (15).
Monocyte Signature Associated with Herpes Simplex Virus Reactivation and Neurological Recovery after Brain Injury
Authors: Tanguy Chaumette, Raphael Cinotti, Alice Mollé, Pierre Solomon, Louise Castain, Cynthia Fourgeux, Hamish E. G. McWilliam, Barbara Misme-Aucouturier, Alexis Broquet, Cédric Jacqueline, Mickael Vourc’h, Delphine Fradin, Celine Bossard, Laurent David, Emmanuel Montassier, Cecile Braudeau, Régis Josien, Jose A. Villadangos, Karim Asehnoune, Celine Bressollette-Bodin, Jeremie Poschmann, Antoine Roquilly
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Brain injury induces systemic immunosuppression, increasing the risk of viral reactivations and altering neurological recovery. Objectives: To determine if systemic immune alterations and lung replication of herpesviridae are associated and can help predict outcomes after brain injury. Methods: We collected peripheral blood mononuclear cells in patients with severe brain injury requiring invasive mechanical ventilation. We systematically searched for respiratory herpes simplex virus (HSV) replications in tracheal aspirates. We also performed chromatin immunoprecipitation sequencing, RNA-sequencing, and in vitro functional assays of monocytes and CD4 T cells collected on Day 1 to characterize the immune response to severe acute brain injury. The primary outcome was the Glasgow Outcome Scale Extended at 6 months. Measurements and Main Results: In 344 patients with severe brain injury, lung HSV reactivations were observed in 39% of the 232 patients seropositive for HSV and independently associated with poor neurological recovery at 6 months (hazard ratio, 1.90; 95% confidence interval, 1.08–3.57). Weighted gene coexpression network analyses of the transcriptomic response of monocytes to brain injury defined a module of 721 genes, including PD-L1 and CD80, enriched for the binding DNA motif of the transcriptional factor Zeb2 and whose ontogenic analyses revealed decreased IFN-γ–mediated and antiviral response signaling pathways. This monocyte signature was preserved in a validation cohort and predicted the neurological outcome at 6 months with good accuracy (area under the curve, 0.786; 95% confidence interval, 0.593–0.978). Conclusions: A specific monocyte signature is associated with HSV reactivation and predicts poor recovery after brain injury. The alterations of the immune control of herpesviridae replication are understudied and represent a novel therapeutic target.
Mitogen-Activated Protein Kinase Inhibitor Selumetinib Fails to Increase the Complete Response Rate of Radioactive Iodine Alone in High-Risk Differentiated Thyroid Cancer: Lessons From the Phase III ASTRA Study
Authors: Marcia S. Brose, Daniel A. Pryma, Kate L. Newbold
Journal: Journal of Clinical Oncology (2022)
Thrombocytopenia and splenic platelet-directed immune responses after IV ChAdOx1 nCov-19 administration
Authors: Leo Nicolai, Alexander Leunig, Kami Pekayvaz, Max Esefeld, Afra Anjum, Justina Rath, Eva Riedlinger, Vincent Ehreiser, Magdalena Mader, Luke Eivers, Marie-Louise Hoffknecht, Zhe Zhang, Daniela Kugelmann, Dario Rossaro, Raphael Escaig, Rainer Kaiser, Vivien Polewka, Anna Titova, Tobias Petzold, Karsten Spiekermann, Matteo Iannacone, Thomas Thiele, Andreas Greinacher, Konstantin Stark, Steffen Massberg
Journal: Blood (2022)

