tbuckley/cabot-search huggingface dataset:
Abstract 18090: Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes
Authors: Muhammad Hammadah, Ibhar Al Mheid, Kobina Wilmot, Ronnie Ramadan, Naser Abdelhadi, Ayman Alkhoder, Malik Obideen, Pratik Pimple, Oleksiy Levantsevych, Heval Mohamed Kelli, Amit J Shah, Ernest Garcia, Yan V Sun, Brad Pearce, Michael Kutner, Qi Long, Laura Ward, Yi-an Ko, Kareem Mohammed, Elizabeth Blackburn, Jinying Zhao, Jue Lin, J. Douglas Bremner, Jinhee Kim, Edmund Waller, Paolo Raggi, Arshed A Quyyumi, Viola Vaccarino
Journal: Circulation (2016)

Background: Leucocyte telomere length (LTL) is a biological marker of aging and reduced LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been suggested as a...
Pim‐1 as a Therapeutic Target in Lupus Nephritis
Authors: Rong Fu, Yong Xia, Meirong Li, Renxiang Mao, Chaohuan Guo, Mianjing Zhou, Hechang Tan, Meiling Liu, Shuang Wang, Niansheng Yang, Jijun Zhao
Journal: Arthritis & Rheumatology (2019)

Lupus nephritis (LN) is a major determinant of morbidity and mortality in systemic lupus erythematosus (SLE). Pim-1 regulates lymphocyte proliferation and activation. The role of Pim-1 in autoimmune disease remains unclear. This study was undertaken to test the hypothesis that inhibition of Pim-1 would have therapeutic potential in patients with LN.Pim-1 expression was analyzed in lupus-prone (NZB × NZW)F1 mice (n = 6), human peripheral blood mononuclear cells (PBMCs) from SLE patients (n = 10), and glomeruli from patients with LN (n = 8). The therapeutic effect of the Pim-1 inhibitor AZD1208 was assessed in the same murine lupus model (n = 10 mice per group). In vitro analysis was conducted to explore the mechanisms of action of Pim-1 in mouse and human podocytes after Pim-1 expression had been induced by anti-double-stranded DNA (anti-dsDNA) antibody-positive serum. Finally, MRL/lpr mice were used to confirm the therapeutic effects of Pim-1 inhibition in vivo (n = 10 mice per group).Up-regulation of Pim-1 was seen in renal lysates from diseased (NZB × NZW)F1 mice and in PBMCs from patients with SLE and renal biopsy tissue from patients with LN, relative to their control counterparts (each P < 0.05). The Pim-1 inhibitor AZD1208 reduced the severity of proteinuria, glomerulonephritis, renal immune complex deposits, and serum anti-dsDNA antibody levels, concomitant with the suppression of NFATc1 expression and NLRP3 inflammasome activation, in diseased (NZB × NZW)F1 mice (each P < 0.05 versus controls). Moreover, in mouse and human podocytes, Pim-1 knockdown with targeted small interfering RNA (siRNA) suppressed NFATc1 and NLRP3 inflammasome signaling in the presence of anti-dsDNA-positive serum (each P < 0.05 versus control siRNA). Mechanistically, Pim-1 modulated NLRP3 inflammasome activation through intracellular Ca2+ (P < 0.05 versus normal controls). The therapeutic effect of Pim-1 blockade was replicated in MRL/lpr mice.These data identify Pim-1 as a critical regulator of LN pathogenesis in patients with SLE. Targeting of the Pim-1/NFATc1/NLRP3 pathway might therefore have therapeutic potential in human LN.
