tbuckley/cabot-search huggingface dataset:
Abstract 18320: A Novel Tandem Duplication Containing a Noncoding Exon of the APOC2 Gene Causes Chylomicronemia With Markedly Reduced Levels of Plasma Apolipoprotein C-II
Authors: Satoru Takase, Hiroyuki Ishiura, Makoto Kurano, Jun Mitsui, Mikio Takanashi, Yoshino Taira, Takeshi Kimura, Sachiko Okazaki, Yoko Iizuka, Hiroshi Yoshida, Norio Tada, Jun-ichi Osuga, Fumio Sawano, Masumi Hara, Kazuhisa Tsukamoto, Shoji Tsuji, Shun Ishibashi, Takashi Kadowaki, Hiroaki Okazaki
Journal: Circulation (2016)

Introduction:  Apolipoprotein C -II (apoC-II) promotes hydrolysis of triglycerides (TG) in TG-rich lipoproteins as a cofactor of lipoprotein lipase (LPL), and apoC-II deficiency, mostly caused by mutations in the coding regions of  APOC2 , leads to severe hypertriglyceridemia (HTG). In several atypical cases, mutations in the promoter region or a splice site of  APOC2  cause markedly reduced, but detectable levels of plasma apoC-II as well as massive HTG (hereafter referred to as hypoapoC-II). Previously, we reported a case of hypoapoC -II with severe HTG (Case 1), in which no rare variant was identified in the coding regions of  APOC2 ; however, the clinical entity of hypoapoC-II still remains controversial because evidence of causality is weak with only sporadic cases reported.   Aim:  The aim of this study is to explore the molecular basis of hypoapoC -II by analyzing Case 1 and two additional cases of hypoapoC-II.   Methods:  Case 1 and two new cases (Cases 2 and 3) of hypoapoC -II were analyzed. Whole genome/exome sequencing was performed using Ilumina HiSeq2000/2500. Southern blot hybridization analysis was performed using  APOC2  or  APOC4  cDNA probes. Breakpoint was analyzed by amplifying the breakpoint region by PCR, followed by subcloning and direct nucleotide sequencing analysis. Custom-made array CGH analysis was performed using probe sets around the  APOE/APOC4/APOC2  gene cluster. Haplotype analysis was performed after SNPs were genotyped by microarray.   Results:  Whole genome sequencing of Case 1 revealed a two-fold increase in coverage in the region containing  APOC4  and a noncoding exon of  APOC2 . Array CGH analysis, Southern blot hybridization analysis, and breakpoint analysis confirmed that the region was homozygous tandem duplication. Surprisingly, Case 2 harbors the same tandem duplication as Case 1 as revealed by array CGH and breakpoint analysis. Although cases 1 and 2 were apparently unrelated, haplotype analysis uncovered a founder haplotype spanning 680 kb.   Conclusions:  We found two independent cases of hypoapoC-II harboring the same tandem duplication containing  APOC4  and a noncoding exon of  APOC2  with founder haplotype. Our cases represent a distinct clinical subtype of hyperchylomicronemia with markedly reduced levels of apoC-II.
Immunotoxin and bcl-2 inhibitor combination therapy targeting chondroitin sulfate proteoglycan 4.
Authors: Xin Yu, Stephen T. Keir, Scott Szafranski, Steven Clayton, Ira Pastan, Darell D. Bigner, Vidyalakshmi Chandramohan
Journal: Journal of Clinical Oncology (2017)

