tbuckley/cabot-search huggingface dataset:
Patterns and Mechanisms of Diminishing Returns from Beneficial Mutations
Authors: Xinzhu Wei, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2019)

Abstract Diminishing returns epistasis causes the benefit of the same advantageous mutation smaller in fitter genotypes and is frequently observed in experimental evolution. However, its occurrence in other contexts, environment dependence, and mechanistic basis are unclear. Here, we address these questions using 1,005 sequenced segregants generated from a yeast cross. Under each of 47 examined environments, 66–92% of tested polymorphisms exhibit diminishing returns epistasis. Surprisingly, improving environment quality also reduces the benefits of advantageous mutations even when fitness is controlled for, indicating the necessity to revise the global epistasis hypothesis. We propose that diminishing returns originates from the modular organization of life where the contribution of each functional module to fitness is determined jointly by the genotype and environment and has an upper limit, and demonstrate that our model predictions match empirical observations. These findings broaden the concept of diminishing returns epistasis, reveal its generality and potential cause, and have important evolutionary implications.
Abstract P303: Early Changes in Vascular Structure and Function after Bariatric Surgery in an Appalachian Population
Authors: Kristin A Grogg, Evan DeVallance, Kent Lemaster, Robert Hull, Lawrence Tabone, Paul Chantler, Stephanie Frisbee
Journal: Circulation (2016)

Obesity is associated with an elevated risk of cardiovascular disease, metabolic disease, and cardiac mortality. Reactive oxygen species and inflammation in an obese individuals are among a number of suspected driving forces behind obesity’s detrimental health effects. These factors can elevate cardiovascular risk by causing impairments in cardiovascular structure and function. It is hypothesized that gastric bypass surgery will lead to near immediate reversal of metabolic deviations and rapid weight reduction, in addition to remodeling and improvements in arterial function as weight is lost. Patients that meet protocol inclusion criteria are invited to join the study during their 1 week pre-operative clinical appointment. At this time patients are consented and instructed to lie supine for 10 minutes of quite relaxation. Patients then begin a sequence of non-invasive examinations starting with a 12-lead electrocardiogram, followed by an echocardiogram, carotid artery ultrasound, radial applanation tonometry, and endothelial function analysis using EndoPAT technology. Upon completion of the non-invasive procedures a blood sample is taken for analysis. Preliminary results on 12 study subjects suggests the following. As hypothesized, body weight had decreased (pre: 131.8 ±5.6 to post: 125 ±5.2 kg) along with BMI (pre: 45.2 ±2.3 to post: 42.9 ± 2.2) and waist circumference (pre: 122.1 ±5.0 to post: 111.9 ± 3.2 cm) at the 1-week time point. Decrease in body size and weight was aided by a reduction in low-density lipoprotein (pre: 127 ±6.2 to post: 113 ±4.5 mg/dL). In addition, a number of improvements to the cardiovascular system were also marked at the 1-week time point. Estimated left ventricular end systolic pressure and direct measure of left ventricular end systolic volume (pre: 66 ±4 to post: 55 ±3 mmHg) declined post-GBS. This is in consort with an increase in contraction rate (dP/dt pre: 672 ±54 post: 737 ±46, p&lt;0.01), a reduction in LV ejection time (pre: 291 ±10 to post: 211 ± 30ms), and a decrease in myocardial oxygen demand (PTIs pre: 2346 ±120 post: 2194 ±107 area/min, p&lt;0.05). Similar improvements in augmentation index can be seen in assessments of peripheral vessels. Independent of brachial artery blood pressure, central systolic blood pressure (pre: 112 ± 4 to post: 105 ±2 mmHg, p=0.08), augmentation index (pre: 16 ±3 to post: 8 ±3, p=0.06), an indirect measure of arterial stiffness, and central augmentation pressure (pre: 4.9 ±1.1 to post: 2.5 ±0.9 mmHg, p=0.06) tended to decrease 1-week post GBS. The data suggests that vascular changes are happening in the early stages of recovery, prior to dramatic weight loss, thus suggesting vascular changes are a result of an alternate surgical benefit. In conclusion, the preliminary results of this study suggest noteworthy cardiovascular improvements post-gastric bypass surgery, yet prior to significant weight loss.
PF451 GLUCOCORTICOID INDUCED LEUCINE ZIPPER (GILZ) IS REQUIRED FOR HEMATOPOIETIC STEM CELL FUNCTION
Authors: O. Bereshchenko, S. Bruscoli, T. Frammartino, S. Flamini, A. Gagliardi, Z. Viana de Barros, C. Riccardi
Journal: HemaSphere (2019)

