tbuckley/cabot-search huggingface dataset:
Two Phase 3 Trials of Adalimumab for Hidradenitis Suppurativa
Authors: Alexa B. Kimball, Martin M. Okun, David A. Williams, Alice B. Gottlieb, Kim A. Papp, Christos C. Zouboulis, April W. Armstrong, Francisco Kerdel, Michael H. Gold, Seth B. Forman, Neil J. Korman, Evangelos J. Giamarellos-Bourboulis, Jeffrey J. Crowley, Charles Lynde, Ziad Reguiai, Errol-Prospero Prens, Eihab Alwawi, Nael M. Mostafa, Brett Pinsky, Murali Sundaram, Yihua Gu, Dawn M. Carlson, Gregor B.E. Jemec
Journal: New England Journal of Medicine (2016)

Hidradenitis suppurativa is a painful, chronic inflammatory skin disease with few options for effective treatment. In a phase 2 trial, adalimumab, an antibody against tumor necrosis factor α, showed efficacy against hidradenitis suppurativa.PIONEER I and II were similarly designed, phase 3 multicenter trials of adalimumab for hidradenitis suppurativa, with two double-blind, placebo-controlled periods. In period 1, patients were randomly assigned in a 1:1 ratio to 40 mg of adalimumab weekly or matching placebo for 12 weeks. In period 2, patients were reassigned to adalimumab at a weekly or every-other-week dose or to placebo for 24 weeks. The primary end point was a clinical response, defined as at least a 50% reduction from baseline in the abscess and inflammatory-nodule count, with no increase in abscess or draining-fistula counts, at week 12.We enrolled 307 patients in PIONEER I and 326 in PIONEER II. Clinical response rates at week 12 were significantly higher for the groups receiving adalimumab weekly than for the placebo groups: 41.8% versus 26.0% in PIONEER I (P=0.003) and 58.9% versus 27.6% in PIONEER II (P<0.001). Patients receiving adalimumab had significantly greater improvement than the placebo groups in rank-ordered secondary outcomes (lesions, pain, and the modified Sartorius score for disease severity) at week 12 in PIONEER II only. Serious adverse events in period 1 (excluding worsening of underlying disease) occurred in 1.3% of patients receiving adalimumab and 1.3% of those receiving placebo in PIONEER I and in 1.8% and 3.7% of patients, respectively, in PIONEER II. In period 2, the rates of serious adverse events were 4.6% or less in all the groups in both studies, with no significant between-group differences.Treatment with adalimumab (40 mg weekly), as compared with placebo, resulted in significantly higher clinical response rates in both trials at 12 weeks; rates of serious adverse events were similar in the study groups. (Funded by AbbVie; ClinicalTrials.gov numbers, NCT01468207 and NCT01468233 for PIONEER I and PIONEER II, respectively.).
Abstract 2617: SUMOylation inhibition attenuates the cancer stem cell population in glioblastoma and basal breast cancer
Authors: Jung M. Park, Tong Wu, Sarah Van Dorin, Ronald Weigel
Journal: Cancer Research (2015)

