tbuckley/cabot-search huggingface dataset:
Abstract 3068: The glycoprotein inhibitors overcome the resistance of the topoisomerase inhibitors in small cell lung cancer
Authors: Rintaro Noro, Miwako Omori, Aya Fukuizumi, kuniko Matsuda, Mariko Hirao, Satoshi Takahashi, Natsuki Takano, Shinji Nakamichi, Teppei Sugano, Akihiko Miyanaga, Yuji Minegishi, Masahiro Seike, Kaoru Kubota, Akihiko Gemma
Journal: Cancer Research (2020)

Abstract Small cell lung cancer (SCLC) is a highly aggressive disease with median survival of &amp;lt;2 years. Most patients respond initially to the topoisomerase inhibitors, resistance rapidly emerges. The purpose is overcoming the resistance of the topoisomerase inhibitors in SCLCs. To identify the key factors for the resistance of the topoisomerase I (SN38) or II (VP-16) inhibitors in SCLCs, we analyzed MTS cell proliferation assay. We identified 8 sensitive cell lines and 2 resistant cell lines. We established 4 resistant cell lines by continuous exposure to increasing concentrations of SN-38 or VP-16 stepwise. RNA sequencing was performed using the established cell lines to discover novel therapeutic targets associated with the resistance to topoisomerase inhibitors. We found that whenever the drug efflux protein ATP-binding cassette transporter B1 (ABCB1) was associated the with resistance of VP-16, ATP-binding cassette super-family G member 2 (ABCG2) was associated with the resistance of SN-38. The silencing of ABCG2 or ABCB1 in every resistant cell line, could induce synergistic apoptosis of every cell line. Elacridar and tariquidar which are glycoprotein inhibitors, recovered the sensitivity of SN38 or VP-16 in every resistant line, increased expression of signaling proteins associated with DNA damage and cell-cycle checkpoints, and promoted G2/M arrest and apoptosis. Furthermore, we are going to analyze the expressions of ABCG2 and ABCB1 in serum before and after the treatment of VP-16 or CPT-11. These results suggested the glycoprotein inhibitors, which phase I study is ongoing, could be a promising therapeutic strategy for the purpose of preventing the resistance of topoisomerase inhibitors in SCLCs. Citation Format: Rintaro Noro, Miwako Omori, Aya Fukuizumi, kuniko Matsuda, Mariko Hirao, Satoshi Takahashi, Natsuki Takano, Shinji Nakamichi, Teppei Sugano, Akihiko Miyanaga, Yuji Minegishi, Masahiro Seike, Kaoru Kubota, Akihiko Gemma. The glycoprotein inhibitors overcome the resistance of the topoisomerase inhibitors in small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3068.
Abstract IA14: Integrated molecular characterization of the genome, transcriptome, and immune microenvironment in oviductal high-grade serous carcinomas arising in genetically engineered mice
Authors: Kathleen R. Cho
Journal: Clinical Cancer Research (2020)

Abstract Robust preclinical models of ovarian high-grade serous carcinoma (HGSC) are needed to advance our understanding of HGSC pathogenesis and to test novel strategies aimed at improving clinical outcomes for women with the disease. Genetically engineered mouse models of HGSC have been developed that recapitulate the likely cell of origin (fallopian tube epithelium), underlying genetic defects, histology, and biologic behavior of human HGSCs, but the degree to which the mouse tumors acquire the somatic genomic changes, gene expression profiles, and immune microenvironment that characterize human HGSCs remains unclear. We used integrative molecular characterization of oviductal HGSCs arising in the context of Brca1, Trp53, Rb1, and Nf1 (BPRN) inactivation to determine whether the mouse tumors recapitulate human HGSCs across multiple domains of molecular features. Targeted DNA sequencing showed that the mouse BPRN tumors, but not endometrioid carcinoma-like tumors based on different genetic defects (e.g., Apc, Pten, Arid1a), acquire somatic mutations and widespread copy number alterations similar to those observed in human HGSCs. RNA sequencing showed that the mouse HGSCs most closely model the immunoreactive and mesenchymal subsets of human HGSCs. A combined immunogenomic analysis showed that the immune microenvironment of BPRN tumors models key aspects of tumor-immune dynamics in human HGSC, with enrichment of immunosuppressive cell subsets (myeloid-derived suppressor cells and regulatory T cells) as observed in the immunoreactive and mesenchymal subsets of human tumors. These findings, as well as early proof-of-principle studies, support the BPRN model as a robust preclinical experimental platform to help overcome barriers to clinical success in preventing, diagnosing, and treating this lethal cancer. Citation Format: Kathleen R. Cho. Integrated molecular characterization of the genome, transcriptome, and immune microenvironment in oviductal high-grade serous carcinomas arising in genetically engineered mice [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA14.
Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer
Authors: Shaobo Mo, Xiaoji Ma, Yaqi Li, Long Zhang, Ting Hou, Han Han-Zhang, Juanjuan Qian, Sanjun Cai, Dan Huang, Junjie Peng
Journal: Journal for ImmunoTherapy of Cancer (2020)

