tbuckley/cabot-search huggingface dataset:
PS1433 RESULTS OF AUTOLOGOUS STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA PATIENTS WITH RENAL FAILURE
Authors: A. Tülin Tuğlular, T. Elibol, C. Uzunoğlu, B. Aldağ, Ö. Dedeoğlu, T. Ercan, Y. İpek, F. Arıkan, A.F. Yılmaz, I. Kaygusuz Atagündüz, T. Toptaş
Journal: HemaSphere (2019)

Background: Multiple Myeloma (MM) is a hematological malignancy in which renal involvement is common. Almost half of MM patients have increased creatinine levels at the time of diagnosis. In 20% of these patients, creatinine level is above 2 mg/dl. Kidney damage can be reversible in 50% of these patients. Aims: In this retrospective study, we evaluated the outcomes of autologous stem cell transplantation (ASCT) which was done in our center in multiple myeloma patients with renal failure. We compared the outcomes of these patients with patients with normal renal functions and who underwent ASCT. In patients with renal failure, melphalan 140 mg/m 2 was used as conditioning regimen. Methods: We retrospectively analyzed the files of 574 patients with multiple myeloma in our center. We identified 106 patients who had ASCT between 2007–2018. We calculated creatinine clearances (CrCl) with Modification of Diet in Renal Disease (MDRD) formula at diagnosis. Patients were divided into 2 categories according to their CrCl results: patients with CrCl above 60 ml/min (n = 41), patients with CrCl below 60 ml/min (n = 28). Demographic data, laboratory results, pre‐transplant treatment and response to treatments were presented in Table 1. Results: Median follow‐up of the patients was 54 months. Median progression‐free survival (PFS) in patients with CrCl&lt;60 ml/min and ≥60 ml/min was 56 months and 62 months, respectively. Three‐year PFS in these patients was 56.4% and 58%, respectively (p = 0.859). Median overall survival in patiens CrCl&lt;60 ml/min was 69 months; median OS was not reached in patients with CrCl≥60 ml/min (p = 0.001). Median OS of all patients was 90 months. Four‐year OS of patients with CrCl&lt;60 ml/min and≥ 60 ml/min was 69.9% vs. 97%, respectively (p = 0.001). We found that patients who had an improvement after ASCT in their renal functions had a better OS than compared to patients who had no improvement after ASCT (49 vs 73 months, respectively, p = 0.095). Four of the 7 patients with dialysis‐dependent renal failure at the time of diagnosis became dialysis independent. Median creatinine clearences of patients with CrCl &lt;60 ml/min before and after ASCT was 25.45 ml/min and 54.39 ml/min respectively. CrCl increased above 60 ml/min in 11 patients. CrCl increased %50 above baseline in 18 patients. Summary/Conclusion: In conclusion treatment response rates and progression‐free survival rates were not affected by renal failure. Treatment of patients with renal insufficiency should not be different than those of patients who do not have renal failure. Standard myeloma treatment and ASCT should be used in these patients; melphalan dose can be reduced to 140 mg/m2 in patients with CrCl &lt;60 ml/min. image
Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas
Authors: Qi Zhang, Yu Lou, Jiaqi Yang, Junli Wang, Jie Feng, Yali Zhao, Lin Wang, Xing Huang, Qihan Fu, Mao Ye, Xiaozhen Zhang, Yiwen Chen, Ce Ma, Hongbin Ge, Jianing Wang, Jiangchao Wu, Tao Wei, Qi Chen, Junqing Wu, Chengxuan Yu, Yanyu Xiao, Xinhua Feng, Guoji Guo, Tingbo Liang, Xueli Bai
Journal: Gut (2019)

