tbuckley/cabot-search huggingface dataset:
Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: Updated results of a first-in-human (FIH) phase I dose escalation study.
Authors: Max S. Topp, Johannes Duell, Gerhard Zugmaier, Michel Attal, Philippe Moreau, Christian Langer, Jan Kroenke, Thierry Facon, Alexey Salnikov, Robin Lesley, Karl Beutner, James Kalabus, Erik Rasmussen, Kathrin Riemann, Alex C. Minella, Gerd Michael Munzert, Hermann Einsele
Journal: Journal of Clinical Oncology (2019)

8007 Background: Objectives of this study included assessing safety and activity of AMG 420/BI 836909, which binds BCMA (B-Cell Maturation Antigen) on MM cells and CD3 on T cells, in relapsed and/or refractory (R/R) MM. Methods: In this FIH study, 6-week cycles of AMG 420 were given for ≤5 cycles or until disease progression (PD), toxicity, or consent withdrawal; 5 more cycles could be given for benefit. Eligible patients had progression after ≥2 lines (incl PI and IMiD). Excluded were PC leukemia, extramedullary relapse, CNS involvement, or prior allo-SCT. MRD was defined as &lt;1 tumor cell / 10 4 bone marrow cells per flow cytometry. Results: As of Dec 10, 2018, 42 patients received AMG 420 (0.2-800 µg/d). Patients D/C for PD (n=24), adverse events (AE, n=7, incl 3 DLTs), death (4), completed 10 cycles (2), and consent (1). Median age was 65 y, median MM duration 5.2 y, and median # prior therapies 4. Patients were treated for a mean (SD) of 2.5 (2.6) cycles. There were 2 deaths from AEs (acute respiratory distress from flu / aspergillosis; fulminant hepatitis related to adenovirus infection); neither treatment related. Of those with serious AEs (SAEs, n=21, 50%), 18 required hospitalization. SAEs occurring in &gt;1 patient were infections (n=12) and polyneuropathy (PN, n=2). Treatment-related SAEs included 2 grade 3 PNs and 1 edema. Grade 2-3 CRS was seen in 3 patients. No anti-AMG 420 Ab were detected. In this study, 800 µg/d was determined to not be tolerable as 2/3 patients had DLTs, 1 case of grade 3 CRS and 1 case of grade 3 PN; both required hospitalization and subsequently resolved. At 400 µg/d, there were 5 minimal residual disease (MRD)-negative sCRs, 1 VGPR, and 1 PR, for a response rate of 7/10 (70%); at Dec datacut, responses lasted for 5.6-10.4 months with 4 patients ongoing on treatment. As of Feb 2019, some responses lasted &gt;1 year. Overall, there were 13/42 responders (6 sCRs, 3 CRs, 2 VGPRs, 2 PRs). Median time to any response was 1 month. Conclusions: In this FIH study of AMG 420, a BiTE vs BCMA, in R/R MM, there was a 70% response rate (7/10) with 5 out of 7 responders achieving a sCR at 400 µg/d, a recommended dose for further investigation. Clinical trial information: NCT02514239.
PS1596 AUTOIMMUNIZATION AND ALLOIMMUNIZATION IN TRANSFUSION DEPENDANT THALASSEMIA MAJOR PATIENTS:STUDY ON 300 PATIENTS
Authors: A. Younas, A. Ghias, S. Farhan
Journal: HemaSphere (2019)

Background: Thalassemia is the most common genetic disorder worldwide and one of the major public health problems. Thalassemia patients are dependent on blood transfusions for their survival but they may be associated with many complications. Development of anti red blood cell antibodies(bot alloantibodies and autoantibodies) is one of them. There is a paucity of data on the incidence of alloimmunization and autoimmunization in thalassemic patients in Pakistan,as pre transfusion antibody screening is not routinely performed. Autoantibodies can result in clinical hemolysis and difficulty in cross matching blood. We studied the frequency of Red cell alloimmunization and autoimmunization among Thalassemia patients who received regular transfusions at Sundas Foundation and also to determine types of these antibodies among Thalassemia patients. Aims: To study the frequency of Red Cell alloimmunization and autoimmunization among multiple transfused Thalassemia patients and to determine the types of these antibodies. Methods: A total of 300 multiple transfused Thalassemia patients were included in this study. Clinical and serological records of all the patients were examined. Screening and identification of antibodies was performed on fresh serum of all patients using 3 cell and 11 cell panel respectively. Detection of autoantibodies was done using using polyspecific Coombs(IgG+C3d) gel cards. Approval of this study was taken from the institutional review board. Informed consent was provided. Results: We identified alloantibodies in 17 patients,the most common were Anti E followed by Anti D,Anti C,Anti K,Anti Fyb,Anti‐M.4 patients developed autoantibodies. Summary/Conclusion: Alloimmunization is an immune respone stimulated by the transfusion of blood products. Overall rate of alloimmunization was 5.66% in our study while it is 30%/190 in Kuwait,4.97%/161 in India,5%/1435 in Italy,3.7%/1200 in Greece,5%/711 in Iran,9.2%/97 and 22.7%/75 in Pakistan.