Previous studies found patients with POLE exonuclease domain mutations (EDMs) in targeted exons were related to significant better outcomes in stage II-III colorectal cancer (CRC). The detailed mutational profile of the entire POLE exonuclease domain, tumor mutation burden (TMB) and immune cell infiltration in POLE EDMs tumors, and the prognostic value of such mutations in stage II CRCs were largely unknown to us. This study was to clarify the characteristics, immune response and prognostic value of somatic POLE EDMs in stage II CRC. A total of 295 patients with stage II CRC were sequenced by next-generation sequencing with a targeted genetic panel. Simultaneous detection of the immune cells was conducted using a five-color immunohistochemical multiplex technique. The detailed molecular characteristics, tumor-infiltrating lymphocyte (TIL) and prognostic effect of POLE EDMs in stage II CRC were analyzed. For stage II CRCs, the POLE EDMs were detected in 3.1% of patients. Patients with POLE EDMs were more prone to be microsatellite instability-high (MSI-H) (33.3% vs 11.2%, p=0.043), younger at diagnosis (median 46 years vs 62 years, p&lt;0.001) and more common at right-sided location (66.7% vs 23.1%; p=0.003). All patients with POLE EMDs were assessed as extremely high TMB, with a mean TMB of 200.8. Compared with other stage II CRCs, POLE EDMs displayed an enhanced intratumoral cytotoxic T cell response, evidenced by increased numbers of CD8+TILs and CD8A expression. Patients with stage II CRCs could be classified into three risk subsets, with significant different 5 years disease-free survival rates of 100% for POLE EDMs, 82.0% for MSI-H and 63.0% for MSS, p=0.013. In conclusion, characterized by a robust intratumoral T cell response, ultramutated POLE EDMs could be detected in a small subset of stage II CRCs with extremely high TMB. Patients with POLE EDMs had excellent outcomes in stage II CRCs, regardless of MSI status. Sequencing of all the exonuclease domain of POLE gene is recommended in clinical practice.
Early childhood growth is associated with lung function at 7 years: a prospective population-based study
Authors: Gabriela P. Peralta, Alicia Abellan, Parisa Montazeri, Mikel Basterrechea, Ana Esplugues, Sandra González-Palacios, Célina Roda, Loreto Santa-Marina, Jordi Sunyer, Martine Vrijheid, Maribel Casas, Judith Garcia-Aymerich
Journal: European Respiratory Journal (2020)