Objective Hepatocellular carcinoma (HCC) is heterogeneous, especially in multifocal tumours, which decreases the efficacy of clinical treatments. Understanding tumour heterogeneity is critical when developing novel treatment strategies. However, a comprehensive investigation of tumour heterogeneity in HCC is lacking, and the available evidence regarding tumour heterogeneity has not led to improvements in clinical practice. Design We harvested 42 samples from eight HCC patients and evaluated tumour heterogeneity using whole-exome sequencing, RNA sequencing, mass spectrometry-based proteomics and metabolomics, cytometry by time-of-flight, and single-cell analysis. Immunohistochemistry and quantitative polymerase chain reactions were performed to confirm the expression levels of genes. Three independent cohorts were further used to validate the findings. Results Tumour heterogeneity is considerable with regard to the genomes, transcriptomes, proteomes, and metabolomes of lesions and tumours. The immune status of the HCC microenvironment was relatively less heterogenous. Targeting local immunity could be a suitable intervention with balanced precision and practicability. By clustering immune cells in the HCC microenvironment, we identified three distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features. We further revealed the specific metabolic features and cytokine/chemokine expression levels of the different subtypes. Determining the expression levels of CD45 and Foxp3 using immunohistochemistry facilitated the correct classification of HCC patients and the prediction of their prognosis. Conclusion There is comprehensive intratumoral and intertumoral heterogeneity in all dimensions of HCC. Based on the results, we propose a novel immunophenotypic classification of HCCs that facilitates prognostic prediction and may support decision making with regard to the choice of therapy.
SAT0195 SYSTEMIC DISEASES ASSOCIATED WITH AUTOIMMUNE LIVER DISEASES
Authors: hela KCHIR, Dhouha Cherif, Dhilel Issaoui, Maha Mtir, Dhia Kaffel, Faten Limaiem, Nadia Maamouri
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Autoimmune liver diseases are considered as a group of hepatobiliary injuries mediated by abnormal immunity in subjects with genetic predisposition. It mainly includes autoimmune hepatitis, primary biliary cholangitis,primary sclerosing cholangitis and overlap syndrome. They are oftently associated with different manifestations of autoimmune systemic diseases such as systemic lupus erythematosus, CREST syndrome …. <h3>Objectives:</h3> The aim of this study was to evaluate the prevalence and the characteristics of systemic diseases associated with autoimmune hepatopathies <h3>Methods:</h3> We carried out a retrospective study from January 1996 to December 2018 including all patients with autoimmune liver diseases followed in our department: 64primary biliary cholangitis (PBC), 22 autoimmune hepatitis (AIH), 23 overlap syndrome (OS), 15 primary sclerosing cholangitis (PSC). <h3>Results:</h3> One hundred and twenty four patients were included in our study : 107 women and 17 men with an average age of 55 years [18-87 years]. An immunological disorder was found in 58 cases (48%): [28 PBC/12 AIH/12 OS/6 PSC] with a female predominance (Sex ratio (Men/Women) = 0.09). Systemic diseases included respectively: Sjögren's syndrome in 20 cases, systemic lupus erythematosus in 7 cases, rheumatoid arthritis in 5 cases, CREST syndrome in 11 cases and autoimmune thyroiditis in 2 cases. The discovery of autoimmune disorder was in most cases concomitant to the diagnosis of the autoimmune liver disease (67%). Our study showed biological assessment perturbation in 20 cases with positivity of : anti-centromere antibodies (11 cases), anti-SSA antibodies (5 cases), anti-cardiolipin antibodies (4 cases) and rheumatoid factor (5 cases) <h3>Conclusion:</h3> Our study shows a strong prevalence of systemic disease during autoimmune hepatopathies. A systematic screening for clinical and biological immune manifestations are highly recommended in those patients. <h3>Disclosure of Interests:</h3> None declared
Ribosome Provisioning Activates a Bistable Switch Coupled to Fast Exit from Stationary Phase