PB2107 UPREGULATION OF PD-1 CHECKPOINT RECEPTOR MOLECULE ON BONE MARROW T-CELLS FROM PATIENTS WITH MULTIPLE MYELOMA, AND ITS POTENTIAL IMPACT ON CLINICAL OUTCOME
Authors: P. Perez-Montero, A. Paniagua, M. Prieto, L. Llorente, A. Serrano, M. Bengochea, G. Mendez, P. Marí Jimenez, S. Varea, E. Rodrigo, F. Lopez Rios, J. Perez De Oteyza
Journal: HemaSphere (2019)

Background: Multiple myeloma (MM) is associated with complex immune deregulation that includes loss of myeloma-reactive effector T-cell populations. PD-1 cell surface expression is a characteristic marker of T cell exhaustion. Therefore, the role of the PD-1/PD-L1 pathway in mediating immune escape in MM could have an influence in response to therapy. Although some investigators have analyzed the presence of PD1 in cell suspension samples from myeloma patients, little is known about their potential impact on clinical outcome. Aims: In the present study, we hypothesized that the presence of PD1+ T-cells in the bone marrow from patients with MM, could be related to the pattern of marrow infiltration and might have an impact on survival. Methods Bone marrow tissue samples from MM patients were obtained at initial diagnosis. Both PD1 expression on T cells, and CD138+ plasma cells were measured by immunohystochemical methods. Plasma cell infiltration pattern was considered diffuse when the percentage of CD138 + cells exceeded 40%. Correlation between number of PD1+ cells, and pattern of infiltration, or the presence of ostheolytic lesions, was evaluated by logistic regression. Kaplan-Meier estimates and Cox regression were used to analyze the impact of PD1 expression on, either progression free survival (PFS), or overall survival (OS). Results: Thirty-one MM patients, diagnosed and treated at a single institution, were included. Median age at diagnosis was 66y (38-89). 59.4% of the patients were on ISS-R clinical stage 2. Poor risk cytogenetic abnormalities were present in 14.3% of the cases. Median percentage of CD138+ plasma cells in the bone marrow was 45% (range 8-100), showing a diffuse pattern in 58.6% of the cases. Maximum PD-1+ T-cell count was highly variable, ranging from 0 to 42 cells per field, with a median of 8 c/f. PD-1+ cells were distributed heterogeneously, either in focal aggregates,or in a widespread fashion. There was no correlation between a diffuse CD138+ plasma cell infiltration pattern, and the number of PD-1+ cells (p = 0.216) There was also no correlation between PD1+ count and the presence of ostheolytic lesions. Kaplan-Meier estimates showed median PFS and OS of 42 and 90 months, respectively. The presence of a high PD1+ cell count (>10/field) showed no impact on PFS (Log-rank p = 0.75) or OS (log-rank p = 0.95) Summary/Conclusion: Taken together, our results showed upregulation of PD1 in bone marrow T-cells from MM patients. Nevertheless this finding had no apparent impact on clinical outcome, in terms of PFS or OS. Larger studies are needed.