Previous studies have related early postnatal growth with later lung function but their interpretation is limited by the methods used to assess a child's growth. We aimed to assess the association of early childhood growth, measured by body mass index (BMI) trajectories up to 4 years, with lung function at 7 years. We included 1257 children from the Spanish Infancia y Medio Ambiente population-based birth cohort. Early childhood growth was classified into five categories based on BMI trajectories up to 4 years previously identified using latent class growth analysis. These trajectories differed in birth size (“lower”, “average”, “higher”) and in BMI gain velocity (“slower”, “accelerated”). We related these trajectories to lung function (forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), FEV 1 /FVC and forced expiratory flow at 25%–75% of FVC (FEF 25–75% )) at 7 years, using multivariable mixed regression. Compared to children with average birth size and slower BMI gain (reference), children with higher birth size and accelerated BMI gain had a higher FVC % pred (3.3%, 95% CI 1.0%–5.6%) and a lower FEV 1 /FVC % pred (−1.5%, 95% CI −2.9%–−0.1%) at 7 years. Similar associations were observed for children with lower birth size and accelerated BMI gain. Children with lower birth size and slower BMI gain had lower FVC % pred at 7 years. No association was found for FEF 25–75% . Independently of birth size, children with accelerated BMI gain in early childhood had higher lung function at 7 years but showed airflow limitation. Children with lower birth size and slower BMI gain in early childhood had lower lung function at 7 years.
YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress
Authors: Elisa De Franco, Maria Lytrivi, Hazem Ibrahim, Hossam Montaser, Matthew N. Wakeling, Federica Fantuzzi, Kashyap Patel, Céline Demarez, Ying Cai, Mariana Igoillo-Esteve, Cristina Cosentino, Väinö Lithovius, Helena Vihinen, Eija Jokitalo, Thomas W. Laver, Matthew B. Johnson, Toshiaki Sawatani, Hadis Shakeri, Nathalie Pachera, Belma Haliloglu, Mehmet Nuri Ozbek, Edip Unal, Ruken Yıldırım, Tushar Godbole, Melek Yildiz, Banu Aydin, Angeline Bilheu, Ikuo Suzuki, Sarah E. Flanagan, Pierre Vanderhaeghen, Valérie Senée, Cécile Julier, Piero Marchetti, Decio L. Eizirik, Sian Ellard, Jonna Saarimäki-Vire, Timo Otonkoski, Miriam Cnop, Andrew T. Hattersley
Journal: Journal of Clinical Investigation (2020)

Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models (YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects β cells. Loss of YIPF5 function in stem cell–derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress–induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.
Recapitulating Evolutionary Divergence in a Single<i>Cis</i>-Regulatory Element Is Sufficient to Cause Expression Changes of the Lens Gene<i>Tdrd7</i>
Authors: Juliana G Roscito, Kaushikaram Subramanian, Ronald Naumann, Mihail Sarov, Anna Shevchenko, Aliona Bogdanova, Thomas Kurth, Leo Foerster, Moritz Kreysing, Michael Hiller
Journal: Molecular Biology and Evolution (2020)

Abstract Mutations in cis-regulatory elements play important roles for phenotypic changes during evolution. Eye degeneration in the blind mole rat (BMR; Nannospalax galili) and other subterranean mammals is significantly associated with widespread divergence of eye regulatory elements, but the effect of these regulatory mutations on eye development and function has not been explored. Here, we investigate the effect of mutations observed in the BMR sequence of a conserved noncoding element upstream of Tdrd7, a pleiotropic gene required for lens development and spermatogenesis. We first show that this conserved element is a transcriptional repressor in lens cells and that the BMR sequence partially lost repressor activity. Next, we recapitulated evolutionary changes in this element by precisely replacing the endogenous regulatory element in a mouse line by the orthologous BMR sequence with CRISPR–Cas9. Strikingly, this repressor replacement caused a more than 2-fold upregulation of Tdrd7 in the developing lens; however, increased mRNA level does not result in a corresponding increase in TDRD7 protein nor an obvious lens phenotype, possibly explained by buffering at the posttranscriptional level. Our results are consistent with eye degeneration in subterranean mammals having a polygenic basis where many small-effect mutations in different eye-regulatory elements collectively contribute to phenotypic differences.
AB0212 Experience with intravenous immunoglobulin therapy in twenty patients with different autoimmune rheumatic diseases
Authors: S Kamali, A Gül, M Inanç, A Çefle, M Sayarlioglu, O Aral, M Koniçe
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> Retrospective evaluation of high dose intravenous immunoglobulin (IVIG) treatment in patients with connective tissue diseases. <h3>Methods</h3> We evaluated the records of 8 patients with systemic lupus erythematosus (SLE), 8 patients with inflammatory muscle disease [polimyositis (PM), juvenil dermatomyositis (JDM), dermatomyositis (DM)] and 4 patients with Wegener's granulomatosis (WG) who received 2 g/kg IVIG in 5 days 1–12 times monthly. <h3>Results</h3> The indications of IVIG therapy were: severe thrombocytopenia with active disease despite corticosteroid and immunosuppressive therapy in 7 patients and concurrent mycobacterial infection in 2 patients with SLE; resistance to standard treatment in 7 patients with PM/DM and 3 patients with WG. Fifteen of 20 patients received concomitant high dose prednisolone, methotrexate, azathioprine and/or pulse cyclophosphamide therapy. In two patients, IVIG was used because of concomitant viral infections (one patient with DM+chronic active hepatitis due to Hepatitis B virus and 1 patient with WG+cytomegalovirus chorioretinitis) Two patients with DM died of underlying malignancies and 3 patients with SLE died of uncontrolled disease activity. No serious side effects related to IVIG therapy were observed. <h3>Conclusion</h3> High dose IVIG is an effective and tolerable option when standard therapies are failed or a rapid response is needed in patients with PM/DM and WG. In SLE the main indication for IVIG is steroid resistant severe thrombocytopenia. IVIG therapy may also be preferable in patients with active disease and concurrent severe infections.
Abstract 176: The Evolution of NANOGP8 and its possible roles in tumorigenesis
Authors: Yande Guo
Journal: Cancer Research (2020)