74 Background: Immunotoxins (ITs) are a class of bifunctional chimeric proteins composed of an antibody fragment linked to a toxin. When ITs internalize into target cells, they induce protein synthesis inhibition and apoptosis. While ITs are highly specific and potent, the efficacy of IT-based therapies in some tumor cells is limited by hyperactive anti-apoptotic pathways and inefficient translocation of ITs from the endoplasmic reticulum to the cytosol. Therefore, to improve the efficacy of IT-based therapies, we evaluated a dual-pathway therapy that combines an IT with the ABT-737, ABT-263, or ABT-199 small molecule Bcl-2 inhibitor. Methods: The immunotoxin 9.2.27-PE38KDEL (9.2.27-IT) was generated by fusing a truncated mutant form of Pseudomonas exotoxin A to a single-chain variable fragment antibody. It targets human chondroitin sulfate proteoglycan 4 (CSPG4), an antigen highly expressed in a variety of cancer cells. We screened and identified 3 human glioblastoma xenografts, 3 human melanoma cell lines, and 5 human breast cancer cell lines resistant to the 9.2.27-IT despite their high levels of cell surface expression of CSPG4 (IC 50 of IT alone was &gt;100 ng/ml in all cell lines except for one melanoma cell line). In vitro cytotoxicity of the 9.2.27-IT —alone or in combination with the individual Bcl-2 inhibitors ABT-737, ABT-263, or ABT199—was assessed. Concentrations of ABT analogues were chosen so that ABT alone did not induce cytotoxicity. Results: The treatment groups that responded to the combination therapy yielded IC 50 values ranging from 0.04 – 9 ng/ml for glioblastoma xenografts, 0.21-15 ng/ml for melanoma cell lines, and 4.5-50 ng/ml for breast cancer cell lines. The most potent combination group showed &gt;1000 fold improvement of IC 50 compared to using the immunotoxin alone. ABT-737 produced the strongest synergistic effects among the ABT analogues. Preliminary results from in vivo studies further demonstrated that this approach engendered a synergistic response and delayed tumor growth in immunotoxin-resistant mouse tumor models. Conclusions: This new combinatorial approach will potentially help to overcome immunotoxin resistance in cancer patients and provide better therapeutic outcomes.
Reply to Rodrigues <i>et al.</i>: Increasing Physical Activity in Daily Life in Chronic Obstructive Pulmonary Disease: To Solve the Puzzle, Every Piece Counts
Authors: Claire M. Nolan, Matthew Maddocks, Jane L. Canavan, Sarah E. Jones, Veronica Delogu, Djeya Kaliaraju, Winston Banya, Samantha S. C. Kon, Michael I. Polkey, William D.-C. Man
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Formation of FcRγ-deficient NK cell subset associated with HCMV-reactivation in hematopoietic cell transplant recipients.
Authors: Jaewon Lee, Sungjin Kim, Jeannine Scott, A. Samer Al-Homsi, Stephanie F. Williams, Marlee Muilenburg, Suyeon Hong, Walter J Esselman
Journal: Journal of Clinical Oncology (2017)

131 Background: We have previously identified a novel subset of human NK cells that lacks FcRγ, a transmembrane signaling adaptor associated with CD16, the Fc receptor for IgG. These FcRγ-deficient NK cells (termed g-NK cells) display enhanced functional activity against target cells, including virus-infected cells, in concert with target-specific antibody molecules. The presence of g-NK cells in humans is associated with prior infection by human cytomegalovirus (HCMV). Additionally, g-NK cells are activated and expand robustly against HCMV-infected cells in the presence of HCMV-specific antibodies, consistent with predicted features of memory-like or adaptive NK cells. Recent studies have reported that expansion of a specific subset of NK cells with an adaptive phenotype can occur in response to HCMV reactivation after hematopoietic cell transplantation. Remarkably, patients with the expanded subset of NK cells showed reduced incidence of leukemia relapse and improved disease-free survival. Methods: Using blood samples obtained from BMT patients pre- and post-transplant, we have performed FACS-based phenotyping and ELISA-based serotyping analyses to explore whether HCMV-reactivation correlates with the generation of FcRγ-deficient NK cells in a bone marrow transplantation (BMT) setting. Results: Our data demonstrate that FcRγ-deficient NK cells appear in transplant patients following HCMV-reactivation, but not in the BMT patients without HCMV-reactivation. Phenotypic analysis indicates that these FcRγ-deficient NK cells display characteristics consistent with those observed in g-NK cells obtained from healthy HCMV-seropositive individuals, e.g. decreased expression of tyrosine kinase SYK. Conclusions: These results provide evidence in support of a causal relationship between HCMV infection and the generation of g-NK cells. Given the enhanced functional capability of g-NK cells against HCMV-infected target cells, the formation and functional activity of g-NK cells within BMT patients may contribute to the control of HCMV infection during the transplant procedure, and impact recovery from other diseases.
People living with undiagnosed HIV infection and a low CD4 count: estimates from surveillance data, Italy, 2012 to 2014
Authors: Vincenza Regine, Maria Dorrucci, Patrizio Pezzotti, Alessia Mammone, Chantal Quinten, Anastasia Pharris, Barbara Suligoi
Journal: Eurosurveillance (2018)

