tbuckley/cabot-search huggingface dataset:
Abstract 12071: Serum Immunoglobulin G4 Level is an Independent Predictor of Major Adverse Cardiovascular Events After Percutaneous Coronary Intervention over Long-Term Follow-Up
Authors: Aiko Sakamoto, Nobukazu Ishizaka, Jiro Ando, Ryozo Nagai, Issei Komuro
Journal: Circulation (2015)

Background: Inflammatory processes contribute to the development of atherosclerosis. However, it remains unclear whether immunoglobulin G4 (IgG4)-related immuno-inflammation may affect the progression of cardiovascular disease. We therefore analyzed the relationship between serum IgG4 level and future major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI). Methods: We measured serum levels of IgG4 in 562 patients (mean age, 66.9 ± 10.3 years) who underwent coronary angiography from October 2005 to September 2008. Furthermore, a total of 108 patients who subsequently received first PCI were followed-up for a median period of 2721 days (interquartile range [IR] 1591-3183). MACE was defined as cardiac death, acute coronary syndrome, cerebral stroke, and target vessel revascularization. Results: Serum levels of IgG4 were significantly higher in patients with coronary artery disease (34.1 mg/dL, IR 18.7-58.9) than in those without (30.5 mg/dL, IR 15.8-50.3, P=0.045). Among patients who received PCI, 40 (37.0%) patients developed MACE during the follow-up period. Patients with serum IgG4 levels of median or greater (≥37.2 mg/dL) had a significantly higher risk of MACE than those with serum IgG4 levels below median (log-rank test, P=0.017). In Cox regression analysis using age, gender, estimated glomerular filtration rate (eGFR), hypertension, dyslipidemia, diabetes, smoking, and serum levels of high-sensitivity C-reactive protein (hsCRP) as covariates, serum IgG4 level was an independent predictor of MACE (hazard ratio 2.39 per 100 mg/dL increase, 95% confidence interval 1.41-4.07, P=0.001). Conclusions: Elevated serum IgG4 level at baseline significantly predicted MACE after PCI, as well as present coronary stenosis, over long-term follow-up even among patients without apparent IgG4-related disease. IgG4-related immuno-inflammation may play a certain role in the progression of coronary atherosclerosis.
Development of a composite biomarker-based calculator to predict the probability of pathologic complete response (pT0) after neoadjuvant pembrolizumab (pembro) in muscle invasive bladder cancer (MIBC).
Authors: Andrea Necchi, Joshua J. Meeks, Marco Bandini, Leigh Ann Fall, Daniele Raggi, Alberto Briganti, Elena Farè, Patrizia Giannatempo, Kimberly A. McLaughlin, Arighno Das, Laura Marandino, Andrea Gallina, Andrea Salonia, Giorgio Gandaglia, Nicola Fossati, Jeffrey S. Ross, Francesco Montorsi, Ryan Dittamore, Elai Davicioni, Ewan Gibb
Journal: Journal of Clinical Oncology (2020)

539 Background: The PURE01 study (NCT02736266) evaluates the use of pembro before radical cystectomy (RC) in MIBC. We assessed selected individual and combined biomarkers for predicting pT0 response after pembro, and developed a tool that may be used as an aid for clinical decision-making. Methods: Patients (pts) enrolled in the PURE01 were clinical (c) stage T≤4aN0M0 MIBC. Analysis to date included a comprehensive genomic profiling (FoundationONE assay), programmed cell-death-ligand-1 (PD-L1) combined positive score assessment (CPS, Dako 22C3 antibody) and whole transcriptome (Decipher assay) and RNA-seq profiling of pre/post therapy samples. Multivariable logistic regression analyses (MVA) evaluated baseline cT-stage and biomarkers in association with pT0 response. Corresponding coefficients were used to develop a risk calculator based on the tumor mutational burden (TMB), CPS, Immune190 signature score, and cT-stage. Decision-curve analysis was performed. Results: Complete biomarker data was available for 84 pts. Increasing TMB, CPS, and Immune190 scores showed a linear positive correlation with the pT0 probability in logistic regression (p=0.02, p=0.004, p=0.02). The c-index of the risk calculator was 0.79. Decision-curve analysis found the net-benefit of the model was higher than the “treat-all” option within the clinically-meaningful threshold probabilities of achieving a pT0 of 40-60%. Within this range, adding the Immune190 score improved the model over TMB and CPS. A significant decrease in median TMB values was observed (p=0.005) in 24 matched RC, versus a non-significant change in median CPS in 38 matched RC. Molecular subtyping switching was observed in 20/31 matched cases (64.5%), most frequently to the luminal-infiltrated subtype (80%). Conclusions: The study presents the first composite biomarker-based pT0 probability calculator for optimal pt selection. Pending validation, the model may be used to recommend neoadjuvant pembro to very selected MIBC pts. The observed changes in biomarker features in post-therapy samples may have an impact on future adjuvant strategies. Clinical trial information: NCT02736266.
Antibacterial and angiogenic chitosan microneedle array patch for promoting wound healing
Authors: Junjie Chi, Xiaoxuan Zhang, Canwen Chen, Changmin Shao, Yuanjin Zhao, Yongan Wang
Journal: Bioactive Materials (2020)

