tbuckley/cabot-search huggingface dataset:
Abstract 2524: MiR-29b may suppress peritoneal metastasis via the effects on peritoneal mesothelial cells as well as on tumor cells
Authors: Yuki Kimura, Hideyuki Ohzawa, Akira Saito, Naohiro Sata, Joji Kitayama
Journal: Cancer Research (2020)

Abstract Background: Peritoneal metastasis (PM) frequently occur in patients with gastric cancer with poor prognosis. Peritoneal cavity is lined with monolayer of mesothelial cells (MC) and contains various types of cells and exosomes. MC play an important role in the development of PM through mesothelial-mesenchymal transition (MMT). MiR-29 family is well known as tumor suppressor. However, the role of miR-29s in PM is not well characterized. We have previously reported that miR-29 family in exosome derived from peritoneal fluid was downregulated in patients with peritoneal metastasis of gastric cancer. In this study, we investigated the functions of miR-29s in the process of peritoneal metastasis. Methods: Exosomes were purified from peritoneal fluids of 85 patients with gastric cancer and miR-29 levels in peritoneal exosomes were quantified with RT-PCR using TaqMan Advanced miRNA Assays. Proliferation and migration of human gastric cancer cell lines, MKN45 and NUGC, were examined with MTT and transwell assays, respectively. Human peritoneal mesothelial cells (HPMCs) were isolated by trypsinization of omental tissues obtained from patients undergoing bariatric surgery and cultured in DMEM supplemented with 20% fetal bovine serum. MiR-29b mimic and negative control were transfected by lipofection method using RNAiMAX. MMT was induced by the culture of HPMCs with 10 ng/ml TGF-β. Expressions of cytokeratin and vimentin were evaluated with flow cytometry. Results: The expressions of miR-29a, miR-29b and miR-29c in peritoneal exosomes were all downregulated in 33 patients with PM as compared to those without PM. Transfection of miR-29b mimic significantly decreased the proliferation of MKN45 and NUGC-4 by 22~58% as compared with negative control miRNA (p&amp;lt;0.01). Migration was inhibited more strongly by 84~90% (p&amp;lt;0.01). After 48 hour-culture with TGF-β, HPMCs apparently changed the morphology from round to spindle shape. The expression level of cytokeratin in HPMCs was decreased while vimentin tended to be upregulated by TGF-β. However, transfection of miR-29b, but not control miRNA, significantly suppressed the morphological changes and reduced the expression levels of vimentin with restored expression of cytokeratin, suggesting the inhibition of MMT in HPMCs. Conclusion: MiR-29b suppresses mesenchymal transition of MC as well as of tumor cells. Replacement of miR-29b to peritoneal cavity might be used for the treatment for peritoneal metastasis. Citation Format: Yuki Kimura, Hideyuki Ohzawa, Akira Saito, Naohiro Sata, Joji Kitayama. MiR-29b may suppress peritoneal metastasis via the effects on peritoneal mesothelial cells as well as on tumor cells [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 2524.
Matching the Patient to the Intraocular Lens
Authors: Elizabeth Yeu, Susan Cuozzo
Journal: Ophthalmology (2020)

The intraocular lens (IOL) selection process for patients requires a complex and objective assessment of patient-specific ocular characteristics, including the quality and quantity of corneal astigmatism, health of the ocular surface, and other ocular comorbidities. Potential issues that could be considered complications after surgery, including dry eye disease, anterior or epithelial basement membrane dystrophy, Salzmann nodular degeneration, and pterygium, should be addressed proactively. Aspheric IOLs are designed to eliminate the positive spherical aberration added by traditional IOLs to the pseudophakic visual axis. Spherical aberration may be a consideration with patient selection. Patient desire for increased spectacle independence after surgery is one of the main drivers for the development of multifocal IOLs and extended depth-of-focus (EDOF) IOLs. However, no one single multifocal or EDOF IOL suits all patients' needs. The wide variety of multifocal and EDOF IOLs, their optics, and their respective impact on patient quality of vision have to be understood fully to choose the appropriate IOL for each individual, and surgery has to be customized. Patients who have undergone previous LASIK or who have radial keratotomy and ocular pathologic features, including glaucoma, age-related macular degeneration, and epiretinal membrane, require specific considerations for IOL selection. Subjectively, patient-centered considerations, including visual goals, lifestyle, personality, profession, and hobbies, are key elements for the surgeon to assess and factor into an IOL recommendation. This holistic approach will help surgeons to achieve optimal surgical outcomes and to meet (and exceed) the high expectations of patients.
A very low number of circulating basophils is predictive of a poor response to omalizumab in chronic spontaneous urticaria
Authors: Matija Rijavec, Mitja Košnik, Ana Koren, Peter Kopač, Julij Šelb, Romana Vantur, Žan Kogovšek, Mojca Bizjak, Nissera Bajrović, Mihaela Zidarn, Peter Korošec
Journal: Allergy (2020)