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are based on a range of novel platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently, a novel complication of SARS-CoV-2-targeted adenovirus vaccines has emerged: immune thrombocytopenia, either isolated, or accompanied by thrombosis (then termed VITT). This complication is characterized by low platelet counts, and in the case of VITT, also by platelet-activating platelet factor 4 antibodies reminiscent of heparin-induced thrombocytopenia, leading to a prothrombotic state with clot formation at unusual anatomic sites. Here, we detected antiplatelet antibodies targeting platelet glycoprotein receptors in 30% of patients with proven VITT (n = 27) and 42% of patients with isolated thrombocytopenia after ChAdOx1 nCov-19 vaccination (n = 26), indicating broad antiplatelet autoimmunity in these clinical entities. We use in vitro and in vivo models to characterize possible mechanisms of these platelet-targeted autoimmune responses leading to thrombocytopenia. We show that IV but not intramuscular injection of ChAdOx1 nCov-19 triggers platelet-adenovirus aggregate formation and platelet activation in mice. After IV injection, these aggregates are phagocytosed by macrophages in the spleen, and platelet remnants are found in the marginal zone and follicles. This is followed by a pronounced B-cell response with the emergence of circulating antibodies binding to platelets. Our work contributes to the understanding of platelet-associated complications after ChAdOx1 nCov-19 administration and highlights accidental IV injection as a potential mechanism of platelet-targeted autoimmunity. Hence, preventing IV injection when administering adenovirus-based vaccines could be a potential measure against platelet-associated pathologies after vaccination.
What are mycorrhizal traits?
Authors: V. Bala Chaudhary, E. Penelope Holland, Suw Charman-Anderson, Aidee Guzman, Lukas Bell-Dereske, Tanya E. Cheeke, Adriana Corrales, Jessica Duchicela, Cameron Egan, Manju M. Gupta, S. Emilia Hannula, Rachel Hestrin, Shabana Hoosein, Amit Kumar, Genet Mhretu, Lena Neuenkamp, Pushpa Soti, Yichun Xie, Thorunn Helgason
Journal: Trends in Ecology & Evolution (2022)
COVID-19 pandemic: what's next for public health?
Authors: None The Lancet Public Health
Journal: The Lancet Public Health (2022)

Two years after SARS-COV-2 was declared a public health emergency, global estimates of excess deaths from the Institute for Health Metrics and Evaluation indicate that 18·2 million people died due to the pandemic by Dec 31, 2021—three times higher than official records suggest. 100 million people have been plunged into extreme poverty by the pandemic, according to World Bank estimates. While the true burden of COVID-19 is being unravelled, is a mental health crisis being unmasked? The pandemic has exposed long-standing gaps and a global underinvestment in mental health care and prevention, disproportionately affecting young people and women.
Epithelial cell responses to rhinovirus identify an early-life–onset asthma phenotype in adults
Authors: Eugene H. Chang, Nima Pouladi, Stefano Guerra, Jana Jandova, Alexander Kim, Haiquan Li, Jianrong Li, Wayne Morgan, Debra A. Stern, Amanda L. Willis, Yves A. Lussier, Fernando D. Martinez
Journal: Journal of Allergy and Clinical Immunology (2022)
Delayed presentation of HIV among older individuals: a growing problem
Authors: Amy C Justice, Matthew B Goetz, Cameron N Stewart, Brenna C Hogan, Elizabeth Humes, Paula M Luz, Jessica L Castilho, Denis Nash, Ellen Brazier, Beverly Musick, Constantin Yiannoutsos, Karen Malateste, Antoine Jaquet, Morna Cornell, Tinei Shamu, Reena Rajasuriar, Awachana Jiamsakul, Keri N Althoff
Journal: The Lancet HIV (2022)
Stepping up to meet the challenge of freezing of gait in Parkinson’s disease
Authors: Simon Lewis, Stewart Factor, Nir Giladi, Alice Nieuwboer, John Nutt, Mark Hallett
Journal: Translational Neurodegeneration (2022)

Abstract There has been a growing appreciation for freezing of gait as a disabling symptom that causes a significant burden in Parkinson’s disease. Previous research has highlighted some of the key components that underlie the phenomenon, but these reductionist approaches have yet to lead to a paradigm shift resulting in the development of novel treatment strategies. Addressing this issue will require greater integration of multi-modal data with complex computational modeling, but there are a number of critical aspects that need to be considered before embarking on such an approach. This paper highlights where the field needs to address current gaps and shortcomings including the standardization of definitions and measurement, phenomenology and pathophysiology, as well as considering what available data exist and how future studies should be constructed to achieve the greatest potential to better understand and treat this devastating symptom.
Response to: Correspondence on ‘No efficacy of anti-IL-23 therapy for axial spondyloarthritis in randomised controlled trials but in post hoc analyses of psoriatic arthritis-related ‘physician-reported spondylitis’?’ by Braun and Landewé
Authors: Robert BM Landewé, Juergen Braun
Journal: Annals of the Rheumatic Diseases (2022)
Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases: an International Organization for Study of Inflammatory Bowel Diseases consensus
Authors: Ashwin N Ananthakrishnan, Gilaad G Kaplan, Charles N Bernstein, Kristin E Burke, Paul J Lochhead, Alexa N Sasson, Manasi Agrawal, Jimmy Ho Tuan Tiong, Joshua Steinberg, Wolfgang Kruis, Flavio Steinwurz, Vineet Ahuja, Siew C Ng, David T Rubin, Jean-Frederic Colombel, Richard Gearry
Journal: The Lancet. Gastroenterology & hepatology (2022)