tbuckley/cabot-search huggingface dataset:
Phase I and Preliminary Phase II Study of TRC105 in Combination with Sorafenib in Hepatocellular Carcinoma
Authors: Austin G. Duffy, Chi Ma, Susanna V. Ulahannan, Osama E. Rahma, Oxana Makarova-Rusher, Liang Cao, Yunkai Yu, David E. Kleiner, Jane Trepel, Min-Jung Lee, Yusuke Tomita, Seth M. Steinberg, Theo Heller, Baris Turkbey, Peter L. Choyke, Cody J. Peer, William D. Figg, Brad J. Wood, Tim F. Greten
Journal: Clinical Cancer Research (2017)

Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium.Experimental Design: Patients with HCC (Child-Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum.Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18-76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1-42.2], and 25% (95% CI, 8.7-49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2-5.6 months); median overall survival was 15.5 months (95% CI, 8.5-26.3 months).Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633-41. ©2017 AACR.
Paradoxical ulcerative colitis during adalimumab treatment of psoriasis resolved by switch to ustekinumab
Authors: A.G.A. Kolios, L. Biedermann, A. Weber, A.A. Navarini, J. Meier, A. Cozzio, L.E. French
Journal: British Journal of Dermatology (2017)

Here we report the case of a patient with psoriasis who developed ulcerative colitis most likely caused by adalimumab. After cessation of adalimumab, colitis improved significantly. However, as psoriasis worsened, the patient was switched to ustekinumab, which resulted in complete cessation of colitis. During the 2‐year follow‐up under ustekinumab therapy, no further gastrointestinal complaints occurred. Paradoxical psoriasis manifestations in inflammatory bowel disease (IBD) under tumour necrosis factor (TNF)‐inhibitor therapy have been reported and paradoxical IBD occurred rarely (mostly Crohn disease) in patients with rheumatological conditions treated with infliximab or etanercept. Due to the highly probable association of adalimumab with the onset of colitis in this case, we would like to suggest the term 'paradoxical ulcerative colitis' (PUC) for this as yet extremely rarely reported phenomenon. To the best of our knowledge this is the first description of PUC in a patient with psoriasis and in adalimumab treatment. Our observation suggests that ustekinumab is an effective treatment option in patients with paradoxical anti‐TNF‐driven inflammatory reactions like psoriasis or IBD.
Recreating a Human Hematopoietic Stem Cell Niche in Vitro by Unique Stroma Cells from the First Trimester Human Placenta and Fetal Liver
Authors: Mattias Magnusson, Melissa Romero, Sacha Prashad, Ben Van Handel, Suvi Aivio, Andy Huang, Matteo Pellegrini, Hanna Mikkola
Journal: Blood (2008)
Human Plasma Thioredoxin-80 Increases With Age and in ApoE <sup>−/−</sup> Mice Induces Inflammation, Angiogenesis, and Atherosclerosis
Authors: Dominique Couchie, Boris Vaisman, Amna Abderrazak, Dler Faieeq Darweesh Mahmood, Magda M. Hamza, Fanny Canesi, Vimala Diderot, Khadija El Hadri, Anne Nègre-Salvayre, Aurélie Le Page, Tamas Fulop, Alan T. Remaley, Mustapha Rouis
Journal: Circulation (2017)

