tbuckley/cabot-search huggingface dataset:
AB0522 SEASONAL DIFFERENCE IN CEREBRAL STROKE FREQUENCY IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: Wen-Nan Huang, Yi-Ming Chen, Yi-Hsing Chen, Wei-Ting Hung, Yu-Wan Liao
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The incidence of stroke is well-known as increased in winter season in general population, but seasonal difference in the systemic lupus erythematosus remain unclearified. <h3>Objectives:</h3> The aim of study was to assess seasonal difference in cerebral stroke among patients with systemic lupus erythematosus. <h3>Methods:</h3> We conducted a retrospective case-control study analyzing hospital database of a tertiary referral center in Taiwan. From January, 2002 to December 2017, subjects with systemic lupus erythematosus and cerebral stroke were enrolled. To examine the seasonal incidence of cerebral stroke, we analyzed data from the date of CT scan/MRI/MRA. The onset time was divided into four seasons (according Local season classification): spring (March, April, May), summer (June, July, August), autumn (September, October, November), and winter (December, January, February). <h3>Results:</h3> In total, 4313 systemic lupus erythematosus patients were identified, 261 patients with cerebral stroke. Age of patients with cerebral stroke ranged 27 between 77 years, a mean age was 55-62 years. Female was predominant. Disease duration was longer in ischemia stroke group (4.8 years). According CT or MRI results, divided 4 types (Ischemia stroke (IS), ICH, SAH, SDH), 83% (150/180) cerebral stroke was ischemia stroke. 8.3% ICH, 5.5% SAH, 2.8% SDH found respectively. We noted a higher incidence of SLE with ischemia stoke in summer season (38.7%), the lowest incidence of ischemia stroke in winter season (18.7%). Patient with ICH has similar trend. But not found in SAH and SDH. <h3>Conclusion:</h3> Incidence of systemic lupus erythematous with cerebral stroke varied in different pattern. The present findings suggested an increase in the incidence of Ischemia stroke and ICH in summer season. Awareness of risk factors (esp. antiphsopholipid antibodies) was essential to prevent cerebral stroke in SLE. <h3>Disclosure of Interests:</h3> None declared
High Amount of PD1+TIM3+ T Helper Cells May Predict Poor Outcome in Adult Acute Lymphoblastic Leukemia
Authors: Helena Hohtari, Oscar Bruck, Sami Blom, Riku Turkki, Antonio Ribeiro, Marjatta Sinisalo, Panu Kovanen, Olli Kallioniemi, Teijo Pellinen, Kimmo Porkka, Satu Mustjoki
Journal: Blood (2017)
SP0200 TARGETED TREATMENTS: WHAT”S ON THE HORIZON FOR OBSTETRIC ANTIPHOSPHOLIPID SYNDROME?
Authors: Jane E. Salmon
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Pregnancy in women with APS and/or lupus is dangerous both for mother and offspring, and, in the past, patients were advised not to have children. Among complications frequently seen in women with lupus are preeclampsia (also known as toxemia of pregnancy), preterm birth, markedly underweight newborns, and fetal death. Identifying women destined for complications remains challenging and limits our ability to counsel and care for pregnant lupus patients. There is currently no effective treatment for women with these high-risk pregnancies; treatments to prevent poor pregnancy outcomes require an understanding of mechanisms of injury. Our research in an animal model that mimics the human condition shows that blockade of well-established mediators of inflammation, specifically complement and TNF-alpha, prevents adverse outcomes. To translate these discoveries to lupus patients, we launched the <b>PROMISSE</b> Study (<b>P</b>redictors of p<b>R</b>egnancy <b>O</b>utcome: bio<b>M</b>arkers <b>I</b>n antiphospholipid antibody <b>S</b>yndrome and <b>S</b>ystemic lupus <b>E</b>rythematosus) to determine which pregnancies were at highest risk for adverse outcomes. Over 20% of pregnancies in patients with SLE resulted in an adverse pregnancy outcome. We discovered that the presence of a lupus anticoagulant which can be detected in the blood before pregnancy or in the first trimester, confers a 10-fold increase in risk of complications. Furthermore, we found that early in pregnancy, measurable alterations in the balance of angiogenic factors (proteins that circulate in blood, promote proper placenta development, and are required to maintain the health of the mother"s vascular system) are highly predictive of preeclampsia and other pregnancy complications. The results of the PROMISSE Study provide models for early risk stratification to allow physicians to identify patients early in pregnancy who are at low risk and reassure them that their pregnancies were likely to be uncomplicated and their babies healthy. Conversely and importantly, we can reliably predict which patients are destined to have poor pregnancy outcomes, and we conducting a trial with a TNF-alpha inhibitor that does not cross the placenta in patients at highest risk an experimental therapy to prevent placental dysfunction. Treatments to prevent poor pregnancy outcomes require an understanding of mechanisms of injury. Experiments in mouse models have enabled us to embark upon a trial of a potential treatment. <h3>Disclosure of Interests:</h3> Jane E. Salmon Shareholder of: Biogen-Idec, BMS, Johnson &amp; Johnson, Regeneron, Merck, Grant/research support from: UCB, Consultant for: BMS, Ionis
MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer
Authors: Qiming Wang, Sen Yang, Kai Wang, Shi-Yong Sun
Journal: Journal of Hematology & Oncology (2019)