Bone marrow stromal cells from β-thalassemia patients have impaired hematopoietic supportive capacity
Authors: Stefania Crippa, Valeria Rossella, Annamaria Aprile, Laura Silvestri, Silvia Rivis, Samantha Scaramuzza, Stefania Pirroni, Maria Antonietta Avanzini, Luca Basso-Ricci, Raisa Jofra Hernandez, Marco Zecca, Sarah Marktel, Fabio Ciceri, Alessandro Aiuti, Giuliana Ferrari, Maria Ester Bernardo
Journal: Journal of Clinical Investigation (2019)

BACKGROUND. The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. β-Thalassemia (BT) is a hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation and HSC gene therapy. Iron overload (IO) is a common complication in BT patients affecting several organs. However, data on the BM stromal compartment are scarce.
P152 Interferon-I activity in early and estblished rheumatoid arthritis (RA) with and without cardiovascular abnormalities in cardiac magnetic resonance (CMR)
Authors: AN Burska, G Harrison, Y El-Sherbiny, L-A Bissell, A Giollo, EM Hensor, G Fent, B Erhayiem, J Greenwood, S Plein, J Andrews, E Vital, MH Buch
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow. <h3>Introduction</h3> RA is a heterogenous disease and there is a substantial evidence to indicate the contribution of type I interferon (IFN-I) in 20%–40% of RA patients with possibly more local IFNβ role; compared to systemic IFN-α action in SLE. Patients with RA have an increased risk of cardiovasular disease (CVD) equivalent to type 2 diabetes, predominantly driven by excess atherosclerosis (ATS). Pre-clinical and human data suggest IFN-I plays a key role in the development of ATS. IFN-I has been shown to underlie cardiovascular (CV) abnormalities in SLE. <h3>Objectives</h3> IFN-I is important at the initiation of the pathological processes in early RA and increased IFN-I activity is associated with CVD in RA. <h3>Methods</h3> The Vital group recently published a continuous 2-score IFN system,<sup>1</sup> IFN scores A and B (as opposed to an often used categorical classification of IFN high/low). We applied this scoring system in a cohort of early (ERA n=75) and established RA (EstRA n=101) as well as in HC n=71. Next RA patients were stratified for CVD using multi-parametric cardiac MRI (CMR) evaluation that included aortic distensibility (vascular stiffness), LV mass/BSA (LV geometry) and Myocardial T1 (indicating myocardial fibrosis) as follows: (i) 'ERA-no CVD' n=37 (no abnormalities on CMR), (ii) 'ERA-sub CVD' n=37 (at least one of the three parameters abnormal), (iii) 'EstRA-no CVD', n=14 (iv) 'EstRA-sub CVD', n=54 (v) 'RA-CVD', n=32 (defined as per 'Major Adverse Cardiovascular Event'(MACE)). <h3>Results</h3> We confirmed a higher IFN score B than A in RA patients, similar to the observation made in the original paper that developed the scoring system. Significantly higher IFN score A and B in was observed in ERA than in EstRA and HCs. There was no association between IFN scores and markers of inflmmation. Increase in expression of IFN score B was observed across a CVD continuum (i.e. from RA-no CVD to RA-sub CVD to RA-CVD) in EstRA but not in ERA. <h3>Conclusions</h3> IFN-I may play a particularly important pathological role at time of development of disease (ERA). CVD stratification suggests that genes included in IFN Scores A and B may be implicated in the progression along a CVD continuum; and appearing to associate with a pro-atherogenic role. This observation only in EstRA may reflect CVD burden over time. If confirmed, these data imply multiple organ specificities for the IFN scores. Further work is planned to interrogate IFN status in RA-CVD, towards improved risk stratification and tailored management of CVD co-morbidity. <h3>Reference</h3> El-Sherbiny YM, <i>et al. Scientific Reports</i> 2018;8(1):5793. <h3>Disclosure of Interest</h3> None declared
Association of Overlapping Surgery With Perioperative Outcomes
Authors: Eric Sun, Michelle M. Mello, Chris A. Rishel, Michelle T. Vaughn, Sachin Kheterpal, Leif Saager, Lee A. Fleisher, Edward J. Damrose, Bassam Kadry, Anupam B. Jena
Journal: JAMA (2019)