Background: Life-long production of blood cells depends on the sustained activity of hematopoietic stem cells (HSC). The maintenance of HSC is linked to their quiescent state, while activation of HSC proliferation is normally associated with differentiation into a more lineage restricted progenitors and a loss of long-term stem cell potential. The balance between HSC proliferation and quiescence is tightly regulated by intrinsic and extrinsic cues in the bone marrow. This regulatory network may become altered by various stresses, leading to aberrant HSC cell cycling, loss of HSC function, and hematological malignancy. Endogenous glucocorticoid hormones (GC) influence the proliferation homing of HSC via regulation of CXCL12-CXCR4 axis. Moreover, pharmacologic doses of synthetic GC induce apoptosis in lymphocytes as well as early lymphoid progenitors. However, the effect of GC on survival, proliferation and lineage commitment of the most primitive HSCs are not yet defined. Aims: GILZ (Glucocorticoid-Induced Leucine Zipper) is a gene rapidly induced by GC that mediates some of its effects, including regulation of cell growth and differentiation. We have found that gilz mRNA is expressed in HSC and progenitor cells (HPC) and is dowregulated in myeloid progenitor cells. Methods: We have addressed the role of GILZ in HSC homeostasis using GILZ knock-out (KO) mice. Results: Under steady state, young GILZ-KO mice show a significant decrease in HSC and an increase in HPC frequency, while the number of HSC remains unchanged. Competitive repopulation studies using WT and GILZ-KO bone marrows cells (CD45.2+) along with WT helper cells (CD45.1+) revealed a significant decrease in the frequency of GILZ-KO compared to WT CD45.2+ cells in the peripheral blood, suggesting that GILZ-deficient HSCs have competitive disadvantage compared to WT cells. Consistently, the number of HSC was significantly decreased in the bone marrows of GILZ-KO transplanted mice, suggesting that GILZ is required for the proper control of the HCS number in the bone marrow. To demonstrate that the lack of GILZ is associated with decreased HSC function, we have performed 5-FU treatment experiments in mice transplanted with WT or GILZ KO bone marrow cells to ensure the hematopoietic cell intrinsic effect of GILZ deletion on mice survival. Mice bearing GILZ KO hematopoietic cells showed significantly earlier mortality caused by the 5-FU treatment. To dissect the mechanism of the defect in HSC function upon GILZ deletion, we performed comprehensive RNAseq analysis of gene expression in WT and GILZ KO HSCs. We identified several deregulated cellular pathways implicated in HSC function. Summary/Conclusion: Overall, these data identify GILZ is a novel critical regulator of HSCs function.
Abstract 10911: Inhibition of Endothelial p53 Improves Metabolic Abnormalities Related to Dietary Obesity
Authors: Masataka Yokoyama, Sho Okada, Atsushi Nakagomi, Junji Moriya, Ippei Shimizu, Aika Nojima, Yohko Yoshida, Yoshio Kobayashi, Tohru Minamino
Journal: Circulation (2013)

There is evidence suggesting that senescent cells promote changes related to aging or age-related diseases. We here identified a crucial role of endothelial p53 activation in the regulation of gluc...
Клінічний випадок автоімунного гепатиту у 59-літньої жінки з ефективним лікуванням будесонідом
Authors: L.Ya. Melnychenko, V.M. Gladun, D.V. Popok
Journal: GASTROENTEROLOGY (2013)