A patch with the capability of avoiding wound infection and promoting tissue remolding is of great value for wound healing. In this paper, we develop a biomass chitosan microneedle array (CSMNA) patch integrated with smart responsive drug delivery for promoting wound healing. Chitosan possesses many outstanding features such as the natural antibacterial property and has been widely utilized for wound healing. Besides, the microstructure of microneedles enables the effective delivery of loaded drugs into the target area and avoids the excessive adhesion between the skin and the patch. Also, vascular endothelial growth factor (VEGF) is encapsulated in the micropores of CSMNA by temperature sensitive hydrogel. Therefore, the smart release of the drugs can be controllably realized via the temperature rising induced by the inflammation response at the site of wounds. It is demonstrated that the biomass CSMNA patch can promote inflammatory inhibition, collagen deposition, angiogenesis, and tissue regeneration during the wound closure. Thus, this versatile CSMNA patch is potentially valuable for wound healing in clinical applications.
Survival outcomes associated with different palliative systemic therapies (PSTs) in patients with metastatic bladder cancer (mBC).
Authors: Saba Vafaei-Nodeh, Arshia Beigi, Longlong Huang, Gillian Mimmack, Shaun Zheng Sun, Jenny J. Ko
Journal: Journal of Clinical Oncology (2020)

450 Background: Cisplatin-based (Cis) chemotherapy (C) is considered standard first-line regimen for treating mBC. In individuals medically unfit for Cis, carboplatin-based (Cb) regimens may be considered. Alternative PSTs include immunotherapy (I) as first or second-line treatments. The purpose of this study is to investigate current trends and clinical outcomes of PSTs in patients with mBC. Methods: A retrospective analysis was conducted on patients initially diagnosed with bladder cancer from Sep 2014 to Dec 2016 and had de novo or recurrent mBC. Kaplan-Meier method and Log-Rank test were used to compare survival outcomes among patients receiving different PSTs. Results: In 273 patients, 123 (45.1%) had de novo and 150 (54.9%) had recurrent disease. The median overall survivals (mOS) were 5.3 (95% CI: 3.7-8.2) and 6.5 months (95% CI 5.1-8.9), respectively (p=0.54). Patients received one of the following: C (23.1%), I (6.2%), C followed by I (C/I, 10.6%), and no treatment (NT, 60.1%). The mOS were 9.5 (95% CI: 7.1-12.5), 9.2 (95% CI: 6.1 - not estimable (NE)), 23.9 (95% CI: 16.30-NE), and 3.5 months (95% CI: 3.03-4.30), respectively. Each treatment group had a longer mOS than the NT group (p&lt;0.01 in all three pairwise comparisons). Additionally, patients receiving C/I had a longer mOS than those receiving either C or I (p&lt;0.001 and p=0.0497, respectively). The mOS were not statistically different between C vs I (p=0.2649). In patients receiving any C, 50.0% received Gemcitabine (G) plus Cis and 30.4% received G plus Cb. The mOS were 11.0 (95% CI: 8.7-19.7) and 14.4 months (95% CI:10.7-19.2), respectively, which were not significantly different (p=0.36). Conclusions: Despite the general preference for G plus Cis over Cb, this study showed that G plus Cb as a PST may be a comparable and efficacious treatment. While C currently remains the preferred initial line of PST, patients receiving I had similar survival outcomes to the C group despite many of the patients having Cis ineligibility. Real-world mOS of 2 years in patients who receive both C and I is unprecedented and indicates efficacy of PST. This study provides further evidence for immunotherapy as first or second-line regimen in treating mBC.
Host-directed therapies and holistic care for tuberculosis
Authors: Alimuddin Zumla, Giuseppe Ippolito, Francine Ntoumi, Vicki Seyfert-Margolies, Tumaini J Nagu, Daniela Cirillo, Jeremiah Muhwa Chakaya, Ben Marais, Markus Maeurer
Journal: The Lancet Respiratory Medicine (2020)
What are the barriers to physical activity in patients with chronic plaque psoriasis?*
Authors: L. Auker, L. Cordingley, S.R. Pye, C.E.M. Griffiths, H.S. Young
Journal: British Journal of Dermatology (2020)

