tbuckley/cabot-search huggingface dataset:
Abstract LB-279: Artificial intelligence aided diagnosis of breast cancer molecular classification based on immunohistochemical images
Authors: Jean J. Zhao, Minzi Ruan, Quancai Cui
Journal: Cancer Research (2019)

Abstract Breast cancer has obvious heterogeneity. Molecular classification of breast cancer has been done through the study of gene expression profile. There were significant differences in gene expression, clinical characteristics, therapeutic response and prognosis among these molecular types, which were lumen A type, lumen B type, her-2 overexpression type and basal cell type, respectively. Compared with other nucleic acid level detection technologies, immunohistochemistry (IHC), as the most commonly used protein expression level detection method, has the advantages of low price, short cycle and more stable. IHC staining, including ER, PR, Ki-67, Her-2, CK5/6 and EGFR, can be used to classify breast cancer into different molecular subtypes and assist in the determination of treatment options. The application of artificial intelligence in pathological morphology is in the ascendant. Different algorithms can be used to evaluate both IHC staining and HE staining morphological evaluation of tumor tissues (including histological grading).In the molecular typing of breast cancer by IHC, the digital slide images obtained by scanning with software analysis can greatly reduce the subjectivity and instability of manual evaluation and improve the repeatability. Firstly, we scanned whole slide digital image of the HE staining slides and the six IHC slides of 200 surgical specimens of breast cancer with different molecular types (non-special types) from a medical center (Peking Union Medical College Hospital).Then compare the immunohistochemical results of each case obtained manually, adjust the algorithm, calibrate the parameters in the software, and finally get the fixed algorithm code and parameters. The algorithms used in study include image classification, nuclei segmentation, channel association and image registration. The algorithms were verified in the other surgical resection specimens of 400 cases of breast cancer with different molecular types (non-special types) from two other medical center, and was compared with the data obtained by manual reading. Finally, the results were encouraging, with the consistency of molecular classification reaching 100%. This study shows AI technology has great application prospect in pathological diagnosis of breast cancer. Citation Format: Jean J. Zhao, Minzi Ruan, Quancai Cui. Artificial intelligence aided diagnosis of breast cancer molecular classification based on immunohistochemical images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-279.
The molecular characteristics of Neisseria meningitidis serogroup Y clonal complex 23 first emerge in China
Authors: Baisheng Li, Liping Zhang, Meizhen Liu, Xueyi Ye, Xin Xu, Zhencui Li, Wenjia Liang, Jieli Deng, Limei Sun, Jie Wu, Qiaoli Zhang, Tie Song
Journal: Journal of Infection (2019)
Abstract 2210: Discovery of a novel third generation EGFR TKI and identification of its potential mechanism of resistance
Authors: Tao Zhang, Rong Qu, Chengbin Chen, Linjiang Tong, Fang Feng, Yi Chen, Meiyu Geng, Ke Ding, Hua Xie, Jian Ding
Journal: Cancer Research (2019)

Abstract Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first generation EGFR inhibitors (such as gefitinib and elortinib), however, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR T790M mutation. In this work, we identified a pyrimidine-backbone compound D7 as a novel irreversible inhibitor of EGFR T790M mutation and sensitizing mutation, with selectivity over the wild type EGFR (WT EGFR). D7 exhibited potent in vitro anti-proliferation activity in tumor cells harboring EGFR T790M (NCI-H1975 cells) and sensitizing mutations (PC-9 and HCC827 cells), whereas it showed moderate or weak inhibition in cells expressing WT EGFR. Oral administration of D7 induced dramatic tumor regression in EGFR mutated NSCLC tumor xenograft models as well as in patient-derived xenograft (PDX) model harboring EGFR T790M mutation. To further explore potential mechanisms mediating drug resistance, we constructed D7-resistant cells by prolonged exposure of parental NCI-H1975 cells to gradually increasing concentration of this compound. Resistant cells exhibited signs of apoptosis-resistance to D7 treatment and demonstrated increased sensitivity when combined with Src kinase inhibitors both in vitro and in vivo. Mechanistic investigation revealed that hyperphosphorylation of Src and subsequent activation of anti-apoptotic signaling via Akt pathway contributed to D7 resistance. These results support D7 as a promising third generation EGFR inhibitor deserving further development, and identify potential combination strategies with potential biomarkers for NSCLC tumors that is resistant to this compound. Keywords: EGFR inhibitor, lung cancer, drug resistance, combination therapy Citation Format: Tao Zhang, Rong Qu, Chengbin Chen, Linjiang Tong, Fang Feng, Yi Chen, Meiyu Geng, Ke Ding, Hua Xie, Jian Ding. Discovery of a novel third generation EGFR TKI and identification of its potential mechanism of resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2210.
Dasatinib in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: Preliminary Results of a Phase I Study.
Authors: Thierry Facon, Xavier Leleu, A. Keith Stewart, Andrew Spencer, Philip Rowlings, Cyrille Hulin, Michel Attal, Felix Garzon, Eric Bleickardt, Konstantina Gialelis, Doreen Tuozzoli, Dominique Derreumaux, Pieter Sonneveld
Journal: Blood (2009)
Abstract 3068: Synergistic effect of BCL-2 inhibitor APG-2575 and CDK9 inhibitor in acute myeloid leukemia and DLBCL preclinical tumor models
Authors: Douglas D. Fang, Ran Tao, Qiuqiong Tang, Shoulai Gu, Guoqin Zhai, Jiajun Li, Qixin Wang, Xu Fang, Na Li, Dajun Yang, Yifan Zhai
Journal: Cancer Research (2019)