Treatment of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutation with EGFR-TKIs has achieved great success, yet faces the development of acquired resistance as the major obstacle to long-term disease remission in the clinic. MET (or c-MET) gene amplification has long been known as an important resistance mechanism to first- or second-generation EGFR-TKIs in addition to the appearance of T790 M mutation. Recent preclinical and clinical studies have suggested that MET amplification and/or protein hyperactivation is likely to be a key mechanism underlying acquired resistance to third-generation EGFR-TKIs such as osimertinib as well, particularly when used as a first-line therapy. EGFR-mutant NSCLCs that have relapsed from first-generation EGFR-TKI treatment and have MET amplification and/or protein hyperactivation should be insensitive to osimertinib monotherapy. Therefore, combinatorial therapy with osimertinib and a MET or even a MEK inhibitor should be considered for these patients with resistant NSCLC carrying MET amplification and/or protein hyperactivation.
PB2219 EFFECTS OF SYSTEMIC MASTOCYTOSIS ON BONE HEALTH IN SOUTH‐EAST SCOTLAND
Authors: N. Peters, C.‐H. Teh, S. Seth
Journal: HemaSphere (2019)

Background: Systemic mastocytosis (SM) is a rare condition characterised by excess mast cell production and often involves multiple organs. One organ system becoming increasingly recognised as being affected by systemic mastocytosis is the skeletal system, with reports of increased prevalence of osteoporosis, osteopenia and osteosclerosis represening the main findings. Aims: We aimed to assess the extent of bony involvement of SM in patients in our area, South‐East Scotland who had been referred to the Haematology services in NHS Lothian in order to help guide local policies regarding assessment of bone health upon a diagnosis of systemic mastocytosis. Methods: Clinical records of patients with a diagnosis of SM referred to our services in NHS Lothian available on our local TRAK system were interrogated to investigate for the presence of osteoporosis, osteopenia, osteosclerosis. Further, where available, DEXA bone scan results were tabulated. Results: We identified 18 patients with a diagnosis of SM with multiple variants identified including indolent (15/18), cutaneous, Aggressive with myelofibrosis (1/18) and SM with eosinophilia (1/18) and unclassified (1/18). It was found that 12/18 patients had evidence of osteoporosis (6/18), osteopenia (5/18) or osteosclerosis (1/18) representing a significant disease burden. Further, 13 of the 18 patients had a DEXA scan meaning there is a large portion of patients not being investigated routinely for bony involvement. The average age of patients with osteoporosis and SM was 60 years old with a range from 41 to 74, suggesting a profound effect on bone health at an early age. Summary/Conclusion: We have identified a significant proportion of patients with SM having bony involvement. It has been suggested that DEXA scans form part of initial workup of these patients upon diagnosis, with bisphosphonates used as a first line treatment. The findings of our study support the proactive investigation of bone health in SM.
SUMO-Specific Protease 1 Is Critical for Myeloid-Derived Suppressor Cell Development and Function
Authors: Xian Huang, Yong Zuo, Xiuzhi Wang, Xuefeng Wu, Hongsheng Tan, Qiuju Fan, Baijun Dong, Wei Xue, Guo-Qiang Chen, Jinke Cheng
Journal: Cancer Research (2019)