Background Psoriasis is associated with an increased risk of cardiovascular disease. Despite recommendation that exercise is important for cardiorespiratory fitness, patients with psoriasis avoid participation in physical activities for reasons that are, as yet, unclear. Objectives This study investigated the relationship between psoriasis-specific experiences and self-reported patterns of exercise, hypothesizing that individuals with psoriasis are less likely to engage in physical activity for reasons that are related to their psoriasis. Methods In total 404 patients with chronic plaque psoriasis were recruited. History, examination and physical activity were assessed for each participant. Results Overall, 52·8% (n = 188) of patients with psoriasis aged 18–65 years and 66% (n = 37) of those aged > 65 years engaged in less than the recommended amount of physical activity for cardiorespiratory fitness. As the severity and psychosocial impact of psoriasis increased, the participation in exercise (of all intensities) decreased. There was a significant negative correlation between Psoriasis Area and Severity Index and total activity in women aged 18–65 years (r = −0·19, 95% confidence interval −0·36 to 0; P = 0·04) and a significant negative correlation between physical activity and Dermatology Life Quality Index (DLQI) in all participants (r = −0·11, 95% confidence interval −0·21 to 0; P = 0·04). Individual components of the DLQI identified barriers to physical activity including skin sensitivity and reluctance to participate in leisure activities. Conclusions Psoriasis-specific factors – severity, skin sensitivity, clothing choice, participation in social/leisure activities, and treatments – contribute to exercise avoidance and may augment the increased risk of cardiovascular disease in patients with psoriasis.
Ceftriaxone allergy in a pediatric cohort
Authors: Ashwag Alsaidalani, Sofianne Gabrielli, MOSHE BEN-SHOSHAN, CHRISTINE McCusker, ANDREW OKEEFE, Elissa Abrams, JENNIFER PROTUDJER, ELANA LAVINE, TRACY PITT, ADELLE ATKINSON, Thomas Eiwegger
Journal: Journal of Allergy and Clinical Immunology (2020)
Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy
Authors: Vicky Brocklebank, Gurinder Kumar, Alexander J. Howie, Jayanthi Chandar, David V. Milford, Janet Craze, Jonathan Evans, Eric Finlay, Michael Freundlich, Daniel P. Gale, Carol Inward, Martin Mraz, Caroline Jones, William Wong, Stephen D. Marks, John Connolly, Bronte M. Corner, Kate Smith-Jackson, Patrick R. Walsh, Kevin J. Marchbank, Claire L. Harris, Valerie Wilson, Edwin K.S. Wong, Michal Malina, Sally Johnson, Neil S. Sheerin, David Kavanagh
Journal: Kidney International (2020)