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Abstract 1628: Activation of the Nrf2E79Q mutation in mouse lung accelerate development of lung squamous dysplasia
Authors: Samera H. Hamad, Stephanie Montgomery, Brittany Bowman, Ryan Murphy, Ben Major, Bernard Weissman
Journal: Cancer Research (2020)

Abstract NFE2-related factor 2 (Nrf2) is a transcription factor that regulates more than 500 genes in human cells to protect them from oxidative damage. Somatic mutations in NRF2 resulting in constitutively Nrf2 signaling have been implicated as driver mutations in cancer, especially lung cancer. However, the mechanisms by which NRF2 activating mutations drive tumor development remains unresolved. Therefore, we used a novel genetically engineered mouse model (GEMM), LSL-Nrf2E79Q/+, to understand the role of this activating mutation (one of the most common mutations found in human tumors) in the development of lung tumors. We compared tumor development in two groups of mice: p53fl/fl; p16fl/fl; LSL-Nrf2+/+ (WT, n=38) and p53fl/fl; p16fl/fl; Nrf2E79Q/+ (Het, n=37). We used intranasal instillation of Adenoviral Cre at 6-8 weeks of age to activate the Nrf2E79Q allele and inactivate p53 and p16. Among other tumors, lung tumors were the most common tumors that were found in the GEMM, with major subtypes of lung squamous dysplasia (LSD: pre-malignant lesions of lung squamous cell carcinoma (LSCC)) and lung adenocarcinoma (LADC). Additionally, Het mice showed significantly higher LSD (30%) compared to WT mice (11%) implicating Nrf2E79Q/+ in LSD initiation. However, no significant difference in LADC was observed in Het mice compared to WT mice. Immunohistochemistry (IHC) including Nrf2, TTF1, CK7 and p63 was used to differentiate lung tumors. LADC of WT and Het mice showed negative Nrf2 staining despite the presence of the recombined Nrf2E79Q/+ allele in the Het tumors. However, LSDs developed by Het mice showed positive Nrf2 staining, while those in WT mice were negative, suggesting the mutant Nrf2 increased the frequency of LSDs. LADC of both groups was positive for TTF1 (A primary-non small lung cancer marker, mostly LADC) and CK7 (Cytokeratin7: a marker of epithelial cells). However, LSD lesions were also positive for TTF1. No p63 (a marker of LSCC) stain was shown for LADC of both groups; while p63 was negative to mildly positive in the case of LSD. Results of this study appear consistent with TCGA results where LADC predominantly contained Keap1 loss, while Nrf2 mutations frequently appeared in LSCC. This is the first study to show that a common activating mutation of Nrf2 promotes initiation of LSD that could further develop into LSCC. Citation Format: Samera H. Hamad, Stephanie Montgomery, Brittany Bowman, Ryan Murphy, Ben Major, Bernard Weissman. Activation of the Nrf2E79Q mutation in mouse lung accelerate development of lung squamous dysplasia [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 1628.
Genomic Predictors of Good Outcome, Recurrence, or Progression in High-Grade T1 Non–Muscle-Invasive Bladder Cancer
Authors: Joaquim Bellmunt, Jaegil Kim, Brendan Reardon, Júlia Perera-Bel, Anna Orsola, Alejo Rodriguez-Vida, Stephanie A. Wankowicz, Michaela Bowden, Justine A. Barletta, Juan Morote, Inés de Torres, Nuria Juanpere, Josep Lloreta-Trull, Silvia Hernandez, Kent W. Mouw, Mary-Ellen Taplin, Paloma Cejas, Henry W. Long, Eliezer M. Van Allen, Gad Getz, David J. Kwiatkowski
Journal: Cancer Research (2020)