Abstract INTRO: TFAP2A and mouse homolog Tcfap2a are transcription factors that play a critical role in development and cancer. We have recently shown that SUMOylation of TFAP2A is a key posttranslational modification that maintains the basal breast cancer phenotype. Treatment with anacardic acid (AA), a SUMOylation inhibitor, led to depletion of the CD44+/hi/CD24-/lo cancer stem cell population. Interestingly, glioblastoma has also been shown to express TFAP2A and demonstrates an expanded cancer stem cell population. METHODS: Mouse 4T1 basal mammary cancer, IOWA-1T human basal breast cancer and UG118 glioblastoma cell lines were analyzed. MTT was used to measure cell viability. Coulter Counter and hemocytometer were used for cell quantification. Matrigel invasion and western blot were used to further characterize the cell lines. RESULTS: Treatment of 4T1 and UG118 cells with AA in vitro resulted in a 67% and 65% decrease in cell viability by MTT assay, respectively (p &amp;lt; 0.05 for both). Quantification of cell number confirmed that AA treatment inhibited cell proliferation. At 48 hours, 4T1 cells demonstrated a decrease of 73-77% (p &amp;lt; 0.01), and UG 118 cells decreased by 97 to 98% (p &amp;lt; 0.001). Cell invasiveness assessed by Matrigel invasion assay was attenuated in 4T1 and UG118 cells after treatment (84%, p &amp;lt; 0.01 and 28%, p &amp;lt; 0.05, respectively). Western blot demonstrated a dose-dependent decrease in expression of the cancer stem cell marker CD44 or the mouse homolog CD49f following AA treatment of UG118 and 4T1 cells, respectively. Western blot confirmed that while total TFAP2A levels were unchanged, SUMO conjugated TFAP2A was decreased after AA treatment of 4T1 cells. To further establish relevance to human cancer, an aggressive chemotherapeutic resistant patient-derived xenograft, IOWA-1T, similarly demonstrated a 41% drop (p &amp;lt; 0.007) in cell invasiveness and a concomitant decrease in SUMOylated TFAP2A with AA treatment. CONCLUSION: Inhibition of the SUMO pathway attenuates the cancer stem cell population in basal breast cancer and glioblastoma. While further investigation is needed, SUMOylation may be a common biological posttranslational modification that defines cancer stem cells. Furthermore, basal breast cancer, brain cancer, and other cancers that express TFAP2A may be amenable to SUMOylation inhibitors such as AA. Citation Format: Jung M. Park, Tong Wu, Sarah Van Dorin, Ronald Weigel. SUMOylation inhibition attenuates the cancer stem cell population in glioblastoma and basal breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2617. doi:10.1158/1538-7445.AM2015-2617
Associations of TNF-alpha gene polymorphisms and mastocytosis. A study of the European competence network in mastocytosis (ECNM)
Authors: B. Nedoszytko, M. Niedoszytko, M. Lange, J. van Doormaal, J. Glen, M. Zabotna, J. Renke, J. Varkonyi, E. Jassem, J. Roszkiewicz, B. Hidvegi, P. Valent
Journal: Allergy (2008)
Defective natural killer cell activity in a mouse model of eczema herpeticum
Authors: Yuko Kawakami, Tomoaki Ando, Jong-Rok Lee, Gisen Kim, Yu Kawakami, Tae Nakasaki, Manando Nakasaki, Kenji Matsumoto, Youn Soo Choi, Toshiaki Kawakami
Journal: Journal of Allergy and Clinical Immunology (2016)
Abstract 4551: Regulation of replicative stress by deacetylation and dephosphorylation
Authors: Anja Göder, Claudia Schäfer, Teodora Nikolova, Günter Schneider, Oliver H. Krämer
Journal: Cancer Research (2016)

Abstract Over 3 billion base pairs of a mammalian cell have to be replicated with every cell division. Limitations in the supply of nucleotides and DNA lesions slow down replication fork speed and trigger a complex replicative stress response to prevent genomic instability and cancer development. The checkpoint kinases ataxia telangiectasia mutated (ATM), ATM and Rad3-related (ATR), checkpoint kinase-1 (CHK1), and checkpoint kinase-2 (CHK2) are at the heart of this response. These factors catalyze processes that slow down the cell cycle as well as mechanisms that stabilize the replication fork and processes that initiate DNA repair. Such pathways ensure the faithful transmission of DNA without epigenetic alterations and DNA mutations. As expected for such a pivotal mechanism, checkpoint kinase signaling is highly regulated. Posttranslational modifications including phosphorylation and acetylation regulate checkpoint kinases at multiple levels. Recent data show that class I histone deacetylases (HDACs) can affect checkpoint kinase signaling and genomic stability. How these HDACs control checkpoint kinases exactly and if they show specificity for certain checkpoint kinases and DNA repair pathways has not been resolved. Moreover, although it is known that phosphorylation triggers checkpoint kinase activation and that the trimeric phosphatase PP2A attenuates checkpoint kinase phosphorylation it is unknown how this activity of PP2A is modulated. PP2A consists of the subunits A (structural component, PPP2R1A/B), C (catalytic activity, PPP2CA/B), and B (discriminates between substrates to allow specificity of the PP2A holoenzyme). Our data illustrate that class I HDACs are required for checkpoint kinase phosphorylation in human and murine cells. We show that these enzymes suppress the expression of certain PP2A subunits and we reveal that one of the B type subunits specifically targets checkpoint kinases for dephosphorylation by the PP2A holoenzyme. With genetic and biochemical approaches, including RNAi, CRISPR-Cas9, DNA fiber assays, confocal microscopy, and DNA and protein analyses, we demonstrate how these mechanisms maintain S phase arrest and the survival of cells undergoing replicative stress. Citation Format: Anja Göder, Claudia Schäfer, Teodora Nikolova, Günter Schneider, Oliver H. Krämer. Regulation of replicative stress by deacetylation and dephosphorylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4551.
Laparoscopic versus open repair for perforated peptic ulcer: A meta analysis of randomized controlled trials
Authors: Shanjun Tan, Guohao Wu, Qiulin Zhuang, Qiulei Xi, Qingyang Meng, Yi Jiang, Yusong Han, Chao Yu, Zhen Yu, Ning Li
Journal: International Journal of Surgery (2016)
Abstract 1120: Differential expression of human cytomegalovirus microRNA in triple-negative breast cancer tumors
Authors: Tia Hudson, Scott Harrison, Dukka K C, Jan Prins, Perpetua M. Muganda
Journal: Cancer Research (2016)

Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of the breast cancer cases. These tumors are heterogeneous and aggressive, fail to respond to targeted therapy, have poor prognosis, and a high risk of relapse. The molecular basis of this breast cancer subtype is currently unknown. Viruses, such as human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human papillomavirus (HPV), are major suspects in the etiology of breast cancer. Since miRNAs have been implicated in the pathogenesis of breast cancer, including triple-negative breast cancer, we hypothesized that viral miRNAs may play a role in this aggressive disease. The objective of this project, therefore, was to determine the identity, prevalence, sequence variation, and differential expression of viral miRNAs in TNBC tumors as compared to control samples. We conducted a comprehensive profiling of viral miRNAs in 48 TNBC tumors as compared to 15 control normal breast tissues, utilizing deep sequencing analysis software and publically available deep sequencing data. Five novel putative HCMV miRNAs were found to be differentially expressed in TNBC tumors as compared to controls. Two of the putative miRNAs were differentially expressed in 60-79% of the TNBC tumors as compared to 0% of normal controls. Two additional putative miRNAs were expressed in 67-88% of TNBC tumors as compared to 25-31% of normal controls. One putative miRNA was expressed in 67% of TNBC tumors as compared to 88% of normal samples, while 1 putative miRNA in addition to HCMV-US25-1-3p displayed no significant differences. These putative HCMV miRNAs localize within genomic regions of HCMV that encode UL56 DNA packaging terminase subunit 2, single-stranded DNA-binding protein, noncoding RNA4.9, and enveloped glycoprotein M. Ongoing work has so far computationally validated one of these miRNAs as a novel HCMV miRNA. This is the first report on the differential expression of HCMV miRNAs in TNBC tumors. Since TNBC tumors are extremely heterogeneous, it is intriguing that 60-80% of TNBC tumors specifically express the same HCMV miRNA. Our findings suggest that these differentially expressed HCMV miRNAs may potentially play a role in the pathogenesis of TNBC. Citation Format: Tia Hudson, Scott Harrison, Dukka K C, Jan Prins, Perpetua M. Muganda. Differential expression of human cytomegalovirus microRNA in triple-negative breast cancer tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1120.
Abstract 3633: OncoGxOneTM - an advanced genomic test for precision cancer treatment
Authors: Yang Han, Pengfei Yu, Qingxuan Song, Min Wei, Guanghui Hu
Journal: Cancer Research (2016)