Автоімунний гепатит є некротично-запальним захворюванням печінки невідомої етіології. Згідно з гістологією хвороба характеризується лобулярним гепатитом, у біохімічних аналізах крові — збільшенням рівня аспартатамінотрансферази і аланінамінотрансферази та за даними серології — збільшеним рівнем автоантитіл і імуноглобуліну G. Ми наводимо для обговорення випадок автоімунного гепатиту в раніше здорової 59-літньої жінки з різко підвищеними рівнями загального білірубіну, аспартатамінотрансферази, аланінамінотрансферази. Враховуючи ці дані, проводилася диференціальна діагностика між автоімунним гепатитом, гепатитами вірусної етіології та механічною жовтяницею. При обстеженні були відсутні маркери вірусних гепатитів А, В, С, результати комп’ютерної томографії та ендоскопічної ретроградної холедохопанкреатографії не підтвердили механічної природи жовтяниці. Біопсія печінки показала наявність перипортального гепатиту та мостоподібного некрозу (лімфомакрофагальна інфільтрація в портальній та перипортальній зонах), типової особливості автоімунного гепатиту. Терапія метилпреднізолоном із переходом на будесонід призвела до поступового зменшення та нормалізації показників загального білірубіну, аспартатамінотрансферази, аланінамінотрансферази. Отже, наш опис стосується автоімунного гепатиту в пацієнтки середнього віку, що підтверджує сучасну думку про поширеність хвороби переважно серед жінок у всіх вікових групах. Досягнута нормалізація активності сироваткових трансаміназ із застосуванням будесоніду, що зіставляється з даними низки досліджень про ефективну терапію автоімунного гепатиту будесонідом.
Abstract 20043: Exercise Test Predicts Mortality in Patients With Coronary Artery Disease on Beta Blockers
Authors: Nóra Sydó, Tibor Sydó, Karina Gonzalez Karta, Ibolya Csécs, Joseph G Murphy, Béla Merkely, Thomas J Randal, Thomas G Allison
Journal: Circulation (2017)

Introduction: Mortality can be predicted by heart rate (HR) response on an exercise test, but beta blockers, commonly used in coronary artery disease (CAD) compromises exercise HR. Hypothesis: The ...
The burden of Legionnaires' disease in New Zealand (LegiNZ): a national surveillance study
Authors: Patricia C Priest, Sandy Slow, Stephen T Chambers, Claire M Cameron, Michelle N Balm, Mark W Beale, Timothy K Blackmore, Andrew D Burns, Dragana Drinković, Juliet A Elvy, Richard J Everts, David A Hammer, Paul J Huggan, Christopher J Mansell, Vicki M Raeder, Sally A Roberts, Murray C Robinson, Vani Sathyendran, Susan L Taylor, Alyssa W Thompson, James E Ussher, Antje J van der Linden, Melanie J Williams, Roslyn G Podmore, Trevor P Anderson, Kevin Barratt, Joanne L Mitchell, David J Harte, Virginia T Hope, David R Murdoch
Journal: The Lancet Infectious Diseases (2019)
PS1559 EFFICACY AND TOXICITY OF SEAM (SEMUSTINE, ETOPOSIDE, CYTARABINE, AND MELPHALAN) CONDITIONING REGIMEN FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION IN LYMPHOMA
Authors: L. Zhang, X. Chen, S. Liu, Q. Zhu, D. Wu, H. Huang
Journal: HemaSphere (2019)

