tbuckley/cabot-search huggingface dataset:
Duration of organ failure impacts mortality in acute pancreatitis
Authors: Na Shi, Tingting Liu, Daniel de la Iglesia-Garcia, Lihui Deng, Tao Jin, Lan Lan, Ping Zhu, Weiming Hu, Zongguang Zhou, Vikesh Singh, J Enrique Dominguez-Munoz, John Windsor, Wei Huang, Qing Xia, Robert Sutton
Journal: Gut (2019)

Figure 1 Pattern of mortality over time in patients with acute pancreatitis, showing the number of patients who died on a weekly basis for a total of 123 deceased out of 3084 patients.Table 1 Unadjusted and adjusted OR and 95% CI in multivariate analysis of risk for mortality Covariate Unadjusted OR (95% CI) P value Adjusted OR (95% CI) * P value POF alone versus POF with IPN 1.522 (0.883 to 2.623) 0.131 1.721 (0.909 to 3.257) 0.
Pretreatment metabolomic markers associated with therapeutic responses to FOLFOX with bevacizumab in chemotherapy-naive patients with colorectal cancer.
Authors: Yusuke Tanigawara, Shinji Sugimoto, Kei Muro
Journal: Journal of Clinical Oncology (2019)

540 Background: FOLFOX with bevacizumab (BV) is a standard treatment for metastatic colorectal cancer (mCRC); however, its clinical response is around 50% and there is no way to predict responders prior to therapy. In this study, we attempted to identify new biomarkers associated with positive therapeutic responses by means of a comprehensive metabolomic analysis of patient serum. Methods: Serum collected from 68 mCRC patients, who were registered in a phase II study of first-line FOLFOX with BV treatment (Nishina, JJCO 2013) was used to conduct a comprehensive metabolomic quantification analysis using a capillary electrophoresis time-of-flight mass spectrometry. Responders (Rs: n = 37) and non-responders (NRs: n = 31) were defined as those achieving a status of CR/PR and SD/PD, respectively, which were assessed by an extramural review board using RECIST. Statistical analyses were performed using a logistic regression model for treatment response and Cox proportional hazard analysis for overall survival (OS). Results: Among 470 annotated endogenous metabolites, cysteine-glutathione disulphide (CSG), gamma-glutamyl cysteine (gGC) and hypoxanthine (HPX) were identified as significant (p &lt; 0.05) metabolites associated with positive therapeutic responses by both response and survival analyses. Patients were divided into two groups according to cutoff values of pretreatment serum levels of these metabolites. The actual response rate in the high CSG, gGC and HPX group were 86, 69 and 8% whereas those in the low group were 40, 26 and 64%, respectively. The hazard ratio (HR) for OS in CSG, gGC and HPX were 0.28 (p &lt; 0.01), 0.37 (p &lt; 0.01) and 2.39 (p &lt; 0.05), respectively. Using CSG, gGC and HPX, we have developed a multivariate logistic regression model to predict Rs/NRs and survival benefit based on the three metabolite levels in pretreatment serum. Sensitivity, specificity, ROC AUC and HR of OS between Rs and NRs were 89%, 65%, 0.83 and 0.36 (p = 0.002), respectively. Conclusions: We identified three novel pretreatment serum metabolomic markers that are associated with treatment response to FOLFOX with BV in chemotherapy-naive mCRC patients. Clinical trial information: UMIN000001490.
Are cell-based therapies for kidney disease safe? A systematic review of preclinical evidence
Authors: Milos Mihajlovic, Kimberley E. Wever, Thom K. van der Made, Rob B.M. de Vries, Luuk B. Hilbrands, Rosalinde Masereeuw
Journal: Pharmacology & Therapeutics (2019)