Abstract High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non–muscle-invasive bladder cancer with unpredictable outcome and poorly understood risk factors. Here, we examined the association of somatic mutation profiles with nonrecurrent disease (GO, good outcome), recurrence (R), or progression (PD) in a cohort of HGT1 patients. Exome sequencing was performed on 62 HGT1 and 15 matched normal tissue samples. Both tumor only (TO) and paired analyses were performed, focusing on 95 genes known to be mutated in bladder cancer. Somatic mutations, copy-number alterations, mutation load, and mutation signatures were studied. Thirty-three GO, 10 R, 18 PD, and 1 unknown outcome patients were analyzed. Tumor mutational burden (TMB) was similar to muscle-invasive disease and was highest in GO, intermediate in PD, and lowest in R patients (P = 0.017). DNA damage response gene mutations were associated with higher TMB (P &amp;lt; 0.0001) and GO (P = 0.003). ERCC2 and BRCA2 mutations were associated with GO. TP53, ATM, ARID1A, AHR, and SMARCB1 mutations were more frequent in PD. Focal copy-number gain in CCNE1 and CDKN2A deletion was enriched in PD or R (P = 0.047; P = 0.06). APOBEC (46%) and COSMIC5 (34%) signatures were most frequent. APOBEC-A and ERCC2 mutant tumors (COSMIC5) were associated with GO (P = 0.047; P = 0.0002). pT1b microstaging was associated with a genomic cluster (P = 0.05) with focal amplifications of E2F3/SOX4, PVRL4, CCNE1, and TP53 mutations. Findings were validated using external public datasets. These findings require confirmation but suggest that management of HGT1 bladder cancer may be improved via molecular characterization to predict outcome. Significance: Detailed genetic analyses of HGT1 bladder tumors identify features that correlate with outcome, e.g., high mutational burden, ERCC2 mutations, and high APOBEC-A/ERCC2 mutation signatures were associated with good outcome.
Abstract B25: Anticancer effects of disulfiram in head and neck squamous cell carcinoma via autophagic cell death
Authors: Young Min Park, Da Hee Kim, Min Seok Kang, Yoon Woo Koh, Eun Chang Choi, Se-Heon Kim
Journal: Clinical Cancer Research (2020)

Abstract Objective: Disulfiram (DSF), which is used to treat alcohol dependence, has been reported to have anticancer effects in various malignant tumors. However, the anticancer effects and mechanism of DSF in head and neck squamous cell carcinoma (HNSCC) have not yet been studied. In this study, we investigated the anticancer effects and mechanism of DSF in HNSCC. Materials and Methods: Head and neck squamous carcinoma cell lines (FaDu and Hep2) were used to analyze the anticancer effects of DSF. The anticancer effects of DSF were confirmed in vivo using a FaDu xenograft tumor model. Results: The anticancer effects of DSF in HNSCC were found to be copper (Cu) dependent. Specifically, DSF/Cu markedly inhibited HNSCC at a concentration of 1 μM, and their combined inhibitory effect was dose-dependent. After DSF/Cu administration, production of reactive oxygen species (ROS) was remarkable starting at 0.5 μM, suggesting that the inhibitory effects of DSF/Cu on HNSCC are mediated through the formation of ROS. In the HNSCC cell lines, levels of phospho-JNK, phospho-cJun and phospho-p38 were increased after DSF/Cu treatment while levels of phospho-Akt were decreased. These results suggested that the inhibitory effects of DSF/Cu on HNSCC cells involve ROS formation and downregulation of Akt-signaling. Through these molecular mechanisms, DSF ultimately induces the inhibitory effects on HNSCC cell lines mainly through autophagic cell death, not apoptotic cell death. Lastly, we investigated the clinical relevance of DSF/Cu using a HNSCC xenograft animal model, which showed that tumor growth was remarkably decreased by DSF (50 mg/kg injection). Conclusion: Treating patients with both HNSCC and alcohol dependence with DSF may contribute to improved patient survival. The anticancer effects of DSF on HNSCC may suggest new therapeutic potential for this medication in HNSCC patients. Citation Format: Young Min Park, Da Hee Kim, Min Seok Kang, Yoon Woo Koh, Eun Chang Choi, Se-Heon Kim. Anticancer effects of disulfiram in head and neck squamous cell carcinoma via autophagic cell death [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 B25.
Abstract 6487: Circulating tumor cells, tumor- and endothelium- derived extracellular vesicles, but not circulating endothelial cells associate with poor prognosis in colorectal cancer
Authors: Afroditi Nanou, Linda Mol, Miriam Koopman, Cornelis J. Punt, Leon W. Terstappen
Journal: Cancer Research (2020)