Background and aims Late HIV diagnosis is associated with onward HIV transmission, higher morbidity, mortality and healthcare costs. In Italy, more than half of people living with HIV were diagnosed late during the last decade, with a CD4 count &lt; 350 cells/mm 3 at diagnosis. We aimed to determine the number and characteristics of people living with undiagnosed HIV infection and low CD4 counts in Italy. Methods: Data on newly reported HIV diagnoses from 2012 –2014 were obtained from the national HIV surveillance system. We used the European Centre for Disease Prevention and Control HIV modelling tool to calculate the undiagnosed prevalence and yearly diagnosed fraction (YDF) in people with low CD4 count. Results: The estimated annual number undiagnosed HIV infections with low CD4 count was on average 6,028 (95% confidence interval (CI): 4,954–8,043) from 2012–2014. In 2014, most of the undiagnosed people with low CD4 count were men (82.8%), a third acquired HIV through sex between men (MSM) (35.0%), and heterosexual transmission (33.4%), respectively. The prevalence of undiagnosed HIV infection was 11.3 (95% CI: 9.3–14.9) per 100,000 residents ranging from 0.7 to 20.8 between Italian regions. Nationally the prevalence rate was 280.4 (95% CI: 173.3–450.2) per 100,000 MSM, 8.3 (95% CI: 4.9–13.6) per 100,000 heterosexual men, and 3.0 (95% CI: 1.4–5.6) per 100,000 women. The YDF was highest among heterosexual women (27.1%; 95% CI: 16.9–45.2%). Conclusions: These findings highlight the importance of improving efforts to identify undiagnosed HIV infections primarily among men, both MSM and heterosexual men.
Antigen-dependent costimulation to improve T-cell therapy for cancer.
Authors: Christopher C. DeRenzo, Phuong Nguyen, Stephen Gottschalk
Journal: Journal of Clinical Oncology (2017)

151 Background: T-cell therapy for cancer faces several challenges, including limited T-cell expansion at tumor sites, and lack of unique tumor antigens that are not expressed in normal tissues. To overcome the first obstacle, we developed Engager (ENG) T cells, which secrete bispecific molecules consisting of single chain variable fragments specific for CD3 and a tumor antigen. ENG T cells have the unique ability to redirect bystander T cells to tumors, amplifying antitumor effects. Costimulatory chimeric antigen receptors (CoCARs) are one potential strategy to restrict full T-cell activation to tumor sites that express a unique "antigen address." The goal of this project was now to generate T cells that express engager molecules and CoCARs (ENG/CoCAR T cells), which recognize distinct tumor antigens, and evaluate their effector function. Methods: We focused on two tumor antigens, EphA2 and HER2, which are expressed in a broad range of solid tumors. RD114-pseudotyped retroviral particles encoding an EphA2-ENG or a HER2-CoCAR were used to transduce CD3/CD28-activated human T cells. Transduced T cells were cocultured with EphA2+/HER2- or EphA2+/HER2+ tumor cells. Results: Both EphA2-ENG and EphA2-ENG/HER2-CoCAR T cells were activated by EphA2+ targets, as judged by IFNγ secretion. EphA2-ENG T cells secreted little IL-2 and died after one stimulation with EphA2+/HER2- or EphA2+/HER2+ tumor cells. In contrast, EphA2-ENG/HER2-CoCAR T cells secreted high levels of IL-2 and proliferated when stimulated with EphA2+/HER2+ cells. Little IL-2 secretion and no proliferation was observed after stimulation of the same T cells with EphA2+/HER2- cells, indicating these T cells are only fully activated in the presence of both target antigens. Upon repeated stimulation with EphA2+/HER2+ tumor cells, EphA2-ENG/HER2-CoCAR T cells continued to secrete IL-2 and proliferate without the addition of external cytokines for at least 10 weeks. Conclusions: EphA2-ENG/HER2-CoCAR T cells demonstrated robust dual antigen dependent IL-2 secretion, and continued proliferation upon repeat stimulation with EphA2+/HER2+ cells. Thus, providing antigen-specific costimulation is a potential strategy to improve the safety and efficacy of T-cell therapy for cancer.
Targeting Gas6/TAM in cancer cells and tumor microenvironment
Authors: Guiling Wu, Zhiqiang Ma, Yicheng Cheng, Wei Hu, Chao Deng, Shuai Jiang, Tian Li, Fulin Chen, Yang Yang
Journal: Molecular Cancer (2018)