The number of individuals affected by acute kidney injury (AKI) and chronic kidney disease (CKD) is constantly rising. In light of the limited availability of treatment options and their relative inefficacy, cell based therapeutic modalities have been studied. However, not many efforts are put into safety evaluation of such applications. The aim of this study was to review the existing published literature on adverse events reported in studies with genetically modified cells for treatment of kidney disease. A systematic review was conducted by searching PubMed and EMBASE for relevant articles published until June 2018. The search results were screened and relevant articles selected using pre-defined criteria, by two researchers independently. After initial screening of 6894 abstracts, a total number of 97 preclinical studies was finally included for full assessment. Of these, 61 (63%) presented an inappropriate study design for the evaluation of safety parameters. Only 4 studies (4%) had the optimal study design, while 32 (33%) showed sub-optimal study design with either direct or indirect evidence of adverse events. The high heterogeneity of studies included regarding cell type and number, genetic modification, administration route, and kidney disease model applied, combined with the consistent lack of appropriate control groups, makes a reliable safety evaluation of kidney cell-based therapies impossible. Only a limited number of relevant studies included looked into essential safety-related outcomes, such as inflammatory (48%), tumorigenic and teratogenic potential (12%), cell biodistribution (82%), microbiological safety with respect to microorganism contamination and latent viruses' reactivation (1%), as well as overall well-being and animal survival (19%). In conclusion, for benign cell-based therapies, well-designed pre-clinical studies, including all control groups required and good manufacturing processes securing safety, need to be done early in development. Preferably, this should be performed side by side with efficacy evaluation and according to the official guidelines of leading health organizations.
Elotuzumab Plus Pomalidomide/Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma: Japanese Subanalysis of the Randomized Phase 2 Eloquent-3 Study
Authors: Mitsuo Hori, Naoki Takezako, Kazutaka Sunami, Shigeki Ito, Junya Kuroda, Mihaela Popa-McKiver, Ying-Ming Jou, Suresh G. Shelat, Masafumi Miyoshi, Kenshi Suzuki
Journal: Blood (2018)
PerspectivesUnderstanding chronic respiratory diseasesAsthma and COPD: Basic Mechanisms and Clinical Management Second Edition, Peter Barnes, Jeffrey Drazen, Stephen Rennard, Neil Thomson (Eds.), Elsevier/Academic Press (2008), Pp 896. US$149·95 (£75·00)., ISBN: 0-12-374001-0
Authors: Klaus F Rabe
Journal: The Lancet (2008)
Insulin-like Growth Factor Binding Protein 7 Activates the Retinoid Acid Differentiation Pathway in Acute Myeloid Leukemia Cells
Authors: Noortje Van Gils, Han J.M.P. Verhagen, Arjo Rutten, Renee X. Menezes, Mei-Ling Tsui, Esmee Dekens, Fedor Denkers, E Vermue, Jeroen J. W. M. Janssen, Gert J. Ossenkoppele, Linda Smit
Journal: Blood (2018)
Longer Distance to a Specialized Treatment Center Does Not Adversely Affect Access to Treatment or Outcome in Acute Myeloid Leukemia: A National Population-Based Cohort Study
Authors: Michael Buch Tostesen, Jan M. Norgaard, Mette Nørgaard, Bruno C. Medeiros, Claus Werenberg Marcher, Ulrik Malthe Overgaard, Claudia Schöllkopf, Marianne Tang Severinsen, Lene Sofie Granfeldt Oestgaard
Journal: Blood (2018)
The safety assessment of robotic versus laparoscopic gastrectomy for gastric cancer using a propensity score matching method.
Authors: Rie Makuuchi, Tetsuro Toriumi, Yuhei Waki, Kenichi Nakamura, Satoshi Kamiya, Yutaka Tanizawa, Etsuro Bando, Masanori Terashima
Journal: Journal of Clinical Oncology (2019)

