tbuckley/cabot-search huggingface dataset:
Age, HLA, and Sex Define a Marked Risk of Organ-Specific Autoimmunity in First-Degree Relatives of Patients With Type 1 Diabetes
Authors: Christiane Winkler, Manja Jolink, Annette Knopff, Nana-Adjoa Kwarteng, Peter Achenbach, Ezio Bonifacio, Anette-G. Ziegler
Journal: Diabetes Care (2019)

OBJECTIVE Autoimmune diseases can be diagnosed early through the detection of autoantibodies. The aim of this study was to determine the risk of organ-specific autoimmunity in individuals with a family history of type 1 diabetes. RESEARCH DESIGN AND METHODS The study cohort included 2,441 first-degree relatives of patients with type 1 diabetes who were prospectively followed from birth to a maximum of 29.4 years (median 13.2 years). All were tested regularly for the development of autoantibodies associated with type 1 diabetes (islet), celiac disease (transglutaminase), or thyroid autoimmunity (thyroid peroxidase). The outcome was defined as an autoantibody-positive status on two consecutive samples. RESULTS In total, 394 relatives developed one (n = 353) or more (n = 41) of the three disease-associated autoantibodies during follow-up. The risk by age 20 years was 8.0% (95% CI 6.8–9.2%) for islet autoantibodies, 6.3% (5.1–7.5%) for transglutaminase autoantibodies, 10.7% (8.9–12.5%) for thyroid peroxidase autoantibodies, and 21.5% (19.5–23.5%) for any of these autoantibodies. Each of the three disease-associated autoantibodies was defined by distinct HLA, sex, genetic, and age profiles. The risk of developing any of these autoantibodies was 56.5% (40.8–72.2%) in relatives with HLA DR3/DR3 and 44.4% (36.6–52.2%) in relatives with HLA DR3/DR4-DQ8. CONCLUSIONS Relatives of patients with type 1 diabetes have a very high risk of organ-specific autoimmunity. Appropriate counseling and genetic and autoantibody testing for multiple autoimmune diseases may be warranted for relatives of patients with type 1 diabetes.
Recessive gene disruptions in autism spectrum disorder
Authors: Ryan N. Doan, Elaine T. Lim, Silvia De Rubeis, Catalina Betancur, David J. Cutler, Andreas G. Chiocchetti, Lynne M. Overman, Aubrie Soucy, Susanne Goetze, Christine M. Freitag, Mark J. Daly, Christopher A. Walsh, Joseph D. Buxbaum, Timothy W. Yu
Journal: Nature Genetics (2019)
PB2289 HEALTH‐RELATED QUALITY OF LIFE AND OXYGEN TRANSPORT IN PATIENTS WITH NEPHROGENIC ANEMIA
Authors: S. Bondarchuk, A. Kovalev, R. Nikolay
Journal: HemaSphere (2019)

Background: End‐stage renal disease (EsRD) is often associated with an anemia. Most patients retrieve erythropoiesis stimulating agents, and so they presents with mild anemia. The tolerance of anemia of each patient is individual. Determination of venous blood gas (VBG) in conjunction with study of health‐related quality of life (HRQoL) can help in the individualization of treatment. Aims: To investigate the relationship between health‐related quality of life and venous blood gas in patients with nephrogenic anemia. Methods: 30 patients with EsRD undergoing hemodialysis and receiving erythropoes stimulating therapy were involved in the study. 20 men, median age 52 years. Polycystic kidney disease was caused by the development of EsRD in 7 (23%) patients, diabetic nephropathy in 6 (20%) patients, glomerulonephritis also in 6 (20%) patients, nephrosclerosis in 5 (17%), and other causes in the remaining 6 patients (20%). HRQoL was studied using the FACT (Functional Assessment of Cancer Therapy Scale) questionnaire. Indicators of complete blood count, VBG were evaluated. Results: The hemoglobin median in the studied patients showed 105 g/l (81‐112 g/l), 26 patients experienced mild anemia (87%), 3 patients (10%) ‐ moderate anemia. in 1 patient there was no anemic syndrome. SvO2 median is 62.3%, while in only 18 (60%) patients the level of SvO2 is ≥60%. In general, the results of HRQoL analysis showed its deterioration in patients on all scales of the FACT questionnaire; the highest score was obtained in the scales “Physical well‐being” (Me 11 points) and “Anemia” (Me 30 points). When conducting a correlation analysis of hemoglobin and HRQoL, a statistically significant relationship was found on the scales “Physical well‐being” (r = ‐0.45; p &lt; 0.05), “Emotional well‐being” (r = ‐0.39 p &lt; 0, 05) and Anemia (r = ‐0.51; p &lt; 0.05). A statistically significant correlation was obtained between the level of hemoglobin and the level of oxygen in venous blood. At the same time, no significant correlation was established between HRQoL and the saturation of venous blood (p &gt; 0.2). Summary/Conclusion: According to the results of the HRQoL analysis, it was established that in patients with nephrogenic anemia, HRQoL decreases depending on the concentration of hemoglobin. The generally accepted target level of hemoglobin (100‐110 g/l) allows to avoid severe complications, but not in all cases it can adequately meet the need for O 2 in patients. According to the data obtained, only 60% of patients achieved SvO 2 ≥ 60%, which indicates the presence of tissue hypoxia.