Abstract Effective treatments are urgently needed for elderly acute myeloid leukemia (AML) and relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients as only 10-25% of the population respond to standard therapies and resistance often occurred. Concurrent overexpression of anti-apoptotic BCL-2 gene and proto-oncogene MYC are frequently found in AML and DLBCL and this molecular characteristic is associated with poor prognosis of patients. CDK9 controls non-ribosomal transcription of genes including MYC and MCL-1. Dysregulation in the CDK9 pathway had been reported in AML and DLBCL, making it an attractive target for the combination with BCL-2 inhibitor to achieve more effective therapy. To test the above hypothesis, in this study, we applied the combination of APG-2575 with a CDK9 inhibitor (alvocidib or dinaciclib) to preclinical tumor models. APG-2575 is a novel, orally bioavailable BH3-mimetic that selectively inhibits BCL-2, but not BCL-xL or MCL-1. After the treatment, synergistic effect of the combination treatment was demonstrated in mice bearing xenograft tumors of human AML or DLBCL. Specifically, in xenograft tumor models derived from human DLBCL cell line U2932, the treatment with APG-2575, alvocidib, or dinaciclib single agent for 22 days exhibited antitumor activity with T/C values of 20-50% (T/C value, average tumor volumes in treatment group vs. the vehicle control group). The combination treatment achieved substantial antitumor activity with T/C value of 5%. All animals in the combination groups showed either partial or complete tumor regression whereas none in the single arms. Similar synergistic antitumor activity of the combination treatment was consistently observed in the myelodysplastic syndrome SKM-1 and AML OCI-AML-3 xenograft models. Taken together, our data suggest that APG-2575 and CDK9 inhibition combination has a potential therapeutic application in treatment of patients with AML and DLBCL. Citation Format: Douglas D. Fang, Ran Tao, Qiuqiong Tang, Shoulai Gu, Guoqin Zhai, Jiajun Li, Qixin Wang, Xu Fang, Na Li, Dajun Yang, Yifan Zhai. Synergistic effect of BCL-2 inhibitor APG-2575 and CDK9 inhibitor in acute myeloid leukemia and DLBCL preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3068.
Abstract 1033: Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer
Authors: Emily N. Arner, Victoria H. Cruz, Wenting Du, Rolf Brekken
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS. Direct inhibition of KRAS through pharmacological means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. We investigated the contribution of TANK-binding kinase 1 (TBK1), a critical downstream effector of mutant active KRAS, to PDA progression. We report that higher levels of TBK1 mRNA are associated with poorer overall survival in human PDA patients and that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. Further, we identify that the receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB-dependent manner. These findings demonstrate that TBK1 is central to an Axl-driven epithelial-mesenchymal transition in KRAS-mutant PDA and suggest that interruption of the Axl-TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease. Citation Format: Emily N. Arner, Victoria H. Cruz, Wenting Du, Rolf Brekken. Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1033.
Abstract 5189: Activity of polycomb repressive complex 2 determines sensitivity to epigenetic therapy
Authors: Fan Chen, Christine F. Brainson
Journal: Cancer Research (2019)

Abstract EZH2 is a histone methyltransferase that tri-methylates histone H3 at lysine 27 (H3K27me) in the context of the Polycomb Repressive Complex 2, and is highly correlated with poor prognosis of many cancers. However, recent data suggest a de-coupling of EZH2 expression from its enzymatic activity, and many poor prognosis tumors also have low H3K27me3. Therefore, we hypothesize that deletion of Ezh2 would drive more aggressive tumors which may have distinct epigenetic vulnerabilities. To test this hypothesis, we generated the LSL:KrasG12D/+; p53 flox/flox (LSL: lox-stop-lox) mice (Kras/p53 mice) with either zero, one or two floxed alleles of Ezh2 and induced lung tumors with intranasal adeno-Cre virus administration. Supporting our hypothesis, we observed mice with two floxed alleles of Ezh2 (Ezh2 null) had higher tumor burden, higher tumor grade and lower survival than Ezh2 wild-type or heterozygous Kras/p53 mice. Ezh2 null tumors also had a higher propensity to metastasize than Ezh2 wild-type tumors. Consistent with these results, Ezh2 null Kras/p53 tumors and cell lines had increased expression of genes involved in epithelial-mesenchymal transition (EMT), KRAS-driven tumorigenesis, metastasis, and cell cycle regulation. In order to examine the therapeutic vulnerabilities of Ezh2 depleted lung cancers, we built a panel of 2-dimensional cell lines and 3-dimensional organoid cultures of the Kras/p53 tumors that were Ezh2 null, heterozygous and wild-type. We reasoned that using the H3K27me3 demethylase inhibitor might be able to stabilize the residual H3K27me3 in Ezh2 null cells and decrease their aggressive properties. Intriguingly, while we observed no difference in sensitivity to H3K27me3 demethylase inhibitor in the various Ezh2 genotypes of 2-dimensional cultures, both 3-dimensional cultures and in vivo allografts demonstrated Ezh2 null tumors but not Ezh2 WT or heterozygous are sensitive to the H3K27me3 demethylase inhibitor. These data are interesting because they suggest that assays of 3-dimensional organoids may more faithfully recapitulate responses to epigenetic drugs than standard cell lines, and that aggressive tumors with low H3K27me3 might be selectively killed by demethylase inhibitor. We are now expanding our studies to include other targeting agents, including inhibitors of the kinase WEE1 and inhibitor of the chromatin reader BRD4. Citation Format: Fan Chen, Christine F. Brainson. Activity of polycomb repressive complex 2 determines sensitivity to epigenetic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5189.
Abstract #2054: Cucurbitacin B has a markedly antiproliferative effect on pancreatic cancer cells in vitro and in vivo.
Authors: Nils Thoennissen, Gabriela Iwanski, Ngan Doan, Ryoko Okamoto, Sam Abbassi, Jee Song, Daniel Nowak, Carsten Müller-Tidow, Jonathan Said, H. Koeffler
Journal: Cancer Research (2009)