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.
Surveillance or no surveillance ultrasonography for deep vein thrombosis and outcomes of critically ill patients: a pre-planned sub-study of the PREVENT trial
Authors: Yaseen M. Arabi, Karen E. A. Burns, Sami J. Alsolamy, Mohammed S. Alshahrani, Fahad M. Al-Hameed, Zia Arshad, Mohammed Almaani, Hassan Hawa, Yasser Mandourah, Ghaleb A. Almekhlafi, Abdulsalam Al Aithan, Imran Khalid, Jalal Rifai, Gulam Rasool, Sheryl Ann I. Abdukahil, Jesna Jose, Lara Y. Afesh, Abdulaziz Al-Dawood
Journal: Intensive Care Medicine (2020)
Prognostic role of Oncological Multidimensional Prognostic Index (Onco-MPI) in elderly patients with urological cancers.
Authors: Davide Bimbatti, Marco Maruzzo, Giuseppina Tierno, Eleonora Bergo, Francesco Pierantoni, Antonella Brunello, Umberto Basso, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2020)

66 Background: MPI is an effective tool for geriatric assessment in elderly patients (pts). An oncological version of MPI (Onco-MPI) has been validated by our group in pts with cancer. We evaluate here the prognostic role of Onco-MPI in pts affected by urological cancer. Methods: Pts aged ≥70 years with prostate, renal and urothelial cancer (bladder or upper urinary tract) referred to the Medical Oncology 1 Unit from Jan 2005 to Aug 2019 received a basal comprehensive geriatric assessment (CGA). Onco-MPI was calculated by a validated algorithm as a weighted linear combination of the CGA domains as previously described, identifying 3 different prognostic groups: low (scores 0.0-0.46), intermediate (scores 0.47-0.63) and high risk (scores 0.64-1.0). Results: A total of 643 pts were included; 382 with prostate, 121 renal and 140 urothelial cancer. Median age was 77 years (68-95). ECOG PS was 0 in 44%, 1 in 34.2% and &gt;1 in 21.6%; 19.3% had stage I or II disease, 29.7% stage III and 51% stage IV. Median overall survival (OS) was 35.4 months (95% CI 29.5-41.2). Onco-MPI score (low vs medium vs high risk) was significantly associated with OS in the overall population as well as in the subgroups of patients with prostate, renal or urothelial cancer (table). In pts with prostate cancer the majority of pts were low risk (93%) and only few intermediate (7%), no one was high risk. Conclusions: Onco-MPI confirmed its prognostic role in elderly pts with prostate, renal and urothelial carcinoma. It may be therefore valuable both in clinical practice for driving decision-making, and in geriatric clinical trials thanks to its standardization.[Table: see text]
Immunology in the Era of Single-Cell Technologies
Authors: Mirjana Efremova, Roser Vento-Tormo, Jong-Eun Park, Sarah A. Teichmann, Kylie R. James
Journal: Annual Review of Immunology (2020)

Immune cells are characterized by diversity, specificity, plasticity, and adaptability-properties that enable them to contribute to homeostasis and respond specifically and dynamically to the many threats encountered by the body. Single-cell technologies, including the assessment of transcriptomics, genomics, and proteomics at the level of individual cells, are ideally suited to studying these properties of immune cells. In this review we discuss the benefits of adopting single-cell approaches in studying underappreciated qualities of immune cells and highlight examples where these technologies have been critical to advancing our understanding of the immune system in health and disease.
Butyrate inhibits human mast cell activation via epigenetic regulation of FcεRI‐mediated signaling
Authors: Jelle Folkerts, Frank Redegeld, Gert Folkerts, Bart Blokhuis, Mariska P. M. van den Berg, Marjolein J. W. de Bruijn, Wilfred F. J. van IJcken, Tobias Junt, See‐Ying Tam, Stephen J. Galli, Rudi W. Hendriks, Ralph Stadhouders, Marcus Maurer
Journal: Allergy (2020)