AB0686 REDUCTION IN THE ABSOLUTE NUMBER OF PERIPHERAL REGULATORY T CELLS CORELATED TO CLINICAL FEATURES IN PATIENTS WITH SYSTEMIC SCLEROSIS
Authors: Lili Shang, Tingting Zhang, Xiaoli Liu, Hui Wang, Chong Gao, Jinfang Zhao, LI Xiao-Feng, Huiying Gao
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The role of regulatory T cells (Tregs) in the development of SSc has started being studied during the last decade with new aspects being disclosed continuously. Although there is a general agreement in the medical literature regarding the decreased functional capacity of circulating Tregs in SSc, the alteration of absolute number of Treg and Th17 cells as well as their associations with clinical characteristics of SSc are still unclear. <h3>Objectives:</h3> The present study was to investigate the relationship between multiple system impairments, disease activity and the absolute number of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) and interleukin 17 producing T help cells (Th17) in peripheral blood of patients with systemic sclerosis (SSc). <h3>Methods:</h3> Clinical indicators were collected from total 54 patients with SSc[8 with localized SSc (lcSSc) and 46 with diffuse SSc (dcSSc)] who were divided into two groups, mainly with skin lesions (n=11) and with multiple system and organ besides skin lesions (n=43). Then according to the SSc EUSTAR index, we divided 54 SSc patients into the inactive (EUSTAR &lt; 2.5 points, n = 22 cases) and the active group (EUSTAR score ≥ 2.5 points, n = 32 cases). The levels of peripheral T lymphocyte were detected with flow cytometry. <h3>Results:</h3> We found that SSc, especially dcSSc patients, had significantly fewer peripheral CD4Treg cells (both absolute number and proportion, p&lt;0.01) than healthy controls (Figure 1). In addition, the absolute number of peripheral Treg cells was significantly reduced in SSc patients with multiple system impairments (P&lt;0.001), however, the number of Th17 cells were significantly increased in SSc patients with simple skin involvement (P = 0.002) (Figure 2). Also the absolute number of peripheral CD4Treg cells in active group with SSc decreased more significantly, thus causing an increase in the ratio of Th17 and Treg cells (Figure 2). <h3>Conclusion:</h3> The reduced absolute number of peripheral Treg cells in SSc patients was contributed to the imbalance of Th17/Treg cells and involved in the pathogenesis of SSc, and may promote multiple system impairments and disease activity. <h3>References</h3> [1] Liu M, Wu W, Sun X, et al. New insights into CD4(+) T cell abnormalities in systemic sclerosis. Cytokine Growth Factor Rev. 2016Apr; 28:31-6. doi: 10.1016/j.cytogfr.2015.12.002. [2] Lee GR. The Balance of Th17 versus Treg Cells in autoimmunity. Int J Mol Sci. 2018Mar3;19(3). pii: E730.doi: 10.3390/ijms19030730. <h3>Disclosure of interests:</h3> None declared
Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes
Authors: Michael Offin, Joseph M. Chan, Megan Tenet, Hira A. Rizvi, Ronglai Shen, Gregory J. Riely, Natasha Rekhtman, Yahya Daneshbod, Alvaro Quintanal-Villalonga, Alexander Penson, Matthew D. Hellmann, Maria E. Arcila, Marc Ladanyi, Dana Pe’er, Mark G. Kris, Charles M. Rudin, Helena A. Yu
Journal: Journal of Thoracic Oncology (2019)
Polo-Like Kinase 1 phosphorylates and stabilizes KLF4 to promote tumorigenesis in nasopharyngeal carcinoma
Authors: Jia Mai, Zhuo-Yan Zhong, Gui-Fang Guo, Xiu-Xing Chen, Yan-Qun Xiang, Xuan Li, Hai-Liang Zhang, Yu-Hong Chen, Xue-Lian Xu, Rui-Yan Wu, Yan Yu, Zhi-Ling Li, Xiao-Dan Peng, Yun Huang, Li-Huan Zhou, Gong-Kan Feng, Xiang Guo, Rong Deng, Xiao-Feng Zhu
Journal: Theranostics (2019)

Rationale: Advanced nasopharyngeal carcinoma (NPC) is an aggressive disease with no targeted therapies and poor outcomes.New innovative targets are urgently needed.KLF4 has been extensively studied in the context of tumors, and current data suggest that it can act as either a tissue-specific tumor-inhibiting or a tumor-promoting gene.Here, we found that KLF4 played as a tumor-promoting gene in NPC, and could be mediated by PLK1.Methods: Tissue immunohistochemistry (IHC) assay was performed to identify the role of KLF4 in NPC.Global gene expression experiments were performed to explore the molecular mechanisms underlying KLF4-dependent tumorigenesis.Small-molecule kinase inhibitor screening was performed to identify potential upstream kinases of KLF4.The pharmacologic activity of polo-like kinase inhibitor volasertib (BI6727) in vitro and in vivo was determined.Result: Our investigation showed that high expression of KLF4 was correlated with poor prognosis in NPC.Moreover, genome-wide profiling revealed that KLF4 directly activated oncogenic programmes, including gene sets associated with KRAS, VEGF, and MYC signalling.We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234.Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization.Moreover, KLF4 could enhance TRAF6 expression at the transcriptional level, thus initiating a KLF4-TRAF6 feed-forward loop.Treatment with the PLK1 inhibitor volasertib (BI6727) significantly inhibited tumor growth in nude mice. Conclusion:Our study unveiled a new PLK1-TRAF6-KLF4 feed-forward loop.The resulting increase in KLF4 ubiquitination leads to stabilization and upregulation of KLF4, which leads to tumorigenesis in NPC.These results expand our understanding of the role of KLF4 in NPC and validate PLK1 inhibitors as potential therapeutic agents for NPC, especially cancer patients with KLF4 overexpression.
Abstract 17165: Myocardial Native T1 Time in Cardiac Magnetic Resonance Imaging as a Possible Marker for Left Ventricular Reverse Remodeling in Patients With Idiopathic Dilated Cardiomyopathy: in Association With Serum Cardiac Troponin-T
Authors: Muneyuki Kadota, Yasuo Sugano, Hiroyuki Miura, Teruo Noguchi, Yoshiaki Morita, Yasuhiro Hamatani, Atsushi Okada, Hiroyuki Takahama, Makoto Amaki, Takuya Hasegawa, Hideaki Kanzaki, Satoshi Yasuda, Toshihisa Anzai
Journal: Circulation (2017)

Backgrounds: Lack of left ventricular reverse remodeling (LVRR) is a marker of a worse prognosis in patient with idiopathic dilated cardiomyopathy (IDC). Native myocardial T1 in cardiac magnetic re...
PS1105 CONGENITAL DEFICIENCY OF COAGULATION FACTOR VII IN THE SOUTH OF TUNISIA: ABOUT 88 CASES
Authors: S. Kacem, F. Megdiche, M. Ghorbel, S. Maalej, Y. Fakhfakh, O. Kassar, I. Frikha, F. Kotti, H. Chaabane, M. Elloumi, C. Kallel
Journal: HemaSphere (2019)

Background: Congenital factor VII deficiency (FVII) is the least rare among uncommon hereditary bleeding disorders (1:500 000). This coagulopathy, inherited in an autosomal recessive pattern, is characterized by a bleeding tendency, varied prognosis and a lack of correlation between clinical phenotypes and biological analysis. Aims: The objective of our study was to describe and to explore the clinical and the biological features of FVII deficiency in the South of Tunisia. Methods: Our FVII‐deficient cohort consisted of 88 patients whose FVII activity was less than 50% and who were referred to our laboratory from January 2000 to December 2018 because of a prolonged prothrombin time (PT) or hemorrhagic manifestations. The FVII deficiency was considered as severe for FVII coagulant activities (FVII:C) &lt;2%, moderate for rates between 2 and 19% and minor for values between 20 and 49%. The statistical analysis was based on Chi‐squared test. Results: The mean age of the patients was 22 years old ranging between 21 months and 63 years old and the sex ratio was about 0.83. Among 88 patients, belonging to 58 unrelated Tunisian families, 45 cases (51.2%) were diagnosed accidentally during presurgical screening, 28 cases (31.8%) were noticed following family screening and 15 patients (17%) were discovered due to bleeding accidents. Clinically, 64 patients (72.7%) were asymptomatic whereas the bleeding frequency was about 27.3%. Clinical examination revealed several bleeding manifestations as follows : gingivorrhagia noticed in 12 patients (50%), followed by epistaxis in nine patients (37.5%). Four cases had hematemesis (16.6%), hematoma was found in three (12.5%) and one of the patients had a cerebral haemorrhage (4.2%). Added to that, some bleeding signs, not commonly related to the FVII deficiency, had been noticed such as: menorrhagia, haemoperitoneum, hematuria and bruising. The laboratory severity of each patient was also determined : FVII deficiency was classified as severe in 3.4%, moderate in 14.8% and minor in 81.8% of cases. With reference to statistics, results showed a weak correlation between clinical data and biological levels of FVII:C (p = 0.004). In fact, 15 patients with a minor FVII deficiency had presented haemorrhages with a variable bleeding severity; while one of the patients was asymptomatic despite the severity of his defect. Summary/Conclusion: Our study, in accordance with the literature, revealed a great interindividual heterogeneity of the clinical phenotype of FVII deficiency. In addition, bleeding severity did not necessarily correlate with FVII:C and varies markedly between individuals with a similar FVII:C. This would explain the delay and the underestimation of the diagnosis. In addition, the family screening had a prominent effect in improving the earliness of the diagnosis and in ensuring an adequate monitoring of these Tunisian patients.