Authors: Philippe Remigi, Gayle C Ferguson, Ellen McConnell, Silvia De Monte, David W Rogers, Paul B Rainey
Journal: Molecular Biology and Evolution (2019)

Observations of bacteria at the single-cell level have revealed many instances of phenotypic heterogeneity within otherwise clonal populations, but the selective causes, molecular bases, and broader ecological relevance remain poorly understood. In an earlier experiment in which the bacterium Pseudomonas fluorescens SBW25 was propagated under a selective regime that mimicked the host immune response, a genotype evolved that stochastically switched between capsulation states. The genetic cause was a mutation in carB that decreased the pyrimidine pool (and growth rate), lowering the activation threshold of a preexisting but hitherto unrecognized phenotypic switch. Genetic components surrounding bifurcation of UTP flux toward DNA/RNA or UDP-glucose (a precursor of colanic acid forming the capsules) were implicated as key components. Extending these molecular analyses-and based on a combination of genetics, transcriptomics, biochemistry, and mathematical modeling-we show that pyrimidine limitation triggers an increase in ribosome biosynthesis and that switching is caused by competition between ribosomes and CsrA/RsmA proteins for the mRNA transcript of a positively autoregulated activator of colanic acid biosynthesis. We additionally show that in the ancestral bacterium the switch is part of a program that determines stochastic entry into a semiquiescent capsulated state, ensures that such cells are provisioned with excess ribosomes, and enables provisioned cells to exit rapidly from stationary phase under permissive conditions.
Efficacy and Safety of Evolocumab in Chronic Kidney Disease in the FOURIER Trial
Authors: David M. Charytan, Marc S. Sabatine, Terje R. Pedersen, KyungAh Im, Jeong-Gun Park, Armando Lira Pineda, Scott M. Wasserman, Prakash Deedwania, Anders G. Olsson, Peter S. Sever, Anthony C. Keech, Robert P. Giugliano
Journal: Journal of the American College of Cardiology (2019)
FRI0221 CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME IN PREGNANCY: CASE SERIES
Authors: Nur Azizah Allameen, Aisha Lateef, Anita Yee Nah Lim
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Catastrophic antiphospholipid syndrome (CAPS) is a rare condition associated with high mortality<sup>1</sup>. Prompt recognition and treatment is important for optimal outcomes. Clinical features of CAPS can overlap with obstetric complications, leading to diagnostic challenge<sup>2</sup>. <h3>Objectives</h3> Describe two patients with CAPS during immediate post-partum period. <h3>Methods</h3> We report two cases in a single centre over two years. <h3>Results</h3> A 38 year old with obstetric Antiphospholipid syndrome (APS) presented with epigastric pain, transaminitis and thrombocytopenia in keeping with evolving HELLP syndrome. Spontaneous complete miscarriage ensued. Post-delivery, she developed worsening abdominal pain and transaminitis (Table 1). Imaging demonstrated hepatic infarcts and patchy ground glass lung opacities. She was treated for CAPS with intravenous steroids and anticoagulation, and recovered. A 39 year old with primary APS (deep venous thrombosis and obstetric features) whose antenatal course was fraught with minor per vaginal bleeding (PVB) presented with heavy PVB at 22 weeks gestation requiring cessation of anticoagulation. She developed a deep venous thrombosis. Risk of clot propagation versus bleeding prompted cautious anticoagulation. Labour was induced for declining maternal health and poor foetal prognosis at 24 weeks, 3 days. Post-delivery, she developed abdominal pain, headache, transaminitis and worsening thrombocytopenia with heavy PVB requiring uterine artery embolization. Given features that were consistent with micro thrombi and ischaemia (Table 1), she was treated as for CAPS and HELLP