Background: BEAM (carmustine, etoposide, cytarabine, and melphalan) is considered the gold standard conditioning regimen for autologous stem cell transplantation (auto‐SCT) in lymphoma. However, a shortage of old drugs is a worldwide problem, and carmustine (BCNU) is on this list. Alternative regimens are therefore being developed and used by many institutions. Semustine (Me‐CCNU), an alternative oral nitrosourea agent, has been chosen as a potential substitute. In China, we substituted BCNU by Me‐CCNU to provide the modified conditioning regimen SEAM (semustine, etoposide, cytarabine, and melphalan). Aims: The aim of this study was to evaluate the safety and efficacy of the SEAM regimen followed by auto‐SCT for malignant lymphoma patients. Methods: We retrospectively reviewed the records of patients with lymphoma who underwent auto‐SCT with SEAM regimen (n = 97) from January 2010 to June 2018 in our center. We evaluated the safety and efficacy of the SEAM regimen by comparing with previous studies using BEAM as conditioning regimen. Results: The median age of patients (n = 97) was 42 years (range, 15–65). The median time to neutrophil engraftment was 9.5 days (range, 7–15 days), and the median time to platelet engraftment was 12 days (range, 7–25 days). Grade 3–4 nausea/vomiting, mucositis and diarrhea were observed in 21.6%, 36.1%, and 11.3% of patients, respectively. Veno‐occlusive disease (VOD) and idiopathic pulmonary syndrome (IPS) were not observed. Treatment‐related mortality (TRM) at 100 days occurred in 2 patients (2.1%). After a median follow‐up time of 53.9 months, 31 patients (32.0%) showed progression over a median duration of 4.87 months (range, 1.1–40.53) after transplantation. In addition, the 3‐year incidence of disease relapse or progression (CIR) was 34%. The estimated progression‐free survival (PFS) and overall survival (OS) at 3 years were 62% and 75%, respectively. Compared with previous studies using BEAM as the conditioning regimen, this study shows that the SEAM conditioning regimen has a comparable efficacy and safety profile. Summary/Conclusion: The incidence and severity of non‐hematological regimen‐related toxicities of the SEAM conditioning regimen in this study were almost identical to that of BEAM conditioning regimen as reported in the previous studies. The SEAM conditioning regimen followed by auto‐SCT was well tolerated and had an efficacy and safety profile comparable to BEAM. Therefore, SEAM conditioning regimen is feasible whether in efficacy, safety or sources of drugs and might be an ideal alternative to BEAM conditioning regimen for auto‐SCT in lymphoma. image
AB1132 THE ROLE OF PET/CT IN THE MANAGEMENT OF GIANT CELL ARTERITIS
Authors: Alessandro Croce, Mattia Bellan, Roberta Pedrazzoli, Daniele Sola, Erinda Puta, Gian Mauro Sacchetti, Daniele Soddu, Erika Zecca, Mario Pirisi, Pier Paolo Sainaghi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Giant cell arteritis (GCA) is a large vessel vasculitis that affects the aorta and/or its major branches including the superficial temporal artery. Together to cranial symptoms such as headache and visual disturbances, extra cranial manifestations have been widely reported, sometimes as unique clinical presentation. Several imaging modalities are available to evaluate aortic involvement including fluorodeoxyglucose (FDG) positron emission tomography (PET), however there are few reports that analyzed the impact of the findings of this advanced imaging in predicting outcomes of the disease. <h3>Objectives</h3> To assess the utility of PET in disease extension assessment to predict, together to clinical manifestations, the disease evolution. <h3>Methods</h3> We retrospectively reviewed all the clinical records of patients receiving a diagnosis of large vessel vasculitis from 1<sup>st</sup> January 2010 to 1<sup>st</sup> January 2016 at a tertiary immunorheumatology clinic of a university Hospital, who underwent a PET. Clinical, laboratory, and imaging data were collected. Non-parametric analysis was performed. <h3>Results</h3> We recruited 19 patients (10 females, 52.6%). The median age was 74.0 [65.5-76.0]; at the diagnosis, the median erythrocyte sedimentation rate (ESR) was 65.5 [49.0-86.0], while C-reactive protein (CRP) was 8.5 [5.5-14.0]. 12 patients showed a typical cranial GCA (63.2%), while 7 (36.8%) were diagnosed with extracranial GCA. The two groups were comparable at diagnosis for age, gender, median ESR and CRP. Interestingly, the PET was significative for aortitis not only in the 7 patients with extracranial involvement, but also in 7/12 patients with cranial GCA (58.3%). Along a median follow-up of 15 months [4.5-26.5], 4 relapses were reported. Notably, all the relapsers were males and showed both aortic and cranial involvement. In a multivariate model, male gender was the only predictor of relapse (p=0.02), while age at onset, clinical subset (cranial vs. extracranial) and steroid dose did not fit the model <h3>Conclusion</h3> The use of PET in GCA is relevant in the assessment of extension of disease since a significative number of patients without cranial symptoms in the end resulted to have large vessel involvement. In addition, PET is useful in identifying patients with cranial involvement that have also aortic inflammation since they seems to have worse prognosis. <h3>Disclosure of Interests</h3> None declared
SP0116 CASE 2 PRESENTER: BREAKING BAD AND TRAGICALLY HIP. A CASE OF A MISSED OPPORTUNITY AFTER VERTEBRAL FRACTURE
Authors: Michael Skjødt
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Mrs A is a 78-year old woman, admitted to the emergency room after a same level fall in her home earlier the same day. She has a history of Chronic Obstructive Pulmonary Disease with recurrent exacerbations, and hysterectomy at the age of 41. At admittance, she is complaining of agonising pain localised to her right hip, and she is unable to move the leg. Upon the physical examination, the right leg is shortened and outwardly rotated. Upon further questioning, Mrs A reveals that she has lost four or five cm of height during the past years. An X-ray of the hip demonstrates a neck of the femur fracture. Mrs A has surgery the following day and two screws are inserted. Due to a hospital-acquired pneumonia, Mrs A stays in the hospital for an additional 9 days after the operation, upon which she is discharged for a temporary placement at a nursing home for further rehabilitation. Two months following discharge, Mrs A was called for a clinical evaluation by the hospital Fracture Liaison Service. Assessment with DXA confirms the osteoporosis diagnosis and VFA shows lower thoracic vertebral fractures. The FLS coordinator noted that Mrs A, related to a hospital admission for an acute exacerbation of her COPD 3 years before, had had a chest x-ray performed, on which vertebral fractures of the thoracic spine could be seen to be present. Mrs A has never previously been assessed nor treated for osteoporosis. <h3>Disclosure of Interests:</h3> None declared
Human type 2 innate lymphoid cells disrupt skin keratinocyte tight junction barrier by IL‐13
Authors: Kazunari Sugita, Can Altunbulakli, Hideaki Morita, Atsuko Sugita, Terufumi Kubo, Ryoko Kimura, Hiroyuki Goto, Osamu Yamamoto, Beate Rückert, Mübeccel Akdis, Cezmi A. Akdis
Journal: Allergy (2019)