Background: Thioredoxin (TRX)-1, a ubiquitous 12-kDa protein, exerts antioxidant and anti-inflammatory effects. In contrast, the truncated form, called TRX80, produced by macrophages induces upregulation of proinflammatory cytokines. TRX80 also promotes the differentiation of mouse peritoneal and human macrophages toward a proinflammatory M1 phenotype. Methods: TRX1 and TRX80 plasma levels were determined with a specific ELISA. A disintegrin and metalloproteinase domain-containing protein (ADAM)-10, ADAM-17, and ADAM-10 activities were measured with SensoLyte 520 ADAM10 Activity Assay Kit, Fluorimetric, and InnoZyme TACE Activity Kit, respectively. Western immunoblots were performed with specific antibodies to ADAM-10 or ADAM-17. Angiogenesis study was evaluated in vitro with human microvascular endothelial cells-1 and in vivo with the Matrigel plug angiogenesis assay in mice. The expression of macrophage phenotype markers was investigated with real-time polymerase chain reaction. Phosphorylation of Akt, mechanistic target of rapamycin, and 70S6K was determined with specific antibodies. The effect of TRX80 on NLRP3 inflammasome activity was evaluated by measuring the level of interleukin-1β and -18 in the supernatants of activated macrophages with ELISA. Hearts were used for lesion surface evaluation and immunohistochemical studies, and whole descending aorta were stained with Oil Red O. For transgenic mice generation, the human scavenger receptor (SR-A) promoter/enhancer was used to drive macrophage-specific expression of human TRX80 in mice. Results: In this study, we observed a significant increase of plasma levels of TRX80 in old subjects compared with healthy young subjects. In parallel, an increase in expression and activity of ADAM-10 and ADAM-17 in old peripheral blood mononuclear cells compared with those of young subjects was observed. Furthermore, TRX80 was found to colocalize with tumor necrosis factor-α, a macrophage M1 marker, in human atherosclerotic plaque. In addition, TRX80 induced the expression of murine M1 macrophage markers through Akt2/mechanistic target of rapamycin–C1/70S6K pathway and activated the inflammasome NLRP3, leading to the release of interleukin-1β and -18, potent atherogenic cytokines. Moreover, TRX80 exerts a powerful angiogenic effect in both in vitro and in vivo mouse studies. Finally, transgenic mice that overexpress human TRX80 specifically in macrophages of apoE −/− mice have a significant increase of aortic atherosclerotic lesions. Conclusions: TRX80 showed an age-dependent increase in human plasma. In mouse models, TRX80 was associated with a proinflammatory status and increased atherosclerosis.
Abstract 17537: Stably Expressed APEX2 Identifies the Integration of iPSC-derived Cardiomyocytes in a Mouse Model of Myocardial Infarction
Authors: Takeshi Hatani, Shunsuke Funakoshi, Thomas J Deerinck, Eric A Bushong, Takeshi Kimura, Shinya Yamanaka, Mark H Ellisman, Masahiko Hoshijima, Yoshinori Yoshida
Journal: Circulation (2015)

Background: Although studies have feasibility of in vivo cardiac transplantation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in animal experiments, nano-structural confirmation of the successful incorporation of the engrafted iPSC-CMs including electron microscopy (EM) has not been accomplished, partly because identification of graft cells in EM has proven to be difficult. However, with a new genetically encoded probe, the monomeric 28-kDa peroxidase reporter 2 (APEX2), which withstands strong EM fixation, this problem can now be done. We have now been able to test whether APEX2 can identify iPSC-CMs in host heart after long-term engrafting, and evaluate the engrafted iPSC-CMs in post-myocardial infarction using EM. Methods: We established human iPSC lines which stably expressed histone H2B-APEX2 (APEX2 iPSCs). After differentiating APEX2 iPSCs into CM in vitro, purified cells were transplanted into NOG mouse hearts with myocardial infarction by direct injections into the myocardium. One and 3 months after transplantation, we mapped engraft iPS-CMs using high resolution micro-CT and evaluated their ultrastructure by EM. Results: APEX2 was stably expressed and labeled histone H2B in iPSCs before and after in vitro differentiation into CM. Graft efficiency of APEX2 iPSC-CMs in NOG heart was excellent and APEX2 expression sustained over 3 months in vivo . APEX2 reaction observed in EM clearly identified engrafted APEX2 iPSC-CMs in niches surrounded by host CMs and their physical interaction was visualized. EM also revealed a progression in the maturation of sarcomeric structure and mitochondria in engrafted iPSC-CMs, by comparing data at 1 and 3 months after transplantation. Conclusion: We demonstrate that APEX2 is a versatile genetic reporter to trace cell fates in living animals over many months. Using APEX2-based staining, we were able to identify and characterize the maturation process of iPSC-CMs, and determine how they distribute within myocardial niches, as well as their interaction with host CMs. This method should be useful to many studies of stem cell-based cell replacement therapy, as it allows both tracking of cells and the ultrastructural characterization of engrafted cell and graft-host interactions.
A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry
Authors: Bente Glintborg, Inge Juul Sørensen, Anne Gitte Loft, Hanne Lindegaard, Asta Linauskas, Oliver Hendricks, Inger Marie Jensen Hansen, Dorte Vendelbo Jensen, Natalia Manilo, Jakob Espesen, Mette Klarlund, Jolanta Grydehøj, Sabine Sparre Dieperink, Salome Kristensen, Jimmi Sloth Olsen, Henrik Nordin, Stavros Chrysidis, Dorte Dalsgaard Pedersen, Michael Veedfald Sørensen, Lis Smedegaard Andersen, Kathrine Lederballe Grøn, Niels Steen Krogh, Lars Pedersen, Merete Lund Hetland
Journal: Annals of the Rheumatic Diseases (2017)