syndrome with intravenous steroids, plasma exchange (PLEX) and intravenous immunoglobulin (IVIG), and recovered. <sup>^</sup>Low molecular weight heparin. <sup>°</sup>Aspartate aminotransferase. <sup>«</sup>Alanine aminotransferase. <sup>◊</sup>Lactate dehydrogenase. <sup>*</sup>Intravenous Methylprednisolone <h3>Conclusion</h3> Recognition of CAPS is complex in pregnancy. Vigilance is required for urgent aggressive treatment to improve outcomes in this uncommon condition. <h3>References</h3> [1] Bucciarelli S, Espinosa G, Cervera R, et al. Mortality in catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients. Arthritis Rheum 2006; 54: 2568–2576. [2] Silver RM. Catastrophic antiphospholipid syndrome and pregnancy. Semin Perinatol. 2018 Feb;42(1):26-32. <h3>Disclosure of Interests</h3> Nur Azizah Allameen: None declared, Aisha Lateef : None declared, Anita Yee Nah Lim Speakers bureau: I have been a speaker for Novartis last year
PF432 EPIDEMIOLOGICAL SHIFT OF GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) MUTATIONS IN NORTHERN ITALY DURING THE LAST 15 YEARS
Authors: L. Duca, M.D. Cappellini, I. Nava, D. Tavazzi, A. Marcon, I. Motta, M. Salvatori, M. Mancarella, F. Landi, G. Graziadei
Journal: HemaSphere (2019)

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive hemolytic anemia caused by G6PD gene mutations which affect 400 million people worldwide. To date, more than 140 G6PD mutations have been reported. The distribution and frequency of genetic variants differ depending on ethnicity and geographical areas. Because of new migrations different variants are now present in Europe. Aims: This retrospective study aims to identify variants among the G6PD deficient subjects referred since 2004 to “Ca’ Granda” Foundation Hospital “in Milan. The subjects were divided into 3 groups: group 1 (2004–2008), group 2 (2009–2013) and group 3 (2014–2018).These subjects were studied because of known or suspected G6PD deficiency or for genetic counselling. Methods: The molecular analysis has been carried out by restriction fragments length polymorphisms (RLFP) and direct DNA sequencing. Results: Three hundred and thirty nine G6PD mutated subjects were identified, classified and divided as shown in table 1:Table 1 - G6PD variants identified in glucose 6-phosphate dehydrogenase-deficient subjects diagnosed since 2004 (number of subjects with G6PD mutations in italic, percentage % in brackets). During 12 years a significant decrease of the Mediterranean and an important increase of the African, Asian and uncommon variants (classified as Others) have been observed. In the first eight years Cassano and Chatham variants have an increase that does not change in the last four years. During each period new mutations were found: in group 1 the Gly485Asp (c.[1454G> A]) in homozygosity (female), in group 2 the Glu195Arg (c.[584A> G]) in heterozygosity and in group 3 the Ile224Phe (c.[670A>T]) in hemizygosity. Referring to the entire period of the study 2004–2018, in 3 subjects (1.1%) were found Portici variant, responsible for chronic non-spherocytic haemolytic anaemia, as well as Puerto Limon and Georgia (0,4%). Other variants identified in less than 1% of subjects studied were: Cairo, Mahidol, Ludhiana, Rignano, Santamaria, Sant’Antioco, Canton, Sibari, Cosenza, Abruzzo, Viangchan, Orissa, and Union. Two cases showed the 1365–13T>C polymorphism coupled with 1311C>T variation, generally associated with Mediterranean variant. Summary/Conclusion: These data reflect the appearance of uncommon G6PD mutations in Northern Italy, probably due to new migrations, as consequence G6PD characterization becomes a diagnostic issue. The evidence of polymorphisms in G6PD deficient subjects suggests that not only single variations in the exonic/intronic boundaries, but also specific haplotypes could be causative for G6PD deficiency.