Multiple rounds of one sample versus two sample faecal immunochemical test-based colorectal cancer screening: a population-based study
Authors: Eline H Schreuders, Esmée J Grobbee, Stella A V Nieuwenburg, Atija Kapidzic, Aafke H C van Roon, Anneke J van Vuuren, Iris Lansdorp-Vogelaar, Wolfert W J Spijker, Kirsten Izelaar, Marco J Bruno, Ernst J Kuipers, Manon C W Spaander
Journal: The Lancet. Gastroenterology & hepatology (2019)
Yogurt consumption and risk of conventional and serrated precursors of colorectal cancer
Authors: Xiaobin Zheng, Kana Wu, Mingyang Song, Shuji Ogino, Charles S Fuchs, Andrew T Chan, Edward L Giovannucci, Yin Cao, Xuehong Zhang
Journal: Gut (2019)

Davenport et al 1 underscored the urgent need to identify new modifiable factors for colorectal adenomas. A few studies2 3 reported that higher yogurt intake may reduce the risk of colorectal cancer (CRC), potentially mediated by the gut microbiome. However, no study has yet evaluated the association between yogurt intake and precursors of CRC.

We prospectively evaluated the association between yogurt intake and risk of conventional adenoma and serrated lesion, among 32 606 men in the Health Professionals Follow-up Study (HPFS) and 55 743 women in the Nurses’ Health Study (NHS), who have undergone lower endoscopy between 1986 and 2012. These participants provided detailed information on demographics, lifestyle and diet including yogurt consumption every 4 years. Multivariable logistic regressions were used to calculate ORs and 95% CIs associated with cumulative average of yogurt intake. We examined the associations by adenoma type (conventional adenomas only, serrated lesions only or both), malignant potential (for conventional adenomas: high-risk (≥1 cm or with villous component or high grade/severe dysplasia, or ≥3 adenomas) vs low risk; for serrated lesions: ≥1 vs <1 cm) and anatomical site (proximal, distal or rectum).

We documented 5811 adenomas in men and 8116 adenomas in women. In men, compared with individuals without yogurt consumption, men who consumed ≥2 servings/week had a lower risk of conventional adenoma (multivariable OR=0.81, 95% CI=0.71 to 0.94, ptrend=0.01; table 1). This inverse association was more pronounced for adenomas with high malignant potential …
Liver infiltrating T cells regulate bile acid metabolism in experimental cholangitis
Authors: Fabian Glaser, Clara John, Bastian Engel, Benedikt Höh, Sören Weidemann, Jan Dieckhoff, Stephanie Stein, Nathalie Becker, Christian Casar, Fenja Amrei Schuran, Björn Wieschendorf, Max Preti, Friederike Jessen, Andre Franke, Antonella Carambia, Ansgar W. Lohse, Harald Ittrich, Johannes Herkel, Joerg Heeren, Christoph Schramm, Dorothee Schwinge
Journal: Journal of Hepatology (2019)
Abstract 25: The Impact of Excess Body Weight on Cardiovascular Disease Mortality From 1990 to 2015 and Drivers of Change at the State-Level in the United States
Authors: Marissa B Reitsma, Ashkan Afshin
Journal: Circulation (2017)

Introduction: Maintaining a healthy weight is a key step toward ideal cardiovascular health and achieving AHA 2020 goals. State-level estimates of excess body weight and its impact on cardiovascular disease (CVD) mortality are necessary to inform interventions and track progress. Objective: To systematically quantify CVD deaths attributable to high body mass index (BMI) by age, sex, and state between 1990 and 2015. Methods: We synthesized 118 surveys (12,972,378 person-years) to characterize the population distribution of BMI by age, sex, and state from 1990-2015. We used a hierarchical mixed-effects linear regression to quantify and adjust for bias in self-reported height and weight data. Using the Global Burden of Disease analytic framework, we estimated CVD deaths attributable to high BMI in five-year increments from 1990 to 2015. We also quantified the contribution of changes in population structure, background mortality rate, and risk exposure to overall changes in CVD mortality. Results: In 2015, 173,180 (95% uncertainty interval: 130,890-218,620) CVD deaths were attributable to high BMI in the US: 70.4% from ischemic heart disease, 11.6% from hypertensive heart disease, 9.7% from hemorrhagic stroke and 8.2% from ischemic stroke. Mississippi had the highest attributable death rate (65.6 per 100,000 [51.6-80.3]), whereas Colorado had the lowest (23.4 [17.1-30.6]) (Figure). While the prevalence of excess body weight increased in all states from 1990-2015, reductions in background mortality rate offset increases in risk exposure (Figure). As a result, over the past 25 years the death rate attributable to high BMI increased in only 3 states (annual percent change: OK [0.53%], AL [0.17%], AK [0.08%]). The 3 states with the greatest annual decrease in attributable death rate were MN (-1.52%), NH (-1.47%), and MA (-1.45%). Conclusions: Our results highlight the need for implementation of evidence-based interventions at the state-level to reduce the prevalence and disease burden of high BMI in order to meet AHA 2020 goals.