Short-chain fatty acids (SCFAs) are fermented dietary components that regulate immune responses, promote colonic health, and suppress mast cell-mediated diseases. However, the effects of SCFAs on human mast cell function, including the underlying mechanisms, remain unclear. Here, we investigated the effects of the SCFAs (acetate, propionate, and butyrate) on mast cell-mediated pathology and human mast cell activation, including the molecular mechanisms involved.Precision-cut lung slices (PCLS) of allergen-exposed guinea pigs were used to assess the effects of butyrate on allergic airway contraction. Human and mouse mast cells were co-cultured with SCFAs and assessed for degranulation after IgE- or non-IgE-mediated stimulation. The underlying mechanisms involved were investigated using knockout mice, small molecule inhibitors/agonists, and genomics assays.Butyrate treatment inhibited allergen-induced histamine release and airway contraction in guinea pig PCLS. Propionate and butyrate, but not acetate, inhibited IgE- and non-IgE-mediated human or mouse mast cell degranulation in a concentration-dependent manner. Notably, these effects were independent of the stimulation of SCFA receptors GPR41, GPR43, or PPAR, but instead were associated with inhibition of histone deacetylases. Transcriptome analyses revealed butyrate-induced downregulation of the tyrosine kinases BTK, SYK, and LAT, critical transducers of FcεRI-mediated signals that are essential for mast cell activation. Epigenome analyses indicated that butyrate redistributed global histone acetylation in human mast cells, including significantly decreased acetylation at the BTK, SYK, and LAT promoter regions.Known health benefits of SCFAs in allergic disease can, at least in part, be explained by epigenetic suppression of human mast cell activation.
N-Cadherin Overexpression Mobilizes the Protective Effects of Mesenchymal Stromal Cells Against Ischemic Heart Injury Through a β-Catenin–Dependent Manner
Authors: Wenjun Yan, Chen Lin, Yongzhen Guo, Youhu Chen, Yunhui Du, Wayne Bond Lau, Yunlong Xia, Fuyang Zhang, Renzhi Su, Erhe Gao, Yajing Wang, Congye Li, Rui Liu, Xin-liang Ma, Ling Tao
Journal: Circulation Research (2020)

Mesenchymal stromal cell-based therapy is promising against ischemic heart failure. However, its efficacy is limited due to low cell retention and poor paracrine function. A transmembrane protein capable of enhancing cell-cell adhesion, N-cadherin garnered attention in the field of stem cell biology only recently.The current study investigates whether and how N-cadherin may regulate mesenchymal stromal cells retention and cardioprotective capability against ischemic heart failure.Adult mice-derived adipose tissue-derived mesenchymal stromal cells (ADSC) were transfected with adenovirus harboring N-cadherin, T-cadherin, or control adenovirus. CM-DiI-labeled ADSC were intramyocardially injected into the infarct border zone at 3 sites immediately after myocardial infarction (MI) or myocardial ischemia/reperfusion. ADSC retention/survival, cardiomyocyte apoptosis/proliferation, capillary density, cardiac fibrosis, and cardiac function were determined. Discovery-driven/cause-effect analysis was used to determine the molecular mechanisms. Compared with ADSC transfected with adenovirus-control, N-cadherin overexpression (but not T-cadherin) markedly increased engrafted ADSC survival/retention up to 7 days post-MI. Histological analysis revealed that ADSC transfected with adenovirus-N-cadherin significantly preserved capillary density and increased cardiomyocyte proliferation and moderately reduced cardiomyocyte apoptosis 3 days post-MI. More importantly, ADSC transfected with adenovirus-N-cadherin (but not ADSC transfected with adenovirus-T-cadherin) significantly increased left ventricular ejection fraction and reduced fibrosis in both MI and myocardial ischemia/reperfusion mice. In vitro experiments demonstrated that N-cadherin overexpression promoted ADSC-cardiomyocyte adhesion and ADSC migration, enhancing their capability to increase angiogenesis and cardiomyocyte proliferation. MMP (matrix metallopeptidases)-10/13 and HGF (hepatocyte growth factor) upregulation is responsible for N-cadherin's effect upon ADSC migration and paracrine angiogenesis. N-cadherin overexpression promotes cardiomyocyte proliferation by HGF release. Mechanistically, N-cadherin overexpression significantly increased N-cadherin/β-catenin complex formation and active β-catenin levels in the nucleus. β-catenin knockdown abolished N-cadherin overexpression-induced MMP-10, MMP-13, and HGF expression and blocked the cellular actions and cardioprotective effects of ADSC overexpressing N-cadherin.We demonstrate for the first time that N-cadherin overexpression enhances mesenchymal stromal cells-protective effects against ischemic heart failure via β-catenin-mediated MMP-10/MMP-13/HGF expression and production, promoting ADSC/cardiomyocyte adhesion and ADSC retention.