Abstract Human NANOG gene is located in Chromosome 12p13. It is a transcription factor in embryonic stem cells. There are 11 NANOG pseudogenes in human genome. NANOGP1 is an unprocessed pseudogene that arose through duplication of the chromosomal region containing NANOG before the human-chimpanzee (H/C) divergence and before insertion of the Alu element into the NANOG gene. NANOGP1 remained functional after duplication. NANOGP2 to NANOGP11 are ten processed pseudogenes in the human genome. NANOGP8 is theoretically unique since it has a complete open reading frame and an Alu element in the 3'-UTR which is homologous to that of Nanog. However, the human NANOGP8 is absent from the chimpanzee genome. Genome DNA sequence analysis revealed that NANOGP8 is the most recent of the NANOG pseudogenes and was inserted into chromosome 15 after the H/C divergence. Its transcription factor binding sites in SVA LTR may promote expression of NANOGP8 in cancer cells. This may be the partial reason of the higher genetic predisposition for cancer in humans compared with other primates. Citation Format: Yande Guo. The Evolution of NANOGP8 and its possible roles in tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 176.
AB1280-HPR REQUIRED FORCE TO OBTAIN A POSITIVE SQUEEZE TEST AUTOMATIZED IN PATIENTS WITH HAND ARTHRALGIA
Authors: M. M. Castañeda-Martínez, G. Figueroa-Parra, D. Vega-Morales, B. R. Vázquez Fuentes, Y. G. Ordoñez Azuara, J. A. Esquivel Valerio, D. Á. Galarza-Delgado
Journal: Annals of the Rheumatic Diseases (2020)

Background: Primary care physicians (PCP) are usually the first contact of people with inflammatory rheumatic diseases, and find the early symptoms of Rheumatoid Arthritis (RA) difficult to distinguish from those of other rheumatic diseases. A time-delay in the reference to Rheumatology is a health issue in several countries. The clinical aspects that general practitioner took into account in hand arthralgia patients are important to make the reference. In particular the Squeeze Test (ST) - which is simple to perform and rapidly done, ST is useful for identifying progression to RA in patients with undifferentiated arthritis. The ST has been described as not reliable because is clinician-dependent. Objectives: To identify the required force that needs to be applied in order to obtain a positive Automatized Squeeze Test (AST) in a cohort of patients with hand arthralgia. Methods: Ninety-seven patients were recruited in Family Medicine Consultation and in Rheumatology Consultation of the Hospital Universitario “Dr. José Eleuterio González” in Monterrey, Nuevo León, México. Eligible patients were adults (aged≥18 years) with hand arthralgia (that wasn’t caused by trauma) as their chief complaint. After obtaining informed consent and after a questionnaire application, patients were submitted to AST maneuver, using an automated compressor with different forces already predetermined in the interface of the software used for compression. Results: In this cohort of 98 patients, 79 (80.6%) were women. The mean age was 51.14 years (SD 14.66). Ninety-six (97.9%) patients were right handed. The diagnoses were Osteoarthritis (OA) (16.3%), RA (5.1%), Undifferentiated arthritis (1.2%), Psoriatic arthritis (1.2%) and Fibromyalgia (2%). Force measures according to diagnoses are reported in Table 1. Table 1. Diagnoses and mean forces Diagnosis n (% ) Right hand force mean (kg/s 2 ) (SD ) Left hand force mean (kg/s 2 ) (SD ) OA 16 (16.3) 3.53 (2.74) 3.18(2.73) RA 5 (5.1) 3.60 (2.53) 3.16(1.36) UA 1 (1.2) 7.60(0) 8.70(0) PsA 1 (1.2) 7.60(0) 7.80(0) FM 2 (2.0) 4.11(4.40) 1.75(1.06) OA , Osteoarthritis; RA , Rheumatoid Arthritis; UA , Undifferentiated Arthritis; PsA , Psoriatic Arthritis; FM , Fibromyalgia; SD , Standard Deviation Conclusion: In the cases of RA and OA, the means of force to obtain a positive AST was lower than in the rest of the diagnoses. References: [1]Stack R, Nightingale P, Jinks C, Shaw K, Herron-Marx S, Horne R et al. Delays between the onset of symptoms and first rheumatology consultation in patients with rheumatoid arthritis in the UK: an observational study. BMJ Open. 2019;9(3):e024361. Disclosure of Interests: None declared
Abstract A10: Treatment of squamous cell carcinoma by alpha radiation-based brachytherapy (Alpha DaRT)
Authors: Aviram Mizrachi, Aron Popovtzer, Eli Rosenfeld, Ran Ben-Hur, Itzhak Kelson, Yona Keisari
Journal: Clinical Cancer Research (2020)