Abstract Elevated tumor-derived EV (tdEV) and Circulating Tumor Cell (CTC) load in patients with metastatic cancer is associated with poor clinical outcome. In this study, we investigated whether endothelium-derived extracellular vesicles (edEVs) can be detected in the blood of metastatic colorectal cancer (mCRC) patients and whether there is an association with prognosis. The open-source ACCEPT software was used to enumerate edEVs, tdEVs and other objects from digitally stored CellSearch® images obtained after Circulating Endothelial Cell (CEC) and CTC enrichment from blood of 395 mCRC patients, before the initiation of a new therapy. Patients had participated in the prospective phase III CAIRO2 study. ACCEPT classified objects, CTC and CEC counts and patient information were used in univariable and multivariable analysis to determine their relation with Progression-Free Survival (PFS) and Overall Survival (OS). edEVs are present in blood of mCRC patients at 5-10 fold higher frequencies than CECs. A significantly shorter PFS and OS was observed for patients with ≥ 3 CTCs/ 7.5 mL, ≥ 40 tdEVs/ 7.5 mL and ≥ 287 edEVs/ 4.0 mL. The Hazard Ratio HR (95% CI) of PFS for increased CTCs, tdEVs and edEVs was 1.4 (1.1-1.9), 2.0 (1.5-2.6) and 1.7 (1.2-2.5), respectively. Similarly, the HR of OS for increased CTCs, tdEVs and edEVs was 2.2 (1.7-3.0), 2.7 (2.0-3.5) and 2.1 (1.5-2.8), respectively. There was no cut-off value for CECs leading to a dichotomization of patients with a significant HR. Both tdEVs and edEVs remained significant predictors of OS in multivariable analysis. edEVs and tdEVs are independent prognostic factors for OS in mCRC patients. Funded by the NWO Applied and Engineering Sciences Cancer-ID project #14190. Citation Format: Afroditi Nanou, Linda Mol, Miriam Koopman, Cornelis J. Punt, Leon W. Terstappen. Circulating tumor cells, tumor- and endothelium- derived extracellular vesicles, but not circulating endothelial cells associate with poor prognosis in colorectal 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 6487.
Abstract 6303: CRISPR/Cas9 RNP mediated efficient gene editing in hard-to-transfect cells
Authors: Peixue Li, Zhao Li, Qing Lin
Journal: Cancer Research (2020)

Abstract It has been challenging for efficient gene editing in cells which are hard to transfect, such as stem cells and primary T cells. Typical sgRNA and Cas9 intracellular delivery techniques are limited by their reliance on cell type and exogenous materials as well as their toxic effects on cells (for example, electroporation) or packaging capacity limitation by viral vectors. Here we established an effective approach for gene editing in different cell types and achieved successful genome editing with CRISPR RNP electroporation. Also, high efficient double knockout mutations could be obtained by electroporation of multiple sgRNAs at one shot. Furthermore, this method also could reduce the exposure time to Cas9 nuclease which may cause potential off-target effects. With the advantages of broad applicability across different cell types, particularly hard-to-transfect cells, and flexibility of application, these methods could potentially enable the development of the stem cell or T cell based therapies. Citation Format: Peixue Li, Zhao Li, Qing Lin. CRISPR/Cas9 RNP mediated efficient gene editing in hard-to-transfect cells [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 6303.
Crystal structure of SARS-CoV-2 papain-like protease
Authors: Xiaopan Gao, Bo Qin, Pu Chen, Kaixiang Zhu, Pengjiao Hou, Justyna Aleksandra Wojdyla, Meitian Wang, Sheng Cui
Journal: Acta Pharmaceutica Sinica B (2020)