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Abstract MP004: Feasibility of an Appetite Awareness Intervention to Reduce Cardiovascular Disease Risk Factors and Binge Eating in African-American Women with Obesity
Authors: Rachel W Goode, Melissa A Kalarchian, Molly Conroy, Linda Craighead, Susan Sereika, Meghan Mattos, Yaguang Zheng, Juliet Mancino, Lora E Burke
Journal: Circulation (2017)

Background: Currently, 82.1% of African-American (AA) women are overweight or obese, and 48.9% of AA women have cardiovascular disease (CVD), the leading cause of death. Binge eating disorder (BED) is associated with severe obesity, psychiatric morbidity, and increased risk for CVD. Among AA women, BED is the most common eating disorder and has a 33% prevalence among those seeking weight loss. Since many adults with BED report becoming overweight after binge eating on a regular basis, intervening with individuals at risk to develop BED may be a viable strategy to prevent CVD and further weight gain. Purpose: To investigate the feasibility of an 8-week, community-based Appetite Awareness Training intervention among AA women who are overweight and obese reporting monthly binge eating episodes, and examine preliminary changes in CVD risk, eating self-efficacy, and binge eating between the intervention and control group. Methods: Eligible individuals were randomized to Appetite Awareness Treatment (AAT, n=16) or Wait-List Control (WLC, n=15) with the WLC receiving the AAT after 8-weeks of observation. The goal of Appetite Awareness Treatment is to help participants relearn their biological signals of hunger and satiety. Participants attend group sessions, and receive weekly homework to self-monitor their appetite cues. Assessments were conducted at 0 and 8 weeks at a community-based site. Linear mixed modeling was used to examine the baseline to 8-week changes between AAT and WLC groups on CVD risk factors (body weight, waist circumference, blood pressure) self-efficacy by Weight Efficacy Lifestyle Questionnaire (WEL), and binge eating by the Binge Eating Scale (BES). Results: The sample (N=31), had a mean age of 48.8 (SD±12.8), and a BMI of 33.7 kg/m 2 (SD±3.90). Retention was 87.5%, session attendance 65.9%, and homework completion 55%. There were significant group differences over time in the WEL score (p&lt;.01, d=1.06), and the BES score (p&lt;.001, d=.52) at the end of the intervention. The AAT group had an increase in the WEL score (+25.14±6.67), with no changes in the WLC group (-1.27±4.15). Additionally, the AAT group had a decrease in the BES score (-5.87±0.61), with no changes in the WLC group (0 ±0.01). There were no significant differences within and between groups in CVD risk factors. Conclusions: Our pilot trial results suggest that AAT is feasible in this population, with good retention, attendance, and preliminary evidence of a positive impact on eating self-efficacy, binge eating behaviors, and weight gain prevention. Future research should investigate the effectiveness of AAT to reduce binge eating and CVD risk in a larger sample and study with a longer duration.