<h3>Importance</h3> Overlapping surgery, in which more than 1 procedure performed by the same primary surgeon is scheduled so the start time of one procedure overlaps with the end time of another, is of concern because of potential adverse outcomes. <h3>Objective</h3> To determine the association between overlapping surgery and mortality, complications, and length of surgery. <h3>Design, Setting, and Participants</h3> Retrospective cohort study of 66 430 operations in patients aged 18 to 90 years undergoing total knee or hip arthroplasty; spine surgery; coronary artery bypass graft (CABG) surgery; and craniotomy at 8 centers between January 1, 2010, and May 31, 2018. Patients were followed up until discharge. <h3>Exposures</h3> Overlapping surgery (≥2 operations performed by the same surgeon in which ≥1 hour of 1 case, or the entire case for those &lt;1 hour, occurs when another procedure is being performed). <h3>Main Outcomes and Measures</h3> Primary outcomes were in-hospital mortality or complications (major: thromboembolic event, pneumonia, sepsis, stroke, or myocardial infarction; minor: urinary tract or surgical site infection) and surgery duration. <h3>Results</h3> The final sample consisted of 66 430 operations (mean patient age, 59 [SD, 15] years; 31 915 women [48%]), of which 8224 (12%) were overlapping. After adjusting for confounders, overlapping surgery was not associated with a significant difference in in-hospital mortality (1.9% overlapping vs 1.6% nonoverlapping; difference, 0.3% [95% CI, −0.2% to 0.7%];<i>P</i> = .21) or risk of complications (12.8% overlapping vs 11.8% nonoverlapping; difference, 0.9% [95% CI, −0.1% to 1.9%];<i>P</i> = .08). Overlapping surgery was associated with increased surgery length (204 vs 173 minutes; difference, 30 minutes [95% CI, 24 to 37 minutes];<i>P</i> &lt; .001). Overlapping surgery was significantly associated with increased mortality and increased complications among patients having a high preoperative predicted risk for mortality and complications, compared with low-risk patients (mortality: 5.8% vs 4.7%; difference, 1.2% [95% CI, 0.1% to 2.2%];<i>P</i> = .03; complications: 29.2% vs 27.0%; difference, 2.3% [95% CI, 0.3% to 4.3%];<i>P</i> = .03). <h3>Conclusions and Relevance</h3> Among adults undergoing common operations, overlapping surgery was not significantly associated with differences in in-hospital mortality or postoperative complication rates but was significantly associated with increased surgery length. Further research is needed to understand the association of overlapping surgery with these outcomes among specific patient subgroups.
Spatiotemporal Regulation of Tumor Angiogenesis by Circulating Chromogranin A Cleavage and Neuropilin-1 Engagement
Authors: Alice Dallatomasina, Anna Maria Gasparri, Barbara Colombo, Angelina Sacchi, Mimma Bianco, Tiziana Daniele, Antonio Esposito, Fabio Pastorino, Mirco Ponzoni, Fabrizio Marcucci, Flavio Curnis, Angelo Corti
Journal: Cancer Research (2019)

The unbalanced production of pro- and antiangiogenic factors in tumors can lead to aberrant vasculature morphology, angiogenesis, and disease progression. In this study, we report that disease progression in various murine models of solid tumors is associated with increased cleavage of full-length chromogranin A (CgA), a circulating vasoregulatory neurosecretory protein. Cleavage of CgA led to the exposure of the highly conserved PGPQLR site, which corresponds to residues 368-373 of human CgA1-373, a fragment that has proangiogenic activity. Antibodies against this site, unable to bind full-length CgA, inhibited angiogenesis and reduced tumor perfusion and growth. The PGPQLR sequence of the fragment, but not of the precursor, bound the VEGF-binding site of neuropilin-1; the C-terminal arginine (R373) of the sequence was crucial for binding. The proangiogenic activity of the CgA1-373 was blocked by anti-neuropilin-1 antibodies as well as by nicotinic acetylcholine receptor antagonists, suggesting that these receptors, in addition to neuropilin-1, play a role in the proangiogenic activity of CgA1-373. The R373 residue was enzymatically removed in plasma, causing loss of neuropilin-1 binding and gain of antiangiogenic activity. These results suggest that cleavage of the R373R374 site of circulating human CgA in tumors and the subsequent removal of R373 in the blood represent an important "on/off" switch for the spatiotemporal regulation of tumor angiogenesis and may serve as a novel therapeutic target. SIGNIFICANCE: This work reveals that the interaction between fragmented chromogranin A and neuropilin-1 is required for tumor growth and represents a novel potential therapeutic target.