Myeloid-derived suppressor cells (MDSC) can suppress immunity and promote tumorigenesis, and their abundance is associated with poor prognosis. In this study, we show that SUMO1/sentrin-specific peptidase 1 (SENP1) regulates the development and function of MDSC. SENP1 deficiency in myeloid cells promoted MDSC expansion in bone marrow, spleen, and other organs. Senp1-/- MDSC showed stronger immunosuppressive activity than Senp1+/+ MDSC; we observed no defects in the differentiation of myeloid precursor cell in Senp1-/- mice. Mechanistically, SENP1-mediated regulation of MDSC was dependent on STAT3 signaling. We identified CD45 as a specific STAT3 phosphatase in MDSC. CD45 was SUMOylated in MDSC and SENP1 could deconjugate SUMOylated CD45. In Senp1-/- MDSC, CD45 was highly SUMOylated, which reduced its phosphatase activity toward STAT3, leading to STAT3-mediated MDSC development and function. These results reveal a suppressive function of SENP1 in modulating MDSC expansion and function via CD45-STAT3 signaling axis. SIGNIFICANCE: These findings show that increased SUMOylation of CD45 via loss of SENP1 suppresses CD45-mediated dephosphorylation of STAT3, which promotes MDSC development and function, leading to tumorigenesis.
Soft Sweeps Are the Dominant Mode of Adaptation in the Human Genome
Authors: Daniel R. Schrider, Andrew D. Kern
Journal: Molecular Biology and Evolution (2017)

The degree to which adaptation in recent human evolution shapes genetic variation remains controversial. This is in part due to the limited evidence in humans for classic "hard selective sweeps", wherein a novel beneficial mutation rapidly sweeps through a population to fixation. However, positive selection may often proceed via "soft sweeps" acting on mutations already present within a population. Here, we examine recent positive selection across six human populations using a powerful machine learning approach that is sensitive to both hard and soft sweeps. We found evidence that soft sweeps are widespread and account for the vast majority of recent human adaptation. Surprisingly, our results also suggest that linked positive selection affects patterns of variation across much of the genome, and may increase the frequencies of deleterious mutations. Our results also reveal insights into the role of sexual selection, cancer risk, and central nervous system development in recent human evolution.
Liver Injury and Failure in Critical Illness
Authors: Thomas Horvatits, Andreas Drolz, Michael Trauner, Valentin Fuhrmann
Journal: Hepatology (2019)

The frequency of acquired liver injury and failure in critical illness has been significantly increasing over recent decades. Currently, liver injury and failure are observed in up to 20% of patients in intensive care units and are associated with significantly increased morbidity and mortality. Secondary forms of liver injury in critical illness are divided primarily into cholestatic, hypoxic, or mixed forms. Therefore, sufficient knowledge of underlying alterations (e.g., hemodynamic, inflammatory, or drug induced) is key to a better understanding of clinical manifestations, prognostic implications, as well as diagnostic and therapeutic options of acquired liver injury and failure. This review provides a structured approach for the evaluation and treatment of acquired liver injury and failure in critically ill patients.
Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial
Authors: Anders Widmark, Adalsteinn Gunnlaugsson, Lars Beckman, Camilla Thellenberg-Karlsson, Morten Hoyer, Magnus Lagerlund, Jon Kindblom, Claes Ginman, Bengt Johansson, Kirsten Björnlinger, Mihajl Seke, Måns Agrup, Per Fransson, Björn Tavelin, David Norman, Björn Zackrisson, Harald Anderson, Elisabeth Kjellén, Lars Franzén, Per Nilsson
Journal: The Lancet (2019)
Abstract P288: Utility of BMI in Determining Excess Adiposity in Children and Adolescents Across the Obesity Spectrum: NHANES 1999-2006
Authors: Justin R Ryder, Alex Kaiser, Kyle D Rudser, Stephen R Daniels, Aaron S Kelly
Journal: Circulation (2016)