Growth arrest-specific 6, also known as Gas6, is a human gene encoding the Gas6 protein, which was originally found to be upregulated in growth-arrested fibroblasts. Gas6 is a member of the vitamin K-dependent family of proteins expressed in many human tissues and regulates several biological processes in cells, including proliferation, survival and migration, by binding to its receptors Tyro3, Axl and Mer (TAM). In recent years, the roles of Gas6/TAM signalling in cancer cells and the tumour microenvironment have been studied, and some progress has made in targeted therapy, providing new potential directions for future investigations of cancer treatment. In this review, we introduce the Gas6 and TAM receptors and describe their involvement in different cancers and discuss the roles of Gas6 in cancer cells, the tumour microenvironment and metastasis. Finally, we introduce recent studies on Gas6/TAM targeting in cancer therapy, which will assist in the experimental design of future analyses and increase the potential use of Gas6 as a therapeutic target for cancer.
Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis
Authors: Milena S. Espindola, David M. Habiel, Rohan Narayanan, Isabelle Jones, Ana L. Coelho, Lynne A. Murray, Dianhua Jiang, Paul W. Noble, Cory M. Hogaboam
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling, which progressively abolishes lung function in an RTK (receptor tyrosine kinase)-dependent manner. Gas6 (growth arrest-specific 6) ligand, Tyro3 (TYRO3 protein tyrosine kinase 3), and Axl (anexelekto) RTK expression and activity are increased in IPF.To determine if targeting these RTK pathways would inhibit fibroblast activation and the development of pulmonary fibrosis.Quantitative genomic, proteomic, and functional analyses were used to determine Gas6/TAM (Tyro3, Axl, and Mertk [MER proto-oncogene, tyrosine kinase]) RTK expression and activation in tissues and fibroblasts from normal and IPF lungs. The profibrotic impact of these RTK pathways were also examined in bleomycin-induced pulmonary fibrosis and in SCID/Bg mice that developed pulmonary fibrosis after the intravenous administration of primary IPF fibroblasts.Gas6, Axl, and Tyro3 were increased in both rapidly and slowly progressive IPF compared with normal lung samples and fibroblasts. Targeting these pathways with either specific antibodies directed at Gas6 or Axl, or with small-molecule TAM inhibitors indicated that the small molecule-mediated targeting approach was more efficacious in both in vitro and in vivo studies. Specifically, the TAM receptor inhibitor R428 (also known as BGB324) significantly inhibited the synthetic, migratory, and proliferative properties of IPF fibroblasts compared with the other Gas6/TAM receptor targeting agents. Finally, loss of Gas6 expression decreased lung fibrotic responses to bleomycin and treatment with R428 inhibited pulmonary fibrosis in humanized SCID/Bg mice.Gas6/TAM receptor activity contributes to the activation of pulmonary fibroblasts in IPF, suggesting that targeting this RTK pathway might be an effective antifibrotic strategy in this disease.
A multi-institutional study of immunosuppressed and immunocompetent patients with cutaneous squamous cell carcinoma of the head and neck treated with definitive surgery and radiotherapy: Outcomes after disease recurrence.
Authors: Shlomo A. Koyfman, Bindu V. Manyam, Adam Arebi Garsa, Re-I Chin, Chandana A. Reddy, Brian Gastman, Wade Thorstad, Sue S. Yom, Brian Nussenbaum, Steven Wang, Allison T. Vidimos
Journal: Journal of Clinical Oncology (2017)