Combined delivery of VEGF and IGF-1 promotes functional innervation in mice and improves muscle transplantation in rabbits
Authors: Theresa M. Raimondo, Hehuan Li, Brian J. Kwee, Sarah Kinsley, Erica Budina, Erin M. Anderson, Edward J. Doherty, Simon G. Talbot, David J. Mooney
Journal: Biomaterials (2019)
AB0661 ASSOCIATION OF ANTI-MDA-5 AUTOANTIBODY WITH AUTOIMMUNE ASSOCIATED HEMOPHAGOCYTIC SYNDROMEIN DERMATOMYOSITIS
Authors: Manabu Honda, Mayuko Moriyama, Masahiro Kondo, Shunichi Kumakura, Yoshiko Sumita, Yohko Murakawa
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Autoimmune associated hemophagocytic syndrome (AAHS) is a rare complication in dermatomyositis (DM). We previously demonstrated by multivariate analysis that one of factors associated with mortality in aAHS is DM (OR 5.57 [95% CI 1.08–28.65], P 0.05) among connective tissue diseases (1). <h3>Objectives</h3> To find out underlying immunological characteristics, we examined the DM patients with aAHS. <h3>Methods</h3> We examined 31 new onset patients with idiopathic inflammatory myopathies (IIM) including clinically amyopathic dermatomyositis (CADM) admitted to our hospital between January 2009 and December 2018. Three patients had been diagnosed as aAHS proven by bone marrow aspiration. We examined these patient clinical and laboratory characteristics. <h3>Results</h3> Two patients were diagnosed as DM and one was CADM. We found that these 3 patients were associated with interstitial pneumonia. Laboratory tests of all 3 patients showed hyperferritinemia and high titer of anti-MDA5 antibody. All patients were diagnosed as aAHS by bone marrow aspiration smears. Two of them died on the 12th and on the 75th hospital day, respectively, in spite of intensive therapies. <h3>Conclusion</h3> Anti-MDA5 may relate not only interstitial pneumonia but also aAHS. <h3>References</h3> [1] 1. Kumakura S and Murakawa Y: arthritis Rheum 2014;66:2297 <h3>Disclosure of interests</h3> Manabu Honda Speakers bureau: asahi Kasei Pharma, ono Pharm., Mayuko Moriyama: None declared, Masahiro Kondo Speakers bureau: Eisai Co., Chugai Pharma, Mitsubishi Tanabe Pharma, Bristol-Myers Squibb, Janssen Pharma, astellas Pharma, Takeda Pharma, NIPPON KAYAKU, Daiichi-Sankyo, asahi Kasei Pharma, abbVie Japan., Shunichi Kumakura: None declared, Yoshiko Sumita: None declared, Yohko Murakawa Grant/research support from: asahi Kasei Pharmaceutical Co., Ltd. Chugai Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd. Daiichi Sankyo Co., Ltd. Teijin Pharma Ltd. Eisai Co., Ltd. Nippon Kayaku Co., Ltd. Mitsubishi Tanabe Pharma Corporation, Paid instructor for: Kissei Pharmaceutical Co., Ltd. Janssen Pharmaceutical K.K. Eisai Co., Ltd., Speakers bureau: ono Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation Astellas Pharma inc. UCB Japan Co. Ltd. Chugai Pharmaceutical Co., Ltd. AbbVie GK Daiichi Sankyo Co., Ltd. AYUMI Pharmaceutical Corporation Janssen Pharmaceutical K.K. Takeda Pharmaceutical Company Limited Sanofi K.K. Teijin Pharma Ltd. Eli Lilly Japan K.K. Eisai Co., Ltd.