AUTOCHTHONOUS MOUSE MODELS OF MYD88 P.L265P - AND BCL2-DRIVEN DIFFUSE LARGE B CELL LYMPHOMA
Authors: R. Fluemann, G. Knittel, P. Nieper, T. Rehkämper, P. Pfeiffer, A. Holzem, M. Peifer, R. Büttner, T. Persigehl, H. Kashkar, C. Reinhardt
Journal: HemaSphere (2019)
FRI0298 ABNORMALITY OF PERCENTAGES AND ABSOLUTE NUMBERS OF CD4+T SUBSETS IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIS AND ITS CORRELATIONS WITH CLINICAL INDICATORS
Authors: Yanlin Wang, Xiang-Cong Zhao, Jing Luo
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> ANCA-associated vasculitis (AAV) is a heterogenous autoimmune disease with unknown etiology [1-2]. During the last decade, a panel of CD<sup>+</sup> T subsets have been identified. However, the exact role and quantitative status of these subsets in AAV patients remains unclear. <h3>Objectives</h3> We therefore investigated these T cell subsets in AAV patients. <h3>Methods</h3> AAV patients (n = 54) and healthy controls (HCs) (n = 19) were enrolled. Of them, ten patients initially presenting with active disease were assessed again after remission was achieved. In addition, 38 patients were renal vasculitis. Proportions and absolute numbers of peripheral CD4+T cell subsets and expression of multiplex cytokines were determined by flow cytometry (FCM). Correlations of clinical indicators with the CD4+ T cell subsets were systematically analyzed. <h3>Results</h3> Percentages of naive T cells (TN) (p&lt;0.001), terminally differentiated effector (TEMRA) T cells (p=0.027) and activated Treg cells (aTreg) in AAV patients were decreased, but those of effector memory T-cell subpopulation (TEM) (p&lt;0.001), regulatory T cell (Treg) cells and FoxP3lowCD45RA- T cells were increased. Similar results were observed when we compared absolute numbers of the above corresponding cells in AAV patients and HCs, except TEM. Furthermore, the percentage of aTreg (p=0.043) was decreased while that of Th17 cells (p=0.027) was increased in renal vasculitis patients. A significant correlation was observed between the ratio of Th17 to Treg subset and creatinine or BUN, as well as the ratio of Th17/aTreg was significantly increased in active and renal vasculitis patient. In addition, we found that cytokine IL-2 and IL-4 exhibited a downward while IL-6, IL-10, TNF, IFN-γ and IL-17A trend upward in AAV patients. <h3>Conclusion</h3> There were abnormally quantitative changes in CD4+ T subsets and cytokines in AVV patients, especially the decrease in the relative and absolute number of aTreg (activated Tregs), which indicates an imbalance of pro- and anti-inflammatory T cells. These T subsets might be associated with the ANCA-related autoimmune response and can be used as diagnosis markers for disease activity and as targets for potentially powerful therapy of AAV. <h3>References</h3> [1] Hutton H L, Holdsworth S R, Kitching A R. ANCA-Associated Vasculitis: Pathogenesis, Models, and Preclinical Testing [J]. Seminars in Nephrology, 2017, 37(5):418. [2] Kerstein A, Silke Schüler, Otávio CabralMarques, et al. Environmental factor and inflammation-driven alteration of the total peripheral T-cell compartment in granulomatosis with polyangiitis [J]. Journal of Autoimmunity, 2016, 78:79. <h3>Disclosure of Interests</h3> None declared
Chronic Hepatitis B Prevalence Among Foreign‐Born and U.S.‐Born Adults in the United States, 1999‐2016
Authors: Michael H. Le, Yee Hui Yeo, Ramsey Cheung, Linda Henry, Anna S. Lok, Mindie H. Nguyen
Journal: Hepatology (2019)

Hepatitis B virus (HBV) infection remains a major global health problem, exacerbated by poor linkage to care. We aimed to determine the prevalence of HBV infection, exposure, self‐reported vaccination, vaccine‐induced immunity, disease awareness, and treatment in the United States by birthplace and race/ethnicity during 1999‐2016. A total of 47,628 adult participants in the National Health and Nutrition Examination Survey who completed HBV core antibody (anti‐HBc) and surface antigen (HBsAg) tests and 47,618 adults who completed HBV surface antibody (anti‐HBs) and anti‐HBc tests were included in the analysis. HBV infection was defined by positive HBsAg and past exposure by positive anti‐HBc. Vaccine‐mediated immunity was defined by positive anti‐HBs and negative anti‐HBc. No significant change in the prevalence of HBV infection was observed between 1999 and 2016 ( P = 0.442), affecting 0.35% (95% confidence interval [CI], 0.28‐0.45) or 0.84 million adults. In contrast, a significant decrease in HBV exposure and increase in vaccine‐mediated immunity was observed. U.S.‐born persons had significantly lower prevalence of HBV infection and exposure as well as higher prevalence of vaccine‐mediated immunity and self‐reported vaccination than foreign‐born persons. Prevalence of HBV infection was highest in non‐Hispanic Asians in both foreign‐ (3.85%; 95% CI, 2.97‐4.97) and U.S.‐born (0.79%; 95% CI, 0.17‐3.59) persons during 2011‐2016. Among infected persons, liver disease awareness was only 15.19%, and treatment rate was only 4.60%. Conclusion: This study revealed disparities of HBV infection among ethnic/racial groups and between U.S.‐born and foreign‐born persons. Awareness of liver disease and treatment rate among infected persons was dismal.