Introduction: Excess adiposity in youth is associated with a number of cardiometabolic complications. However, normative data defining excess adiposity cut-points utilizing gold-standard measures of adiposity [e.g. dual energy X-ray absorptiometry (DXA)] are lacking in youth. Moreover, the proportion of youth within a given BMI-based obesity category with excess adiposity is not well described. Therefore, we generated pediatric body fat distribution curves using DXA data from the National Health and Nutrition Examination Survey (NHANES) to identify cut-points and evaluate the accuracy of BMI in determining excess adiposity among youth. Hypothesis: A high proportion of youth with severe obesity using BMI based definitions (class 2 and 3) will have excess adiposity as measured by DXA. Heterogeneity and misclassification will be increasingly common across youth with obesity (class 1), overweight, and normal-weight. Methods: DXA data from NHANES 1999-2006 (Males (M) = 5,933; Females (F) = 4,532) were utilized for this analysis. Normal-weight (&lt;85th BMI-percentile), overweight (≥85th-&lt;95th BMI-percentile), class 1 obesity (≥95th BMI-percentile-&lt;1.2 times the 95th percentile), class 2 obesity (≥1.2-&lt;1.4 times the 95th BMI-percentile), and class 3 obesity (≥1.4 times the 95th percentile) were defined using Center for Disease Control based definitions for age and sex. Excess adiposity was defined using cohort-specific cut-points of the 75th, 85th, and 90th percentile for DXA-derived body fat by age and sex determined using quantile regression models with natural cubic splines (df=6). Results: Nearly all youth with class 3 obesity (100% M, 100% F; 97% M, 99.3% F; and 94.7% M, 95.9% F; for 75th, 85th, and 90th DXA-percentile respectively) and a high proportion of those with class 2 obesity (98% M, 99% F; 92.2% M, 90.6% F; and 76.2% M, 76.3% F; for 75th, 85th, and 90th DXA-percentile respectively) had excess adiposity. A high degree of discordance was observed between BMI and DXA-derived excess adiposity among youth with class 1 obesity (81.4% M, 85.5% F; 52.7% M, 59.6% F; and 32.9% M, 36.9% F; for 75th, 85th, and 90th DXA-percentile respectively). Only a small proportion of youth with overweight or normal weight had excess adiposity. Conclusions: The vast majority of youth with severe obesity defined by BMI-based obesity categories have excess adiposity, regardless of the cut-point used. Significant discordance was observed between DXA-derived excess adiposity in youth with obesity and overweight suggesting a high degree of misclassification using BMI-based definitions.
Humoral Response Against LL‐37 in Psoriatic Disease: Comment on the Article by Yuan et al
Authors: Maria De Santis, Natasa Isailovic, Elena Generali, Angela Ceribelli, Lorenzo Altamore, Feliciana Real‐Fernandez, Anna Maria Papini, Paolo Rovero, Giuseppina Sabatino, Carlo Selmi
Journal: Arthritis & Rheumatology (2019)
PB2262 HEALTHCARE RESOURCE UTILIZATION (HRU) ASSOCIATED WITH MINIMAL RESIDUAL DISEASE (MRD) STATUS IN ADULTS WITH B‐CELL PRECURSOR (BCP) ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Authors: A. Pigneux, P. Montesinos, Z. Cong, X. Zhang, A. K. Pownell, H. Wieffer, J. McKendrick
Journal: HemaSphere (2019)

Background: The presence of MRD is the most important risk factor for relapse and mortality in patients with BCP ALL who achieve complete remission (CR). Given the poor outcomes associated with MRD‐positive (MRD+) ALL, achieving MRD‐negativity (MRD‐) is critical. However, the HRU associated with MRD status is unknown. Aims: To investigate the HRU associated with MRD status among adult patients with BCP ALL in first CR (CR1) in France, Germany, Italy, Spain and UK (EU5). Methods: A cross‐sectional survey of physicians who use MRD testing in adults with BCP ALL in the EU5 countries was used to estimate the HRU. Physicians must be board‐certified or specialized in hematology/hemato‐oncology, have ≥ 5 years’ experience with ALL, have seen ≥ 2 ALL patients in the last 12 months or ≥ 5 patients in the last 5 years, and have experience using MRD testing in clinical practice. Two to 4 physicians were recruited in each country. Each physician completed a web‐based questionnaire and was followed by a telephone interview. Descriptive analyses were conducted. Outpatient visits to healthcare professionals and hospital resource use for ALL patients in CR1 with or without MRD during an average period of 6 months (assuming no relapse or allogeneic hematopoietic stem‐cell transplant occurred) were reported for each country and across countries. Results: According to the survey, across the countries, patients with MRD+ ALL had an average of 9.2 (ranging 4∼12) visits to hematologist/oncologist, 1.4 (0∼2.5) visits to radiologist, 1.8 (0∼3) visits to other specialist physician and 2.6 (0∼4.5) visits to general physician during a 6‐months period, compared with 7.4 (1∼11), 1.1 (0∼2.3), 1.4 (0∼2.3) and 2.3 (0∼4.0) visits, respectively, in patients with MRD‐ ALL (Table 1). The average proportion of patients with at least one hospital admission in patients with or without MRD was 64.7% (ranging 40.0%∼83.3%) vs 39.3% (0∼83.3%). Of the patients with at least admission, patients with MRD+ ALL had an average of 3.2 (1.5∼4.3) admissions with a mean length of stay (LOS) of 13.2 (0.5∼19.8) days per admission, compared with 2.1 (0∼4.3) admissions and a mean LOS of 8.9 (0∼15.3) days per admission in patients with MRD‐ ALL (Table 2). Summary/Conclusion: From the physicians’ estimates of the HRU for patients with ALL in CR1 in the EU5 countries, presence of MRD+ is generally associated with higher use of outpatient visits to physicians across different specialties and with higher use of hospital resources (except Spain). The results should be interpreted with the limitation of small sample sizes in each country. image
Transcriptional consequences of targeting the i-motif structure of the c-Myc promoter with TMPyP4
Authors: Tiffanie Bialis, Thomas Dexheimer, Mary Gleason-Guzman, Danzhou Yang, Laurence Hurley
Journal: Cancer Research (2007)