Abstract The fundamental cause of cancer is the aberration of genes that control cell proliferation and apoptosis. With the rapid advancement of genomic technologies and increased arsenal of targeted therapies, genomic profiling has been largely accepted by physicians to assist cancer diagnosis and treatment. Developed by Admera Health, OncoGxOneTM is a CLIA certified and CAP accredited genomic profiling panel detecting all actionable mutations in 64 cancer genes. All the FDA approved targeted therapies and registered clinical trials are covered by this carefully designed panel. Utilizing cutting edge Next Generation Sequencing technology combined with accurate analysis and data interpretation, OncoGxOneTM detects all 4 types of genomic alterations including single nucleotide mutation, insertion/deletion, copy number variation and gene rearrangement. Using fresh frozen tissue or routine FFPE samples, OncoGxOne TM offers both high sensitivity and specificity greater than 99% from samples with as low as 10% tumor cell content. Citation Format: Yang Han, Pengfei Yu, Qingxuan Song, Min Wei, Guanghui Hu. OncoGxOneTM - an advanced genomic test for precision cancer treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3633.
Thermal vapour ablation to reduce segmental volume in patients with severe emphysema: STEP-UP 12 month results
Authors: Pallav L Shah, Daniela Gompelmann, Arschang Valipour, William H McNulty, Ralf Eberhardt, Christian Grah, Jim Egan, Joachim H Ficker, Manfred Wagner, Christian Witt, Uta Liebers, Peter Hopkins, Wolfgang Gesierich, Martin Phillips, Franz Stanzel, Christoph Petermann, Charles Strange, Greg Snell, Felix J F Herth
Journal: The Lancet Respiratory Medicine (2016)
Therapeutic Strategies in Patients with Atypical CML (aCML) and Unclassified MDS/MPN (MDS/MPN-U). a Single Center Report
Authors: Thorsten Braun, Aziza Debache, Hervé Roudot, Daniel Lusina, Sylvain Thépot, Virginie Eclache, Antoine Martin, Juliette Soret, Stephanie Harel, Sabine Bréchignac, Charikleia Kelaidi, Lionel Adès, Pierre Fenaux, Claude Gardin
Journal: Blood (2014)
Abstract 666: Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer
Authors: Kevin P. O’Rourke, Lukas E. Dow, Scott W. Lowe
Journal: Cancer Research (2016)

Abstract Colorectal cancer (CRC) accounts for almost 10% of all cancer mortality in the United States. The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. Using a novel mouse model in which Apc can be conditionally suppressed using a doxycycline-regulated shRNA, we previously showed that Apc suppression in adenomas and carcinomas drives rapid and widespread tumor-cell differentiation and sustained regression without relapse. However, this study was unable to explore Apc action in metastasis, which is the most common cause of death in CRC patients, since models do not live long enough for metastatic dissemination to occur. To produce a system that would enable further disease progression, we generated a comprehensive panel of colon organoid cultures that reflect iterative combinations of the 3 most common genetic lesions in human CRC: Apc-mut, Apc-mut;KrasG12D, Apc-mut;p53-mut and Apc-mut;KrasG12D;p53-mut. These cultures can be transplanted orthotopically into the colon of recipient mice or seeded in the circulation to assess primary tumor behavior and metastatic dissemination. We show that Apc silencing in organoid culture results in the dysregulated proliferation of stem and progenitor cells but this is reversible upon Apc restoration or pharmacologic inhibition of the Wnt pathway. When engrafted into the colon of recipient mice, these cells create ∼1-3 focal colon tumors that can be tracked using colonoscopy, ultrasound and bioluminescence imaging, and are largely indistinguishable from tumors that develop in transgenic models. Most importantly, triple mutant (Apc/Kras/p53) organoids form invasive adenocarcinoma and colonize the lung following tail vein injection, providing a setting to dissect the importance of Wnt pathway activity in various stages of disease progression. Ultimately, the ability to study cellular and molecular phenotypes in vitro, and assess tumor development in vivo, provides a flexible system to explore the genetic factors underlying CRC progression and metastasis, and overcomes many of the previous technical challenges of modelling advanced CRC. Citation Format: Kevin P. O’Rourke, Lukas E. Dow, Scott W. Lowe. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 666.
Abstract 231: Uncovering the Mechanism and Function of Newly Discovered KCNQ1-Transporter Complexes
Authors: Daniel L Neverisky, Geoffrey W Abbott
Journal: Circulation Research (2014)