According to guidelines, a nationwide non-medical switch from originator (INX, Remicade) to biosimilar infliximab (Remsima, CT-P13) was conducted in Danish patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). We investigated disease activity before/after switching and retention rates in the DANBIO registry.Disease activities 3 months before and after switch and changes over time were calculated. Flare was defined as change in 28 Joint Disease Activity Score (∆DAS28) ≥1.2 (RA/PsA) or Ankylosing Spondylitis Disease Activity Score (∆ASDAS) ≥1.3 (AxSpA). Crude and adjusted retention rates were compared with a historic cohort of INX-treated patients.Eight hundred and two patients switched (403 RA/120 PsA/279 AxSpA; 51% women, age (median (IQR): 55 (44-66)) years). Follow-up was 413 (339-442) days. Prior INX treatment duration was 6.8 (4.3-9.5) years. Disease activities were similar 3 months before/after switch. Crude 1-year CT-P13 retention rate (84.1 (95% CI 81.3 to 86.5)) was similar to the historic IFX cohort (86.2 (95% CI 84.0 to 88.0), p=0.22). The adjusted absolute retention rates were 83.4 (95% CI 80.8 to 86.2) and 86.8% (95% CI 84.8 to 88.8), respectively (p=0.03). In total 132 patients withdrew (lack of effect: 71/132=54%, adverse events: 37/132=28%). Patients with previous INX treatment duration >5 years had longer CT-P13 retention.In 802 arthritis patients treated with INX for median >6 years, a nationwide non-medical switch to CT-P13 had no negative impact on disease activity. Adjusted 1-year CT-P13 retention rate was slightly lower than for INX in a historic cohort.
Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial
Authors: Jin Kyun Park, Min Ah Lee, Eun Young Lee, Yeong Wook Song, Yunhee Choi, Kevin L Winthrop, Eun Bong Lee
Journal: Annals of the Rheumatic Diseases (2017)