63 Background: Our multi-institutional group previously demonstrated that immunosuppressed (IS) patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) treated with surgery and adjuvant radiotherapy had inferior survival compared to immunocompetent (IC) patients. This study further examines those patients who experienced disease recurrence and compares the impact of immune status on overall survival after recurrence. Methods: Pts who received surgical resection and postoperative RT for primary or recurrent, stage I-IV (non-metastatic) cSCC-HN between 1995-2015 at Cleveland Clinic, Washington University St. Louis, and University of California San Francisco were included in this IRB approved study. Pts were categorized as IS if they were diagnosed with chronic hematologic malignancy, HIV/AIDS, or were treated with immunosuppressive therapy for organ transplantation ≥ 6 months prior to diagnosis. Pts with recurrence included those who experienced local, regional, or distant failure after completion of definitive surgery and radiation. Overall survival (OS) and progression free survival (PFS) were calculated using the Kaplan Meier method. Results: In the initial study of 205 pts, 138 (67.3%) were immunocompetent (IC) and 67 (32.7%) were IS, and were followed for a median of 25 months. PFS was significantly lower in IS pts compared to IC at 2 years (38.7% vs. 71.6%; p = 0.002), while 2yr OS demonstrated a similar but non-significant trend (60.9% vs. 78.1%; p = 0.135). A total of 72 patients (35%) recurred, including 31 with distant failure. 1yr post-recurrence OS was 42% with a median survival of 8.4 months. Median survival did not significantly differ between the IS and IC groups (8.0 vs. 12.9 months; p = 0.9). Conclusions: Pts with cSCC-HN who experience disease recurrence after definitive treatment with surgery and radiation have poor survival, irrespective of immune status. Clinical trials testing immunotherapies are needed for both IC and IS patients with this understudied disease.
Rendezvous recanalization of a postoperative coloanal anastomotic dehiscence with a lumen-apposing metal stent
Authors: Omid Sanaei, Olaya Brewer Gutierrez, Robert Moran, Juliana Yang, Mouen Khashab
Journal: Endoscopy (2018)

Corrected by: Correction: Rendezvous recanalization of a postoperative coloanal anastomotic dehiscence with a lumen-apposing metal stentEndoscopy 2018; 50(06): C10-C10DOI: 10.1055/a-0666-6284
Margaret McCartney: Trust has to be earned
Authors: Margaret McCartney
Journal: BMJ (2018)

The NHS is a brand beyond advertising. The British public are proud of it and trust it more than any other institution,1 and 90% support its founding values.2 Some of this is a genuine, deep emotional bond; some is a loving tolerance despite its struggles and failings.

The NHS has also provided the British public with an absence of something. Not having to worry about accessing healthcare when we need it. Not fretting over policy documents and expiry dates or about adding new conditions to our coverage. When we sleep at night, the fear of getting the healthcare …
Abstract 1313: Pro-atherogenic Effects Of Lipid Peroxidation Products: Role Of The Unfolded Protein Response
Authors: Elena Vladykoskaya, Petra Haberzettl, Yonis Ahmed, Bradford G Hill, Srinivas D Sithu, Stanley E D’Souza, Aruni Bhatnagar, Sanjay Srivastava
Journal: Circulation (2007)