55 Background: We have previously reported the safety of robotic gastrectomy (RG) for clinical Stage IA or IB gastric cancer in single arm phase II studies. To date, a number of retrospective case control studies comparing RG and laparoscopic gastrectomy (LG) have been performed. However, since randomized controlled trials have never been conducted, no definitive conclusion demonstrating benefits of RG over LG has been demonstrated. In this study, we aimed to evaluate the safety of RG compared to LG using propensity score matching (PSM) methods. Methods: We retrospectively reviewed 766 consecutive patients who underwent either RG (n = 231) or LG (n = 535) for gastric cancer between January 2012 and December 2017. A 1:1 PSM was performed with the matched variables of age, sex, body mass index, performance status, clinical Stage, type of gastrectomy, and extent of lymphadenectomy. We compared short-term outcomes between the patients who underwent RG (RG group) and LG (LG group). Results: After PSM analysis, 231 patients were included in the RG group and 230 in the LG group. Intraoperative blood loss was similar between the groups. Operation time was significantly longer in the RG group (326 min vs. 281 min, P &lt; 0.001). Significantly more lymph nodes were retrieved in the RG group (42 vs. 38.5, P = 0.031). Serum CRP level were significantly lower in the RG group in postoperative day 3 (9.0 mg/dL vs. 9.8 mg/dL, P = 0.049) and 6 (3.1 mg/dL vs. 3.7 mg/dL, P = 0.034), and drain amylase level in postoperative day 3 was also significantly lower in the RG group (612 U/L vs. 856 U/L, P &lt; 0.001). Overall postoperative complication (Clavien–Dindo classification grade IIIA or greater) was similar between the groups (RG: 3.9% vs. LG: 5.6%, P = 0.656). However, pancreatic fistula tended to be less frequent in the RG group than in the LG group (0.4% vs. 2.2%, P = 0.122), although it did not reach statistically significant difference. Conclusions: Although RG takes longer operation time, it appears to be less invasive than LG with the possibility of decreased postoperative complications. To validate the results, randomized controlled trial should be performed.
Abstract 426: Laminin Downregulation Facilitates Cardiomyocyte Coupling <i>in situ</i> to Increase Contractile Function
Authors: Ayla Sessions, Gaurav Kaushik, Adam Engler
Journal: Circulation Research (2016)

Aging is associated with extensive remodeling of the heart, including basement membrane extracellular matrix (ECM) components that surround cardiomyocytes. Remodeling is thought to contribute to impaired cardiac mechanotransduction, but the contribution of specific basement membrane ECM components to age-related cardiac remodeling is unclear, owing to current model systems being complex and slow to age. To investigate the effect of basement membrane remodeling on mechanical function in genetically tractable, rapidly aging, and simple model organisms, we employed Drosophila melanogaster, which has a simple trilayered heart tube composed of only basement membrane ECM. We observed differential regulation of collagens between laboratory Drosophila strains , i.e. yellow-white ( yw ) and white-1118 ( w 1118 ), leading to changes in muscle physiology, which were linked to severity of dysfunction with age. Therefore, we sought to understand the extent to which basement membrane ECM modulates lateral cardiomyocyte coupling and contractile function during aging. Cardiac-restricted knockdown of ECM genes Pericardin , Laminin A , and Viking in Drosophila prevented age-associated heart tube restriction and increased contractility, even under viscous load. Most notably, reduction of Laminin A expression decreased levels of other genes that co-assemble in ECM, leading to overall preservation of contractile velocity and extension of median organismal lifespan by 3 weeks or 39%. These data provide new evidence of a direct link between basement membrane ECM homeostasis, contractility, and maintenance of lifespan.
Adct-301 (Camidanlumab Tesirine), a Novel Pyrrolobenzodiazepine-Based CD25-Targeting Antibody Drug Conjugate, in a Phase 1 Study of Relapsed/Refractory Non-Hodgkin Lymphoma Shows Activity in T-Cell Lymphoma
Authors: Graham P. Collins, Steven M. Horwitz, Andrew Davies, Anand Karnad, Felipe Samaniego, Alexander I Spira, Paul A Fields, Tobias Menne, Joseph Boni, Hans Cruz, Jay Feingold, Shui He, Jens Wuerthner, Mehdi Hamadani
Journal: Blood (2018)
20+ Years and Alive with Primary Myelofibrosis: Phenotypic Signature of Very Long-Lived Patients
Authors: Domenico Penna, Maura Nicolosi, Mythri Mudireddy, Natasha Szuber, Rangit Vallapureddy, Terra L. Lasho, Christy Finke, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani, Naseema Gangat, Ayalew Tefferi
Journal: Blood (2018)
Chemerin as a Biomarker Linking Inflammation and Cardiovascular Diseases
Authors: Fabian Eichelmann, Matthias B. Schulze, Clemens Wittenbecher, Juliane Menzel, Cornelia Weikert, Romina di Giuseppe, Ronald Biemann, Berend Isermann, Andreas Fritsche, Heiner Boeing, Krasimira Aleksandrova
Journal: Journal of the American College of Cardiology (2019)