To investigate whether temporary discontinuation of methotrexate (MTX) improves the efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis (RA).In this prospective randomised parallel-group trial, patients with RA taking stable dose of MTX were randomly assigned at a ratio of 1:1:1:1 to continue MTX (group 1), suspend MTX for 4 weeks before vaccination (group 2), suspend MTX for 2 weeks before and 2 weeks after vaccination (group 3) or suspend MTX for 4 weeks after vaccination (group 4). All participants were vaccinated with trivalent influenza vaccine containing H1N1, H3N2 and B-Yamagata. The primary outcome was frequency of satisfactory vaccine response (≥4-fold titre increase 4 weeks postvaccination). Secondary endpoints included fold change in antibody titres from baseline.The per-protocol population consisted of 199 patients (n=54, 44, 49 and 52 in groups 1, 2, 3 and 4, respectively). Group 3 achieved higher satisfactory vaccine response against all three antigens than group 1 (51.0% vs 31.5%, p=0.044). The anti-H3N2 antibody fold increase (95% CI) was significantly higher in groups 3 and 4 (12.2 (8.4 to 17.5), p <0.001 and 10.0 (6.8 to 14.8), p=0.043, respectively) than group 1 (5.9 (4.3 to 8.1)). The anti-B-Yamagata antibody responses of groups 3 and 4 were higher (4.7 (3.3 to 6.7), p=0.048; 6.1 (4.2 to 8.8), p <0.001, respectively) than group 1 (2.9 (2.2 to 3.8)). RA flare occurred in 24.1%, 21.2%, 34.1% and 38.8% in groups 1, 2, 3 and 4, respectively (p=NS).Temporary MTX discontinuation improves the immunogenicity of seasonal influenza vaccination in patients with RA.Trial registration number is: www.clinicaltrials.gov, NCT02748785.
Endoscopic ultrasound-guided transjejunal rendezvous access to the common bile duct
Authors: Lea Fayad, Yen-I Chen, Yamile Chavez, Vivek Kumbhari, Mouen Khashab
Journal: Endoscopy (2017)

The patient was an 83-year-old man with a history of gastric cancer for which he underwent total gastrectomy with Roux-en-Y esophagojejunostomy. He presented with cholestasis, and imaging revealed evidence of choledocholithiasis.
Conditional approval of medicines by the EMA
Authors: Rita Banzi, Chiara Gerardi, Vittorio Bertele’, Silvio Garattini
Journal: BMJ (2017)

The process fails to improve the evidence after early licensing

Like other expedited procedures for early marketing authorisation, conditional approval12 stems from the assumption that immediate availability of new drugs offers patients a benefit that outweighs the risks of limited clinical information. To some extent, this assumption applies to all licensed drugs, but early approval magnifies the need for “managing the unknown.”34

Earlier this year, the European Medicines Agency reported its experience so far with conditional approval of new medicines.5 The report is an important step towards greater transparency and contributes useful data to help reflections on two important questions: what is the minimum evidence acceptable at the time of early approval, and do postmarketing commitments improve the evidence in a meaningful way?

In response to the first question, between 2006 and 2016 the EMA granted conditional approval to 30 medicines on the basis of 58 pivotal studies. The regulator reports that over half of these studies were preliminary phase II studies (30, including phases I/II and IIb); …
Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition
Authors: Kamaleldin E. Elagib, Chih-Huan Lu, Goar Mosoyan, Shadi Khalil, Ewelina Zasadzińska, Daniel R. Foltz, Peter Balogh, Alejandro A. Gru, Deborah A. Fuchs, Lisa M. Rimsza, Els Verhoeyen, Miriam Sansó, Robert P. Fisher, Camelia Iancu-Rubin, Adam N. Goldfarb
Journal: Journal of Clinical Investigation (2017)