What Parents Need to Know About Genetic Testing
Authors: Marni J. Falk, Megan A. Moreno
Journal: JAMA Pediatrics (2019)

What Parents Need to Know About Genetic TestingPediatricians may recommend a genetics consult or genetic testing for a child.This may be recommended if a child experiences developmental disabilities or delay of motor, speech, or cognitive function.Children with structural birth defects, either single-organ defects or multiple major and/or minor anomalies that are present in different organs, may also seek genetic testing.Children who have chronic functional problems in 1 or more organs, such as problems with vision or hearing, neuromuscular problems affecting movement and activity, seizures, chronic behavioral or mood problems, immune problems with frequent illness, hormone problems, poor growth, chronic digestive problems, or heart rhythm problems, among others, may also benefit from genetic testing.A family history of genetic disease may be a sufficient reason to consider genetic testing.
P109 Expression levels of miR-21 and miR-29 in the serum of systemic sclerosis patients
Authors: R Shumnalieva, D Kachakova, V Shoumnalieva-Ivanova, P Miteva, R Kaneva, Z Kolarov, S Monov
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Assistant. <h3>Introduction</h3> Recent studies reveal the important role of microRNAs (miRNAs) in the pathogenesis of systemic sclerosis (SSc). miRNAs are involved in key biological pathways that regulate the fibrotic process in SSc.<sup>1</sup> Deregulated expression of miRNAs has been found in the serum, in skin tissues, in skin fibroblasts as well as in endothelial cells of patients with SSc.<sup>2</sup> <h3>Objectives</h3> The aim of our study was to evaluate the expression levels of miR-21 and miR-29 in the serum of SSc patients and to determine their correlation with clinical and immunological parameters. <h3>Methods</h3> 34 patients fulfilling the ACR/EULAR 2013 classification criteria for SSc were included in the study. miR-21 and miR-29 expression levels in the serum were determined by PCR (SYBR Green technology). 2<sup>-ΔΔCt</sup> method was used for analysis. 14 healthy donors were used as controls. <h3>Results</h3> Expression levels of miR-21 were upregulated in the serum of 17 (50.0%) of the patients. The expression of miR-29 was downregulated in 15 (44.12%) of the patients. Receiver operating characteristic (ROC) curve analysis was conducted in order to evaluate the diagnostic accuracy of the expression levels of the studied miRNA in the serum. Area under the curve (AUC) for miR-21 was 0.634 (95% CI=0.479–0.790), p=0.147 with 64.7% sensitivity and 64.3% specificity. AUC for miR-29 was 0.605 (95% CI=0.420–0.790), with 64.3% sensitivity and 52.9% specificity but without statistical significance (p=0.257). The multimarker analysis of the ROC curves for both miRNAs showed AUC=0.714 (95% CI=0.569–0.860), p=0.021 with 79.4% sensitivity and 42.9% specificity. Levels of miR-29 correlated with the levels of miR-21 in the serum (with Spearman correlation coefficient 0.517, p=0.00017) and with the presence of anti-Scl70 antibodies in the serum (with Spearman correlation coefficient 0.438, p=0.010). <h3>Conclusions</h3> Our data showed a deregulation of miR-21 and miR-29 in the serum of patients with SSc which could suggests their potential role in the disease pathogenesis. Further analysis with higher number of patients is needed to confirm if these miRNAs could be used in the clinical practice as diagnostic biomarkers as well as biomarkers for both disease activity and progression. <h3>References</h3> Li Y, Huang J, Guo M, Zuo X. MicroRNAs Regulating Signaling Pathways: Potential Biomarkers in Systemic Sclerosis. <i>Genomics, Proteomics &amp; Bioinformatics</i>. 2015;13(4):234–241. Maurer B, Stanczyk J, Jüngel A, <i>et al</i>. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. <i>Arthritis &amp; Rheumatism</i> 2010;62:1733–1743. <h3>Acknowledgements</h3> The study was supported by Grant 62/2015 funded by Medical University – Sofia, Bulgaria. <h3>Disclosure of Interest</h3> None declared.