The KCNQ1 voltage-gated potassium channel is essential for human ventricular repolarization, permitting potassium efflux from excited cardiomyocytes to end each action potential and repolarize the heart. In cardiomyocytes, KCNQ1 is modulated by interaction with beta-subunits from the KCNE gene family, each of which significantly alters KCNQ1 channel function. KCNQ1 mutations are the most common identified genetic basis for Long QT syndrome (LQTS) and are also associated with lone atrial fibrillation (AF). The sodium-dependent myo-inositol transporter 1 (SMIT1) mediates cellular uptake of myo-inositol, an essential osmolyte that also represents an important substrate for phosphatidylinositol signaling pathways that regulate a plethora of ion channels including those essential for human cardiac function. We recently discovered that KCNQ1 can form heteromeric, co-regulatory complexes with Na+-coupled solute transporters including SMIT1, SMIT2 and glucose transporter SGLT1. These findings represent the first reported example of formation of an ion channel-solute transporter complex. Having discovered KCNQ1-SMIT1 complexes in mouse choroid plexus epithelium, we are currently investigating whether these types of complexes occur in the heart, how their function is altered by the various cardiac-expressed KCNE regulatory subunits or by arrhythmia-associated mutations, and which parts of KCNQ1 coordinate complex formation. Here, we present evidence of KCNQ1-SMIT1 co-assembly in pig heart based on co-immunoprecipitation experiments. Using KCNQ1-KCNQ4 chimeras we also begin to define which specific regions of KCNQ1 are required for complex formation with SMIT1. Finally, we present data showing the effects of SMIT1 on complexes formed by KCNQ1 and KCNE1, 2 and 3. KCNQ1-transporter complexes provide a potential hub for electrochemical crosstalk in normal cardiac function and in arrhythmogenesis.
Abstract 316: FTY720 enhances the efficacy of paclitaxel and of carboplatin in drug-resistant ovarian cancer cells
Authors: Kelly M. Kreitzburg, Ronald D. Alvarez, Charles N. Landen, Karina J. Yoon
Journal: Cancer Research (2016)

Abstract Objectives: Our long-term goal is to develop effective therapies for ovarian cancer by targeting molecules that contribute to drug resistance in this tumor type. Preliminary RNA-seq data were generated using a patient-derived xenograft model. These data identified the sphingosine-1-phosphate (S1P) signaling pathway as one of the pathways most affected by carboplatin and paclitaxel, the current standards of care for ovarian cancer. We then examined whether a synthetic analog of sphingosine, FTY720, enhanced the cytotoxicity of platinum and taxane resistant ovarian cancer cell lines. Methods: To assess the efficacy of FTY720 + carboplatin and of FTY720 + paclitaxel, we exposed three pairs of parental and drug resistant human ovarian cancer cell lines to each combination. The cell lines used were: SKOV3-ip1 and SKOV3-TR (taxane resistant), A2780 and A2780-CP20 (platinum resistant), and HeyA8 and HeyA8-MDR (taxane-platinum resistant). We used alamarBlue cell proliferation assays to determine the efficacy of FTY720 as a single agent or in combination with paclitaxel or carboplatin, and immunoblots to assess the expression of proteins involved in the S1P pathway. Results: FTY720 as a single agent decreased cell viability in a dose-dependent manner in all three pairs of cell lines, with IC50 values ranging from 5 to 8 μM. When cells were exposed to the IC50 of FTY720 + a range of concentrations of carboplatin or paclitaxel, FTY720 had little effect in any of the three parental cell lines and in SKOV3-TR cells. Interestingly, however, FTY720 decreased the IC50 of carboplatin 15- to 16-fold and the IC50 of paclitaxel 20- to 90- fold in A2780-CP20 and HeyA8-MDR cells, respectively. We also observed that FTY720 altered the expression of sphingosine kinase2, S1P lyase, and acid ceramidase, each of which contributes to the ceramide-sphingosine-S1P rheostat that tightly regulates expression of S1P pathway proteins. Conclusions: Our data show that FTY720 sensitized drug resistant ovarian cancer cell lines A2780-CP20 and HeyA8-MDR to carboplatin and to paclitaxel 15- to 90-fold. The data suggest that the S1P pathway may contribute to carboplatin and paclitaxel resistance in this cell type. We propose that proteins of the S1P pathway merit further study as effective molecular targets in drug resistant ovarian cancer cells. Citation Format: Kelly M. Kreitzburg, Ronald D. Alvarez, Charles N. Landen, Karina J. Yoon. FTY720 enhances the efficacy of paclitaxel and of carboplatin in drug-resistant ovarian cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 316.
Caregiver Perspectives on End-of-Life Experiences of Patients With Left Ventricular Assist Devices
Authors: Haruka Nakada, Mamoru Arakawa
Journal: JAMA Internal Medicine (2016)

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