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are associated with atherosclerosis. Expression of UPR target genes such as activating transcription factor 3 (ATF3) and ATF4 is markedly increased in human atherosclerotic lesions. Staining for these proteins co-localizes with the staining with antibodies that recognize the aldehydic epitopes of oxidized LDL, suggesting that lipid-derived aldehydes could be involved in mediating ER stress and UPR. We examined the role of phospholipid aldehyde, 1-palmitoyl-2-(5-oxovaleroyl)- sn -glycero-3-phosphocholine (POVPC), unsaturated lipid-derived aldehydes- 4-hydroxy, trans -2-nonenal (HNE) and acrolein in the induction of ER-stress and UPR in human aortic endothelial cells (HAEC) and human umbical vein endothelial cells (HUVEC). POVPC, HNE and acrolein (10 –25 μM) increased the phosphorylation of eIF2α (eukaryotic initiation factor-2α) by 1.5–5 fold (P&lt;0.001) and induced its downstream effector proteins - ATF4 (1.5–3.5 fold; P&lt;0.001) and ATF3 (4–10 fold; P&lt;0.0001). Incubation of HAEC with these aldehydes also increased the adhesion of THP-1 cells (monocyte) to HAEC by 1.4–1.6 fold (P&lt;0.01). Moreover, incubation of endothelial cells with POVPC increased the mRNA level of the pro-inflammatory cytokine IL-8 by &gt;25 fold (P&lt;0.0001). Chemical chaperone, phenyl butyric acid (PBA), diminished aldehydes-induced expression of ATF3 and ATF4 proteins, endothelial cell-monocyte adhesion and IL-8 formation by 80–95% (P&lt;0.001). POVPC (10–25 μM) also activated JNK by (3–6 fold) in HAEC. Reduction of POVPC to its corresponding alcohol, 1-palmitoyl-2-(5-hydroxyvaleroyl)- sn -glycero-3-phosphocholine (PHVPC) inhibited JNK activation by 74 ± 14 % (P&lt;0.001). Pharmacological inhibition of JNK, inhibited the aldehyde-induced induction of ATF3 and ATF4 proteins by 70–90 % (P&lt;0.001) but not the phosphorylation of eIF2α, and PBA inhibited the POVPC-induced JNK activation by 85 ± 11 % (P&lt;0.001). These data suggest that lipoprotein oxidation products activate endothelial cells in part by inducing ER-stress and their inflammatory signaling could be attenuated by chemical chaperones of protein folding.
5P Heterogeneity of PD-L1 expression in primary tumors and paired lymph node metastases of non-small cell lung cancer
Authors: Y. Saito, S. Horiuchi, H. Morooka, T. Ibi, N. Takahashi, T. Ikeya, E. Hoshi, S. Shimizu
Journal: Journal of Thoracic Oncology (2018)
RNF6 Promotes Colorectal Cancer by Activating the Wnt/β-Catenin Pathway via Ubiquitination of TLE3
Authors: Lei Liu, Yanquan Zhang, Chi Chun Wong, Jingwan Zhang, Yujuan Dong, Xiangchun Li, Wei Kang, Francis K.L. Chan, Joseph J.Y. Sung, Jun Yu
Journal: Cancer Research (2018)

Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer. Previous whole-genome sequencing of colorectal cancer clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we showed that RNF6 is upregulated in 73.5% (147/200) of patients with colorectal cancer and was positively associated with RNF6 gene amplification. Furthermore, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of patients with colorectal cancer. RNF6 promoted cell growth, cell-cycle progression, and epithelial-to-mesenchymal transition in colorectal cancer cells; RNF6 also promoted colorectal tumor growth and lung metastasis in mouse models. Mechanistic investigations revealed that RNF6 bound and ubiquitylated transducin-like enhancer of split 3 (TLE3), a transcriptional repressor of the β-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of β-catenin to TCF4/LEF, triggering Wnt/β-catenin activation. Restoration of TLE3 expression abolished the oncogenic effects of RNF6. Taken together, these results demonstrate that RNF6 plays a pivotal oncogenic role in colorectal tumorigenesis.Significance: RNF6-mediated ubiquitination and degradation of TLE3 activates the Wnt/β-catenin pathway in colorectal carcinogenesis. Cancer Res; 78(8); 1958-71. ©2018 AACR.
60P Circulating miR-31 as a predictive marker of EGFR TKI treatment efficacy in squamous cell lung cancer (SCC): A sub-analysis of the LUX-Lung 8 trial
Authors: Y. Gaston Mathé, P. Fogel, S. Martin-Lannerée, C. Marcaillou, E. Lallet, N. Krämer, N. Gibson, F. Solca, E. Ehrnrooth, J. Cadranel
Journal: Journal of Thoracic Oncology (2018)