Anti‐dipsotropic isoflavones: The potential therapeutic agents for alcohol dependence
Authors: Wing Ming Keung
Journal: Medicinal Research Reviews (2003)

Daidzin is the active principle of Radix puerariae (RP), an herbal remedy that has been used apparently safely and effectively for the treatment of "alcohol addiction" in China for more than a millennium. It has been shown to reduce alcohol consumption in all animal models tested to date. A link between daidzin's capacity to reduce alcohol consumption and its ability to increase liver mitochondrial monoamine oxidase (MAO): aldehyde dehydrogenase (ALDH-2) activity ratio has been established. Daidzin analogs that potently inhibit ALDH-2 but not MAO are the most anti-dipsotropic, whereas those that also inhibit MAO are not. On the basis of these findings, it was proposed that the liver mitochondrial MAO-ALDH-2 pathway is the primary site of action of daidzin and that a biogenic aldehyde derived from the action of MAO mediates its anti-dipsotropic action. Therefore, to design and synthesize more potent anti-dipsotropic analogs, structural features that would enhance ALDH-2 inhibition and/or decrease MAO inhibition needed to be evaluated. Structure-activity-relationship (SAR) studies have revealed that a sufficient set of criteria for a potent anti-dipsotropic analog is an isoflavone with a free 4'-OH function and a straight-chain alkyl at the 7 position that has a terminal polar function such as -OH, -COOH, or -NH2. The preferable chain lengths for the 7-O-omega-carboxy, 7-O-omega-hydroxy, and 7-O-omega-amino substituents are 5 < or = n < or = 10, 2 < or = n < or = 6, and n > or = 4, respectively. Analogs that meet these criteria have increased potency for ALDH-2 inhibition and/or decreased potency for MAO inhibition and are, therefore, likely to be potent anti-dipsotropic agents.
A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration
Authors: Clayton P. Santiago, Casey J. Keuthan, Sanford L. Boye, Shannon E. Boye, Aisha A. Imam, John D. Ash
Journal: Molecular Therapy (2018)

Retinal degenerations are a large cluster of diseases characterized by the irreversible loss of light-sensitive photoreceptors that impairs the vision of 9.1 million people in the US. An attractive treatment option is to use gene therapy to deliver broad-spectrum neuroprotective factors. However, this approach has had limited clinical translation because of the inability to control transgene expression. To address this problem, we generated an adeno-associated virus vector named RPF2 that was engineered to express domains of leukemia inhibitory factor fused to the destabilization domain of bacterial dihydrofolate reductase. Fusion proteins containing the destabilization domain are degraded in mammalian cells but can be stabilized with the binding of the drug trimethoprim. Our data show that expression levels of RPF2 are tightly regulated by the dose of trimethoprim and can be reversed by trimethoprim withdrawal. We further show that stabilized RPF2 can protect photoreceptors and prevent blindness in treated mice.Graphical abstract