Dental-craniofacial manifestation and treatment of rare diseases
Authors: En Luo, Hanghang Liu, Qiucheng Zhao, Bing Shi, Qianming Chen
Journal: International Journal of Oral Science (2019)

Rare diseases are usually genetic, chronic and incurable disorders with a relatively low incidence. Developments in the diagnosis and management of rare diseases have been relatively slow due to a lack of sufficient profit motivation and market to attract research by companies. However, due to the attention of government and society as well as economic development, rare diseases have been gradually become an increasing concern. As several dental-craniofacial manifestations are associated with rare diseases, we summarize them in this study to help dentists and oral maxillofacial surgeons provide an early diagnosis and subsequent management for patients with these rare diseases. Rare diseases are typically genetic, chronic, incurable disorders with a relatively low incidence, and a number of dental and craniofacial manifestations are associated with such diseases. A team headed by En Luo and Hanghang Liu at Sichuan University in China conducted a large-scale review of the manifestations and treatment of rare diseases related to dental and craniofacial disorders. The authors found that in their early stages, several rare diseases exhibit distinctive dental and craniofacial characteristics. Provided they understand the clinical features, dentists and oral surgeons are the individuals best placed to make an early identification of such diseases. The authors believe that their findings will help clinicians fully grasp the related clinical signs and potential treatments of rare diseases, thereby facilitating early diagnosis and patient management as well as improving prognosis.
Long-term PM<sub>2.5</sub>Exposure and Neurological HospitalAdmissions in the Northeastern United States
Authors: Marianthi-Anna Kioumourtzoglou, Joel D. Schwartz, Marc G. Weisskopf, Steven J. Melly, Yun Wang, Francesca Dominici, Antonella Zanobetti
Journal: Environmental Health Perspectives (2015)

BackgroundLong-term exposure to fine particles (particulate matter ≤ 2.5 μm; PM2.5) has been consistently linked to heart and lung disease. Recently, there has been increased interest in examining the effects of air pollution on the nervous system, with evidence showing potentially harmful effects on neurodegeneration.ObjectiveOur objective was to assess the potential impact of long-term PM2.5 exposure on event time, defined as time to first admission for dementia, Alzheimer's (AD), or Parkinson's (PD) diseases in an elderly population across the northeastern United States.MethodsWe estimated the effects of PM2.5 on first hospital admission for dementia, AD, and PD among all Medicare enrollees ≥ 65 years in 50 northeastern U.S. cities (1999–2010). For each outcome, we first ran a Cox proportional hazards model for each city, adjusting for prior cardiopulmonary-related hospitalizations and year, and stratified by follow-up time, age, sex, and race. We then pooled the city-specific estimates by employing a random effects meta-regression.ResultsWe followed approximately 9.8 million subjects and observed significant associations of long-term PM2.5 city-wide exposure with all three outcomes. Specifically, we estimated a hazard ratio (HR) of 1.08 (95% CI: 1.05, 1.11) for dementia, an HR of 1.15 (95% CI: 1.11, 1.19) for AD, and an HR of 1.08 (95% CI: 1.04, 1.12) for PD admissions per 1-μg/m3 increase in annual PM2.5 concentrations.ConclusionsTo our knowledge, this is the first study to examine the relationship between long-term exposure to PM2.5 and time to first hospitalization for common neurodegenerative diseases. We found strong evidence of association for all three outcomes. Our findings provide the basis for further studies, as the implications of such exposures could be crucial to public health.CitationKioumourtzoglou MA, Schwartz JD, Weisskopf MG, Melly SJ, Wang Y, Dominici F, Zanobetti A. 2016. Long-term PM2.5 exposure and neurological hospital admissions in the northeastern United States. Environ Health Perspect 124:23–29; http://dx.doi.org/10.1289/ehp.1408973