Multiple stimulation parameters influence efficacy of deep brain stimulation in parkinsonian mice
Authors: Jonathan S. Schor, Alexandra B. Nelson
Journal: Journal of Clinical Investigation (2019)

Deep brain stimulation (DBS) is used to treat multiple neuropsychiatric disorders, including Parkinson's Disease (PD). Despite widespread clinical use, its therapeutic mechanisms are unknown. Here, we developed a mouse model of subthalamic nucleus (STN) DBS for PD, to permit investigation using cell type-specific tools available in mice. We found that electrical STN DBS relieved bradykinesia, as measured by movement velocity. In addition, our model recapitulated several hallmarks of human STN DBS, including rapid onset and offset, frequency dependence, dyskinesia at higher stimulation intensity, and associations between electrode location, therapeutic benefit, and side effects. We used this model to assess whether high frequency stimulation is necessary for effective STN DBS, or if low frequency stimulation can be effective when paired with compensatory adjustments in other parameters. We found that low frequency stimulation, paired with greater pulse width and amplitude, relieved bradykinesia. Moreover, a composite metric incorporating pulse width, amplitude, and frequency predicted therapeutic efficacy better than frequency alone. We found a similar relationship between this composite metric and movement speed in a retrospective analysis of human data, suggesting correlations observed in the mouse model may extend to human patients. Together, these data establish a mouse model for elucidating mechanisms of DBS.
PB1673 FEASIBILITY AND OUTCOME OF ALLOGENEIC BONE MARROW TRANSPLANTATION IN ADULT PHI NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Y. Fakhfakh, I. Frikha, N. Ben Abdeljlil, L. Tojmen, S. Hdiji, M. Mdhaffar, S. Ladab, O. Kassar, M. Ghorbel, T. Benothmen, M. Elloumi
Journal: HemaSphere (2019)

Background: Acute lymphoblastic leukemia (ALL) is a rare disease in adults. Despite the novels therapies, clinical outcomes remain unsatisfactory. Bone marrow allograft still holds its place as a consolidation treatment for patients in complete remission in order to improve the prognosis and lengthen survival. Aims: We study in this work the feasibility and outcome of bone marrow allograft for adult Philadelphia chromosome negative ALL. Methods: Our study is retrospective including the cases of high‐risk adult ALL (HR) diagnosed in the hematology department of Hédi Chaker Hospital of Sfax during the period from January 2004 to December 2015. These patients were treated according to protocols inspired by GRAALL 2003 and 2005. The indication of bone marrow allograft is systematic in patients whose age are &lt;50 years and having a compatible intrafamilial donor. For our patients we studied the allograft indication, the search for a family compatible HLA donor, the feasibility of the allograft and finally the result of this one which was carried out at the national center of bone marrow transplantation in Tunis. Results: Among the 36 cases of adult phi negative ALL treated with the GRAALL 2003 and 2005 protocols, 28 patients were in complete remission (CR) and 22 patients (79%) were classified as HR. Twenty patients had indication of bone marrow allograft (2 were&gt; 50 years of age). Of the 20 patients who had an HLA study, 14 patients (70%) had a compatible HLA family donor. Allogeneic bone marrow allograft could only be performed for 9 patients: 64% of patients with a compatible HLA donor and 45% of patients with CR. For the 5 others the transplant could not be done for: relapsed before allograft for 2 cases and severe comorbidities for the 3 others. The median time to completion of the allograft was 15 weeks. Among the allografts, 6 patients (67%) were living in CR after a follow‐up of 74 months, one patient relapsed at 6 months post‐transplant and 2 patients died of acute GVH. Of the 19 non‐allograft CR patients, 6 patients were living in CR (31%) and 1 died during consolidation therapy and 12 relapsed. The 5‐year DFS of both allografted and non‐allografted patients was 72% and 21%, respectively. Summary/Conclusion: Despite the cost‐effectiveness of the intra‐familial HLA study (70% donor) in our study, allografting could only be performed for a small number of patients (45%), hence the need to expand the indication of allograft for subjects over 50 years old or perform a mini allograft, do the same haplo transplant and even expand donor sources on files (pheno‐identical donors). Two‐thirds of the allografted patients in our series did not relapse, an interesting result and comparable to the literature.