3169  The nuclease hypersensitivity element III1 (NHE III1) upstream of both the P1 and P2 promoters in the c-Myc gene controls the majority of transcriptional activity (80â\#8364;“90%) of the gene and has been shown to form secondary DNA structures. It has also been shown as the target for the cationic porphyrin TMPyP4 molecule, which has been previously shown to downregulate c-Myc gene expression (Siddiqui-Jain et al., Proc. Natl. Acad. Sci. U.S.A., 2002, 99, 11593). Through a series of experiments, an additional target to the G-quadruplex has been identified for TMPyP4 binding, which is the i-motif structure that forms from the pyrimidine-rich strand of the NHE. Using a cleavage assay, it has been shown that TMPyP4 binds specifically to the top of the i-motif structure. This binding of TMPyP4 increases the melting temperature of the i-motif, making it more stable, as seen by CD spectrometry. Using the ChIP assay it was shown that binding of TMPyP4 to the i-motif structure prevents the association of hnRNP K, a transcription factor known to regulate the expression of c-Myc. In addition, NMR confirms the binding of TMPyP4 to the i-motif structure. Finally, gene transcription was detected using real-time PCR, illustrating the effects of TMPyP4 in cells. These experiments suggest that an important target for TMPyP4, in addition to the G-quadruplex, is the i-motif and that stabilization of this structure prevents binding of hnRNP K, resulting in transcriptional silencing.
Regulatory roles of IL-10–producing human follicular T cells
Authors: Pablo F. Cañete, Rebecca A. Sweet, Paula Gonzalez-Figueroa, Ilenia Papa, Naganari Ohkura, Holly Bolton, Jonathan A. Roco, Marta Cuenca, Katharine J. Bassett, Ismail Sayin, Emma Barry, Angel Lopez, David H. Canaday, Michael Meyer-Hermann, Claudio Doglioni, Barbara Fazekas de St Groth, Shimon Sakaguchi, Matthew C. Cook, Carola G. Vinuesa
Journal: The Journal of Experimental Medicine (2019)

Mucosal lymphoid tissues such as human tonsil are colonized by bacteria and exposed to ingested and inhaled antigens, requiring tight regulation of immune responses. Antibody responses are regulated by follicular helper T (TFH) cells and FOXP3+ follicular regulatory T (TFR) cells. Here we describe a subset of human tonsillar follicular T cells identified by expression of TFH markers and CD25 that are the main source of follicular T (TF) cell–derived IL-10. Despite lack of FOXP3 expression, CD25+ TF cells resemble T reg cells in high CTLA4 expression, low IL-2 production, and their ability to repress T cell proliferation. CD25+ TF cell–derived IL-10 dampens induction of B cell class-switching to IgE. In children, circulating total IgE titers were inversely correlated with the frequencies of tonsil CD25+ TF cells and IL-10–producing TF cells but not with total T reg cells, TFR, or IL-10–producing T cells. Thus, CD25+ TF cells emerge as a subset with unique T and B cell regulatory activities that may help prevent atopy.