Abstract Objective: The first clinical trial in humans with skin and oral cavity squamous cell carcinoma (SCC) was performed in order to evaluate the effect of a unique intratumoral alpha radiation-based tumor ablation treatment termed Diffusing Alpha-emitters Radiation Therapy (DaRT). Methods: Radium-224 loaded sources (DaRT seeds) were inserted into solid tumors and released by recoil short-lived alpha-emitting atoms (Rn-220, Po-216, Pb-212, Bi-212, Po-212, Tl-208). These atoms disperse in the tumor and spray it with highly destructive alpha radiation. The decay products diffuse in the tumor mass to a distance of at least 5 mm. Results: A feasibility and safety clinical study is ongoing and currently 28 patients were treated at the Rabin Medical Center (Israel) and IRST (Italy). Patients with histopathologic confirmed skin or head and neck SCC, and tumor size ≤5 centimeters in the largest diameter, were enrolled. Treatment was delivered based on a CT-simulation pretreatment plan. The seeds (1 cm long and 0.7 mm in diameter), each carrying a dose of 2 μCi, were placed up to 5 millimeters from each other. CT was used in order to confirm the position of the radioactive seeds. Two weeks after implantation the seeds were removed, and six weeks after treatment a CT scan was performed to assess the effect of treatment. Study results are available for 18 cases that were treated per protocol and reached the 30-day follow-up period. Age of the patients ranged from 60 to 102 years (median 80 years). Ten patients had oral cavity SCC and 18 were diagnosed with cutaneous SCC. Thirteen subjects were treated within prior radiation failure fields (radiation dosage &amp;gt;60Gy). All tumors responded to the treatment; 13 tumors exhibited a complete response and five tumors showed partial response. No major toxicity was noted. Conclusions: In this first feasibility and safety human study we demonstrated that alpha-based treatment (DaRT) resulted in enhanced radiobiologic potential. Furthermore, the treatment was effective against radioresistant SCC tumors without any major side effects. Citation Format: Aviram Mizrachi, Aron Popovtzer, Eli Rosenfeld, Ran Ben-Hur, Itzhak Kelson, Yona Keisari. Treatment of squamous cell carcinoma by alpha radiation-based brachytherapy (Alpha DaRT) [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A10.
Abstract 10425: Angiotensin Converting Enzyme Inhibitor Suppresses Cardiac Remodeling After Myocardial Infarction by Regulating Dendritic Cells and Angiotensin Receptor 2 Mediated Mechanism in Mice
Authors: Yuanji Ma, Junbo Ge
Journal: Circulation (2018)

Introduction: Dendritic cells (DCs) are highly proficient antigen-presenting cells, which play a complex role in the progression of MI. DCs can express Ang 2 receptors, including AT1R and AT2R and ...