AB0599 CLINICAL MANIFESTATIONS OF BEHÇET’S SYNDROME IN A LARGE COHORT OF ITALIAN PATIENTS: FOCUS ON GENDER DIFFERENCES
Authors: Pietro Leccese, Nancy Lascaro, Maria Carmela Padula, Teresa Carbone, Angela Padula, Salvatore D’angelo
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Behçet's syndrome (BS) is a chronic multisystemic inflammatory disorder classified among primary vasculitis. BS clinical hallmarks are mucocutaneous manifestations which include oral aphtosis (OA), genital ulcers (GU) and a wide spectrum of skin lesions. Other BS features include ocular inflammation, articular, gastrointestinal, vascular and neurological involvement. Some evidences suggest that in non endemic regions the disease tend to be less severe and women seem to be more commonly affected [1-3]. <h3>Objectives:</h3> The aim of this study was to investigate the clinical phenotypes of Italian BS patients with respect to gender and HLA-B51 status. <h3>Methods:</h3> We retrospectively evaluated 324 Italian patients (185 males and 139 females), seen consecutively at Rheumatology Institute of Lucania (IReL) from 1<sup>st</sup> January 2000 to 31<sup>th</sup> December 2017. Demographics, clinical features during follow-up and HLA status were obtained from a review of medical records. The analysis was limited to patients fulfilling the ISG criteria. <h3>Results:</h3> 324 BS patients were identified in our database. 39 (17 males and 22 females) were excluded because did not satisfied ISG criteria and 285 (168 males and 117 females) resulted eligible for the present study. Results are summarized in table 1. We found statistically significant differences in papulopustolar lesions, posterior uveitis and deep venous thrombosis (DVT), which occur more frequently in males compared with females (83.3% versus 46.2%, 37% versus 18.8% and 8.3% versus 0.9% respectively; p&lt;0.01). Erythema nodosum (EN) (59% versus 41,1%, p&lt;0,01), arthralgia (52.1% versus 31.5%, p&lt;0.01) and intestinal involvement (11.3% vs 21.4% p&lt;0.05) resulted more frequent in females compared with males. No differences were found in HLA status (M 67.9% vs F 61.5%). <h3>Conclusion:</h3> In our cohort of Italian BS patients the disease results slightly more prevalent in males. Gender-related differences were observed for posterior uveitis, DVP and papulopustolar lesions which are more frequent in males, whereas EN-like lesions, arthralgia and intestinal involvement are more frequently observed in females. These data confirm that BS tend to be less aggressive in Italian female patients. No sex-differences were observed in HLA-B51 status. <h3>Reference</h3> [1] Leccese P, et al. Curr Opin Rheumatol.2017;29(1):12-16. [2] Hatemi G, et al. Clin Exp Rheumaology.2016;34 Suppl 102:10-22. [3] Pipitone N, et al. Clin Exp Rheumatol.2004;22(6 Suppl 36):S46-51. <h3>Acknowledgement:</h3> Many thank to Professor Olivieri for his teachings <h3>Disclosure of Interests:</h3> Pietro Leccese: None declared, Nancy Lascaro: None declared, Maria Carmela Padula: None declared, Teresa Carbone: None declared, Angela Padula Speakers bureau: Lilly Italia EMS, Salvatore D'Angelo: None declared
THE DIFFERENT MUTATIONAL LANDSCAPES OF A PANEL GENES BY NEXT GENERATION SEQUENCING IN 967 CASES OF MDS AND AML
Authors: Y. Liu, L. Liao, S. Wang, C. Wang, T. Li, Y. Li, Y. Chang, Q. Hao, W. Wang, J. Ma, S. Chen, Z. Jiang
Journal: HemaSphere (2019)