SAT0426 TOPHI, THE PREDICTIVE FACTOR OF ARTERIAL STIFFNESS IN PATIENTSWITH GOUT AND HYPERURICEMIA
Authors: WooSeong Jeong, Jinseok Kim, Joonhyouk Choi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Gout is the most common form of inflammatory arthritis and its prevalence is increasing in recent decades. Many studies have reported that gout and hyperuricemia are associated with an increase in all-cause mortality and cardiovascular mortality. Increased arterial stiffness is an independent marker of cardiovascular diseases and risk predictors. Many studies have shown a significant correlation between uric acid levels and arterial stiffness. Augmentation Index (AI) is an indirect measure of arterial stiffness. Tophi is formed when gout is left untreated for a long time. <h3>Objectives:</h3> The aim of this study is to determine whether the presence of tophi could predict an increase in arterial stiffness. <h3>Methods:</h3> Between June 2017 and June 2018, augmentation index was measured using SphygmoCor for patients who visited Jeju National University Hospital in South Korea with gout or hyperuricemia. Medical records, laboratory and AI data were retrospectively analyzed. <h3>Results:</h3> One hundred twenty two patients participated in the study and AI was measured. Most (96.7%) of the patients were male. At the time of the examination, 99 patients (81.1%) were treated with uric acid lowering agent and the mean duration of the disease was 6.9 years. When the patients were divided into two groups according to the presence or absence of Tophi, the average age (60.2±11.6 vs 53.4±13.2, p=0.023) of the patients with Tophi was significantly higher, duration of disease (13.0±6.5 vs 5.4±5.4, p=0.000) was longer and the AI (28.7±7.8 vs 20.7±10.4, p=0.001) was higher. When multiple linear regression analysis was performed to exclude the effects of other variables (DM, HTN, hyperlipidemia, age, BMI, total cholesterol, creatinine), tophi was a predictor of high AI (b = 5.478; 95% CI, 0.343-10.613; p=0.037). Multiple logistic regression analysis was performed to determine the predictors of tophi. The duration of disease and AI @ 75 values were significantly predictive of the presence of tophi (Odds ratio 1.113; 95% CI, 1.024-1.209; p=0.012) <h3>Conclusion:</h3> This study suggests that the presence of tophi is an independent predictor of increased arterial stiffness in patients with gout and hyperuricemia. <h3>References</h3> [1] Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med2005;143:499-516. [2] Kuo C-F, Grainge MJ, Zhang W, Doherty M. Global epidemiology of gout: prevalence, incidence and risk factors. Nature Reviews Rheumatology2015;11:649. [3] Mehta T, Nuccio E, McFann K, Madero M, Sarnak MJ, Jalal D. Association of Uric Acid With Vascular Stiffness in the Framingham Heart Study. Am J Hypertens2015;28:877-83. <h3>Disclosure of Interests:</h3> None declared
Mortality Due to Aortic Stenosis in the United States, 2008-2017
Authors: Graham H. Bevan, David A. Zidar, Richard A. Josephson, Sadeer G. Al-Kindi
Journal: JAMA (2019)

This study uses US National Center for Health Statistics data to describe trends in mortality due to aortic stenosis between 2008 and 2017, when use of transcatheter aortic valve replacement (TAVR) in older adults was becoming more common.