Immune-inflammatory pathways have been increasingly implicated in the pathogenesis of atherosclerosis and associated cardiovascular outcomes [(1)][1]. Novel inflammatory biomarkers may help in better understanding these links. Chemerin is a recently discovered chemoattractant protein involved in the
PD-L1 Expression, Tumor Mutational Burden, and Cancer Gene Mutations Are Stronger Predictors of Benefit from Immune Checkpoint Blockade than HLA Class I Genotype in Non–Small Cell Lung Cancer
Authors: Marcelo V. Negrao, Vincent K. Lam, Alexandre Reuben, Maria Laura Rubin, Lara Lacerda Landry, Emily B. Roarty, Waree Rinsurongkawong, Jeff Lewis, Jack A. Roth, Stephen G. Swisher, Don L. Gibbons, Ignacio I. Wistuba, Vassiliki Papadimitrakopoulou, Bonnie S. Glisson, George R. Blumenschein, J. Jack Lee, John V. Heymach, Jianjun Zhang
Journal: Journal of Thoracic Oncology (2019)
Sunitinib in patients with pancreatic neuroendocrine tumors (panNETs): Exploratory pharmacogenomic analyses.
Authors: Nicola Fazio, Jean-Francois Martini, Adina-Emilia Croitoru, Michael Schenker, Sherry Li, Brad Rosbrook, Kathrine C. Fernandez, Jiri Tomasek, Espen Thiis-Evensen, Matthew H. Kulke, Eric Raymond
Journal: Journal of Clinical Oncology (2019)

255 Background: In a phase IV trial (NCT01525550), median progression-free survival (PFS) was 13.2 mo in sunitinib-treated patients (pts) with well-differentiated panNETs. Objective response rate (ORR) was 24.5% and median overall survival (OS) was 37.8 mo. Exploratory analyses evaluated potential associations between single nucleotide polymorphisms (SNP) in genes involved in angiogenesis, protein transport or inflammatory response and clinical outcomes. Methods: Blood samples were genotyped using TaqMan assays for 12 SNPs previously associated with panNET risk, prognosis or drug effect. Associations between SNP and PFS or OS were assessed by comparing genotypes within treatment-naïve (TN), previously treated (PT) and combined groups, and within a genotype between treatment groups, using Kaplan-Meier analysis and Cox proportional hazards models. Fisher’s exact test was used for association between ORR and genotype. PFS and ORR were investigator-assessed. P values displayed are unadjusted and Bonferroni method was used for multiplicity adjustment. Results: 56 pts were genotyped: 25 TN and 31 PT. There were no significant associations between genotype and PFS or OS but there was a trend toward shorter PFS in pts with VEGFR1 rs9554320 C/A versus C/C (hazard ratio [HR] 1.78; 95% confidence interval [CI] 0.83–3.82; p = 0.117) and VEGFR1 rs9582036 A/C versus A/A (HR 1.88; 95% CI 0.9–3.93; p = 0.102). The genotypes G/G of VEGFA rs2010963 (p = 0.041) , G/G of VEGFA rs833068 (p = 0.041) and A/C of VEGFR1 rs9582036 (p = 0.046) showed a trend toward a higher ORR in the PT versus TN group. Genotype T/T of VEGFR2 rs7692791 (p = 0.103) showed a trend toward to a lower ORR in the TN versus PT group. Higher ORR was associated with IL1B rs16944 G/A versus G/G (46.4% vs 4.5%; p = 0.001) in the combined group. Conclusions: Potential associations between ORR and VEGFA rs2010963 and rs833068, VEGFR1 rs9582036 and VEGFR2 rs7692791 were observed. IL1B rs16944 was significantly associated with ORR, consistent with the role of IL1B in panNET etiology and development. Most correlations were not significant after adjustment for multiplicity. Clinical trial information: NCT01525550.
Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas
Authors: Keisuke Kataoka, Hiroaki Miyoshi, Seiji Sakata, Akito Dobashi, Lucile Couronné, Yasunori Kogure, Yasuharu Sato, Kenji Nishida, Yuka Gion, Yuichi Shiraishi, Hiroko Tanaka, Kenichi Chiba, Yosaku Watatani, Nobuyuki Kakiuchi, Yusuke Shiozawa, Tetsuichi Yoshizato, Kenichi Yoshida, Hideki Makishima, Masashi Sanada, Masahiro Onozawa, Takanori Teshima, Yumiko Yoshiki, Tadao Ishida, Kenshi Suzuki, Kazuyuki Shimada, Akihiro Tomita, Motohiro Kato, Yasunori Ota, Koji Izutsu, Ayako Demachi-Okamura, Yoshiki Akatsuka, Satoru Miyano, Tadashi Yoshino, Philippe Gaulard, Olivier Hermine, Kengo Takeuchi, Koichi Ohshima, Seishi Ogawa
Journal: Leukemia (2019)

Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3'-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.
Abstract B81: SUMO and ubiquitin post-transcriptional modifications regulate the stability of the IRF2BP2 transcriptional cofactor
Authors: Renata Ramalho-Oliveira, Matheus Rajão, Vilenia Souza, João P. B. Viola
Journal: Clinical Cancer Research (2018)

Abstract IRF2BP2 (Interferon Regulatory Factor 2 Binding Protein 2) protein is a gene expression regulator, acting as transcriptional cofactor. IRF2BP2 acts in different cellular process including DNA damage repair, apoptosis, and immune response. Even though a few targets are known, there are several putative IRF2BP2-regulated genes. Novel evidence suggests that IRF2BP2 plays central functions in gene expression regulation. Recently, our group characterized the IRF2BP2 as an NFAT1 transcriptional repressor. To further understand the IRF2BP2 role in cellular functions, this work aims to clarify mechanisms involved in IRF2BP2 regulation. Initially, we performed a yeast two-hybrid screening to identify IRF2BP2-interacting proteins using IRF2BP2 as a bait. Among others, the UBE2I SUMO-conjugating enzyme and SUMO1 were identified as possible IRF2BP2 partners. Confocal microscopy demonstrated that these proteins colocalized in the nucleus. Furthermore, analysis by His-pull down and FRET confirmed the interaction between IRF2BP2 and UBE2I. Moreover, yeast two-hybrid assays showed that the interaction occurs independently of N-terminus C4-zinc finger of IRF2BP2. Subsequently, we observed that IRF2BP2 protein is SUMO1-modified in vivo. Our results indicated that three SUMO-1 molecules are added at three lysine residues. Finally, we demonstrated that the SUMO-modification favors disperse nuclear IRF2BP2 distribution and does not affect its repressor activity on NFAT1 transcription factor. Nevertheless, different assays showed that IRF2BP2 has a long half-life and that SUMO-1 conjugation increases IRF2BP2 protein stability. On the other hand, we showed that IRF2BP2 protein is also poliubiquitinated. Interestingly, the modifications observed were mainly Lys6- and Lys11-linked ubiquitin chains. Moreover, our data suggest that IRF2BP2 is not degraded by the proteasome and that Lys11-linked chain may constitute a signal for lysosome degradation. In conclusion, SUMO-modification upregulates IRF2BP2 protein stability. However, the consequences of Lys6 and Lys11 atypical ubiquitin chains linkage remain to be elucidated. Citation Format: Renata Ramalho-Oliveira, Matheus Rajão, Vilenia Souza, João P. B. Viola. SUMO and ubiquitin post-transcriptional modifications regulate the stability of the IRF2BP2 transcriptional cofactor [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B81.
Extensive Pigment Incontinence Mimicking Persistent Melanoma After Talimogene Laherparepvec Therapy
Authors: Melissa Danesh, Beverly Faulkner-Jones, Anupam Desai, Caroline C. Kim
Journal: JAMA Dermatology (2019)

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