Association between heterozygous β1-antitrypsin deficiency and genetic hemochromatosis
Authors: Mordechai Rabinovitz, Judith S. Gavaler, Robert H. Kelly, David H. Van Thiel
Journal: Hepatology (1992)

Primary hemochromatosis is a genetically determined autosomal recessive disorder characterized by the excessive accumulation of body iron, most of which is deposited in the parenchymal cells of various organs. β1-Antitrypsin deficiency is characterized among others by defective secretion of β1-antitrypsin from liver cells. Whereas the risk of cirrhosis is increased in homozygous patients (P1 ZZ) and possible in heterozygous patients (non-PI MM) as well, a greater risk for hepatocellular carcinoma has been suggested only in homozygous patients. Because these two metabolic disorders are relatively common, it has been difficult to determine whether they are associated with each other. In this study, we tried to determine the relationship between these two disorders using the case material seen at the University of Pittsburgh during a 7-yr period. We studied 15 patients with genetic hemochromatosis. β1-Antitrypsin quantitation and phenotyping were performed in each case using standard methods. The distribution of the various Pi phenotypes was compared with that found in a normal population and reported elsewhere. Odds ratio and χs2 tests were used to measure the relative risk and significance of association, respectively. Eleven patients (73%) were found to be PI M and four (27%) were identified as being heterozygotes: three (20%) were PI MZ, and one (7%) was PI MS. The prevalence of the PI MS phenotype was similar to that in the general population (7% vs. 6.4%; NS). The PI MZ phenotype, however, was statistically more common in patients with hemochromatosis than in the general population (20% vs. 2.2%; p <0.004). The odds of having hemochromatosis among PI MZ patients is increased 11-fold (odds ratio = 11.25; 95% confidence interval: 1.95, 44.23). The mean serum level of β1 antitrypsin and the occurrence of hepatocellular carcinoma was similar in the patients with the PI M and non-PI M phenotypes. It can be concluded that abnormal β1-antitrypsin alleles are seen more frequently in patients with genetic hemochromatosis than in the general population. Their coexistence may contribute to the earlier development of cirrhosis in some of these patients. However, it does not increase the risk for hepatocellular carcinoma despite the fact that each disorder alone is known to do so. (HEPATOLOGY 1992;16:145–148.)
Functional Genomic Landscape of Genes with Recurrent Mutations in Multiple Myeloma
Authors: Ricardo De Matos Simoes, Ryosuke Shirasaki, Huihui Tang, Michal Sheffer, Olga Dashevsky, Sara Gandolfi, Eugen Dhimolea, Megan Bariteau, Jonathan D. Licht, Brian Glassner, Richard WJ Groen, Joan Levy, Daniel Auclair, Francisca Vazquez, Aviad Tsherniak, William C. Hahn, Aedin Culhane, Constantine S. Mitsiades
Journal: Blood (2018)
Cursed by Knowledge — Building a Culture of Psychological Safety
Authors: Lisa Rosenbaum
Journal: New England Journal of Medicine (2019)

Audio roundtable discussion on learning to foster better teams. (32:51)Download Because physicians often set the cultural tone of the hospital, it’s worth considering barriers to health care professionals’ “psychological safety” for which we’re largely responsible. Why doesn’t it always feel like everyone caring for a patient is on the same team?