Spliced X-box Binding Protein 1 Stimulates Adaptive Growth Through Activation of mTOR
Authors: Xiaoding Wang, Yingfeng Deng, Guangyu Zhang, Chao Li, Guanqiao Ding, Herman I. May, Diem H. Tran, Xiang Luo, Ding-Sheng Jiang, Dan L. Li, Xiang Wei, Lin Xu, Anwarul Ferdous, Thomas G. Gillette, Philipp E. Scherer, Xuejun Jiang, Zhao V. Wang
Journal: Circulation (2019)

Background: The unfolded protein response plays versatile roles in physiology and pathophysiology. Its connection to cell growth, however, remains elusive. Here, we sought to define the role of unfolded protein response in the regulation of cardiomyocyte growth in the heart. Methods: We used both gain- and loss-of-function approaches to genetically manipulate XBP1s (spliced X-box binding protein 1), the most conserved signaling branch of the unfolded protein response, in the heart. In addition, primary cardiomyocyte culture was used to address the role of XBP1s in cell growth in a cell-autonomous manner. Results: We found that XBP1s expression is reduced in both human and rodent cardiac tissues under heart failure. Furthermore, deficiency of XBP1s leads to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac-restricted overexpression of XBP1s prevents the development of cardiac dysfunction. Mechanistically, we found that XBP1s stimulates adaptive cardiac growth through activation of the mechanistic target of rapamycin signaling, which is mediated via FKBP11 (FK506-binding protein 11), a novel transcriptional target of XBP1s. Moreover, silencing of FKBP11 significantly diminishes XBP1s-induced mechanistic target of rapamycin activation and adaptive cell growth. Conclusions: Our results reveal a critical role of the XBP1s–FKBP11–mechanistic target of rapamycin axis in coupling of the unfolded protein response and cardiac cell growth regulation.
Application of Low Tube Potentials in CCTA
Authors: Thomas J. Stocker, Jonathon Leipsic, Martin Hadamitzky, Marcus Y. Chen, Ronen Rubinshtein, Simon Deseive, Mathias Heckner, Jeroen J. Bax, Kakuya Kitagawa, Hugo Marques, Axel Schmermund, Claudio Silva, John Mahmarian, Joon-Won Kang, Erik L. Grove, John Lesser, Steffen Massberg, Jörg Hausleiter
Journal: JACC. Cardiovascular imaging (2019)
RIP3 promotes colitis-associated colorectal cancer by controlling tumor cell proliferation and CXCL1-induced immune suppression
Authors: Zhen-Yu Liu, Ming Zheng, Yi-Ming Li, Xin-Yu Fan, Jian-Chao Wang, Zhu-Chun Li, Hai-Jiao Yang, Jing-Min Yu, Jian Cui, Jian-Li Jiang, Juan Tang, Zhi-Nan Chen
Journal: Theranostics (2019)

Rationale:Necroptosis is a programmed form of non-apoptotic cell death that requires receptor-interacting protein 3 (RIP3).RIP3 has been shown to be relevant in multiple tumor types and has differential impact on tumor progression.We investigated whether RIP3 is involved in the progression of colitis-associated cancer (CAC) in mice.Methods: Tissues from colorectal cancer patients were examined for RIP3 expression.CAC was induced using azoxymethane (AOM) injection followed by dextran sodium sulfate (DSS) treatment in RIP3-deficient or wild-type mice.Colon tissues were collected and analyzed by Western blotting and gene expression profile analyses.Immune cell infiltration and CXCL1 expression were examined by flow cytometry and Real-time PCR, respectively.Results: RIP3 expression was upregulated in mouse CAC and human colon cancer.RIP3-deficient mice showed significantly attenuated colitis-associated tumorigenesis.Bone marrow transplantation experiments suggested that RIP3's function in hematopoietic cells primarily contributes to the phenotype.RIP3 supported epithelial proliferation and tumor growth via JNK signaling but had no effect on apoptosis.RIP3 deletion increased T cell accumulation and reduced infiltration by immunosuppressive subsets of myeloid cells during acute colitis and CAC.The immune-suppressive tumor microenvironment was dependent on RIP3-induced expression of the chemokine attractant CXCL1, and administration of recombinant CXCL1 during CAC restored tumorigenesis in Rip3 -/-mice.Conclusion: Our results reveal an unexpected function of RIP3 in enhancing the proliferation of premalignant intestinal epithelial cells (IECs) and promoting myeloid cell-induced adaptive immune suppression.These two distinct mechanisms of RIP3-induced JNK and CXCL1 signalling contribute to CAC progression.