The pandemic of coronavirus disease 2019 (COVID-19) is changing the world like never before. This crisis is unlikely contained in the absence of effective therapeutics or vaccine. The papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays essential roles in virus replication and immune evasion, presenting a charming drug target. Given the PLpro proteases of SARS-CoV-2 and SARS-CoV share significant homology, inhibitor developed for SARS-CoV PLpro is a promising starting point of therapeutic development. In this study, we sought to provide structural frameworks for PLpro inhibitor design. We determined the unliganded structure of SARS-CoV-2 PLpro mutant C111S, which shares many structural features of SARS-CoV PLpro. This crystal form has unique packing, high solvent content and reasonable resolution 2.5 Å, hence provides a good possibility for fragment-based screening using crystallographic approach. We characterized the protease activity of PLpro in cleaving synthetic peptide harboring nsp2/nsp3 juncture. We demonstrate that a potent SARS-CoV PLpro inhibitor GRL0617 is highly effective in inhibiting protease activity of SARS-CoV-2 with the IC50 of 2.2 ± 0.3 μmol/L. We then determined the structure of SARS-CoV-2 PLpro complexed by GRL0617 to 2.6 Å, showing the inhibitor accommodates the S3-S4 pockets of the substrate binding cleft. The binding of GRL0617 induces closure of the BL2 loop and narrows the substrate binding cleft, whereas the binding of a tetrapeptide substrate enlarges the cleft. Hence, our results suggest a mechanism of GRL0617 inhibition, that GRL0617 not only occupies the substrate pockets, but also seals the entrance to the substrate binding cleft hence prevents the binding of the LXGG motif of the substrate.
Myopia Prevalence and Ocular Biometry Features in a General Japanese Population
Authors: Shin-ya Nakao, Masahiro Miyake, Yoshikatsu Hosoda, Eri Nakano, Yuki Mori, Ayako Takahashi, Sotaro Ooto, Hiroshi Tamura, Yasuharu Tabara, Kenji Yamashiro, Fumihiko Matsuda, Akitaka Tsujikawa, Takeo Nakayama, Akihiro Sekine, Shinji Kosugi
Journal: Ophthalmology (2020)
Abstract 1569: TGFβ signaling suppresses alternative end joining associated with genomic mutations and PARP Inhibition sensitivity
Authors: Qi Liu, Luis Palomero, Jade Moore, Ines Guix, Miquel Angel Pujana, Mary Helen Barcellos-Hoff
Journal: Cancer Research (2020)

Abstract Differential use of DNA repair pathways in cancer leads to distinct clinical outcomes following genotoxic therapies. We found that deficient TGFβ signaling due to human papilloma virus (HPV) in head and neck squamous cell carcinoma (HNSCC) results in impaired DNA repair proficiency, increased use of alternative end joining (alt-EJ) and that a 50-gene TGFβ signature is negatively correlated with prognosis (Clin Ca Res 2018, 24(23): 6001). To assess the molecular consequence of TGFβ signaling in the DNA damage response (DDR), we performed a Nanostring assay on SAS HNSCC and U251 glioblastoma cell lines using the 180 gene DNA damage and repair panel. The results showed that treatment with TGFβ type 1 receptor kinase inhibitor LY2157299 or TGFβ profoundly altered DDR gene expression profiles. TGFβ inhibition for 24 hr significantly (p&amp;lt;0.05) increased critical alt-EJ genes, POLQ (DNA polymerase theta) and PARP1 (poly(ADP-ribose) polymerase 1), which was confirmed by qRT-PCR. To interrogate the relationship between TGFβ and alt-EJ in The Cancer Genome Atlas (TCGA), we used the literature to curate a 36 gene alt-EJ signature. Single specimen gene set enrichment analyses (ssGSEA) showed that the alt-EJ signature was significantly anti-correlated with the TGFβ signature in 15 of 17 cancer types (PCC = -0.35; p =10-16). This anti-correlation was also observed in 875 cancer cell lines in Catalogue of Somatic Mutations in Cancer (COSMIC) database, suggesting a conserved, cancer cell intrinsic mechanism by which TGFβ regulates alt-EJ. Alt-EJ is an error prone DNA repair mechanism that generates gross genomic alterations. Consistent with this, low ssGSEA score for TGFβ and high ssGSEA score for alt-EJ are correlated with increased deletions or insertions in genome sequence of patient tumors in TCGA as well as cancer cell lines in COSMIC (p&amp;lt;0.05). PARP1 requirement prompted analyses of drug sensitivity data in the Sanger database, which showed that cell lines with high alt-EJ and low TGFβ ssGSEA score are significantly more sensitive to PARP1 inhibitors, olaparib and ABT-888, (p &amp;lt; 0.0001). These data lead to the novel hypothesis that TGFβ signaling actively suppresses alt-EJ. If true, the TGFβ/alt-EJ signature may be useful as a biomarker for precision cancer medicine with genotoxic agents, TGFβ or PARP inhibitors. Citation Format: Qi Liu, Luis Palomero, Jade Moore, Ines Guix, Miquel Angel Pujana, Mary Helen Barcellos-Hoff. TGFβ signaling suppresses alternative end joining associated with genomic mutations and PARP Inhibition sensitivity [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 1569.