Hematopoietic transitions that accompany fetal development, such as erythroid globin chain switching, play important roles in normal physiology and disease development. In the megakaryocyte lineage, human fetal progenitors do not execute the adult morphogenesis program of enlargement, polyploidization, and proplatelet formation. Although these defects decline with gestational stage, they remain sufficiently severe at birth to predispose newborns to thrombocytopenia. These defects may also contribute to inferior platelet recovery after cord blood stem cell transplantation and may underlie inefficient platelet production by megakaryocytes derived from pluripotent stem cells. In this study, comparison of neonatal versus adult human progenitors has identified a blockade in the specialized positive transcription elongation factor b (P-TEFb) activation mechanism that is known to drive adult megakaryocyte morphogenesis. This blockade resulted from neonatal-specific expression of an oncofetal RNA-binding protein, IGF2BP3, which prevented the destabilization of the nuclear RNA 7SK, a process normally associated with adult megakaryocytic P-TEFb activation. Knockdown of IGF2BP3 sufficed to confer both phenotypic and molecular features of adult-type cells on neonatal megakaryocytes. Pharmacologic inhibition of IGF2BP3 expression via bromodomain and extraterminal domain (BET) inhibition also elicited adult features in neonatal megakaryocytes. These results identify IGF2BP3 as a human ontogenic master switch that restricts megakaryocyte development by modulating a lineage-specific P-TEFb activation mechanism, revealing potential strategies toward enhancing platelet production.
State-specific influenza A (H1N1) 2009 monovalent vaccination coverage - United States, October 2009-January 2010.
Authors: P. J. Lu, H. Ding, G. L. Euler, C. Furlow, L. N. Bryan, B. Bardenheier, D. Yankey, E. Monsell, A. G. Gonzalez-Feliciano, C. LeBaron, J. A. Singleton, M. Town, L. Balluz
Journal: MMWR Morbidity and Mortality Weekly Report (2010)
Targeting HDAC3, a new partner protein of AKT in the reversal of chemoresistance in acute myeloid leukemia via DNA damage response
Authors: J Long, W Y Fang, L Chang, W H Gao, Y Shen, M Y Jia, Y X Zhang, Y Wang, H B Dou, W J Zhang, J Zhu, A B Liang, J M Li, Jiong Hu
Journal: Leukemia (2017)
Long-term change in reactance by forced oscillation technique correlates with FEV<sub>1</sub> decline in moderate COPD patients
Authors: Takefumi Akita, Toshihiro Shirai, Taisuke Akamatsu, Mika Saigusa, Akito Yamamoto, Yuichiro Shishido, Satoru Morita, Kazuhiro Asada
Journal: European Respiratory Journal (2017)

Since the landmark study of the natural history of chronic obstructive pulmonary disease (COPD) by Fletcher and Peto [1], lung function decline has been an issue of great concern and an important therapeutic target. The annual decline in forced expiratory volume in 1 s (FEV1) is generally used as a marker of disease progression. A review of large longitudinal studies found that the mean rate of FEV1 decline was highest at Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II (47–79 mL·year−1), indicating the need for treatment at earlier stages of the disease [2]. Respiratory system reactance changed over 5 years and the initial level predicted the rate of change in COPD patients <http://ow.ly/ONzz308E3aD>
QUANTITATIVE STUDIES ON THE MIXED LYMPHOCYTE INTERACTION IN RATS
Authors: Darcy B. Wilson, Willys K. Silvers, Peter C. Nowell
Journal: The Journal of Experimental Medicine (1967)

The influence of the immunologic status of the cell donors on the proliferative behavior of rat lymphocytes in the mixed lymphocyte interaction has been studied. Mixed cultures of cells from various parental and F(1) combinations having morphologically distinguishable sex chromosomes exhibited unidirectional proliferative reactivity. The mitotic figures were predominately of parental origin. Lymphocytes from donors made tolerant at birth to homologous transplantation isoantigens were specifically unreactive against cells bearing antigens of the tolerance inducing strain, but not to indifferent third party homologous lymphocytes. Cells from animals that had been surgically thymectomized at birth exhibited a markedly and sometimes totally diminished reactivity against homologous lymphocytes. Presensitization of the cell donors resulted in a curtailment of proliferative reactivity in cultures with cells bearing the immunizing antigens. This may reflect the destructive properties that lymphocytes from sensitized animals are known to possess. The results of these experiments show that the proliferative activity of lymphocytes in the mixed lymphocyte interaction accurately reflects the immunologic status of the cell donors, and these findings provide further support for the premise that the mixed lymphocyte interaction represents a primary immunologic response by cells in culture against homologous cells bearing histocompatibility antigens.