Pancreatic cancer is the fourth most common malignancy in the United States. Gemcitabine is currently the best treatment available for pancreaticcancer, but the disease develops resistance to the drug overtime. Recently, we were able to show that cucurbitacin B (CuB), one particularly potent family member of triterpenoid substances isolated from plants, has antiproliferative activity on breast cancer and glioblastoma multiforme cells. In this study, the antiproliferative effects of CuB against human pancreatic cancer cells were tested. Dose-response studies showed that CuB inhibited 50 % growth (ED50) of 10 human pancreatic cancer cell lines in liquid culture at 1 - 5 x 10-7 M. The pancreatic cancer cell lines showed rapid morphological changes after exposure to CuB, including reduced cytoplasmic volume and loss of cell surface pseudopods. Prominent multi-nucleation was observed after the cells were pulse-exposed (10-7 M, 24 hours) to the drug, washed and cultured in normal medium for an additional 48 hours. Soft-gel assays showed that the clonogenic pancreatic cancer cells were significantly inhibited at 10-7 M of CuB. Pancreatic cancer cells treated with a combination of CuB (10-7 M) and gemcitabine(1 µg/ml) showed significant increase in apoptosis (P = 0.001 versus control;P = 0.007 versus gemcitabine alone) as determined by Annexin V staining, suggesting that CuB synergistically potentiated the antitumor effectsof gemcitabine in pancreatic cancer. Furthermore, FACS analysis demonstrated that CuB induceddose- and time-dependentgrowth arrest in pancreatic cancercells by decreasing the S - phase and arresting cells in the G2/M - phase. On protein level, the drug inhibited the activation of STAT3 and decreased levels of Bcl-X(L)in vitro which led to cleavage of Caspase-9 and PARP without inhibition of AKT, ERK, or JNK activation as seen by Western blot. The human pancreatic cancer cell line PANC1 was used for xenobiotic tumor induction in athymic nude mice who intraperitoneally received either CuB 1.0 mg / kg or vehicle (5 mice / group). The volume of the induced tumors was reduced by 72 % (p   Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2054.
Abstract 2160: Microfragmented human fat tissue is a natural scaffold for drug delivery: potential application in cancer chemotherapy
Authors: Giulio Alessandri, Valentina Coccè, Fabio Pastorino, Rita Paroni, Michele Deicas, Francesco Restelli, Carlo Tremolada, Angiola Berenzi, Eugenio Parati, Anna Teresa Brini, Giampietro Bondiolotti, Augusto Pessina, Mirco Ponzoni
Journal: Cancer Research (2019)

Abstract Localization of chemotherapy at the tumor site can improve therapeutic efficacy and reduce systemic toxicity. In previous studies we have shown that mesenchymal stromal cells (MSCs) isolated from bone marrow or fat tissue, can be loaded with the anti-cancer drug Paclitaxel (PTX) and kill cancer cells when localized nearby. We here investigated the capacity of human micro-fragmented adipose tissue (MFAT), used as a natural container of MSCs, to delivery PTX with the idea to improve local drug concentration and to prolong the therapeutic activity. Surprisingly, we found that both fresh but also devitalized MFAT (DMFAT) (by freezing/thawing procedure) were very effective biomaterials able to deliver and release significant amount of PTX, killing several human cancer cell lines in vitro with an impressive long lasting activity. In an orthotopic mice model of Neuroblastoma (NB) transplant, we found that DMFAT loaded with PTX prevents or delay NB relapse when placed in the surgical area of tumor resection, without any collateral toxicity. We concluded that MFAT, but also DMFAT, may work as natural biomaterials that can be used to localize and release anti-cancer molecules at the tumor site. In addition, the procedure to easily prepare DMFAT did not alter its natural scaffold structure. This suggest that such biomaterial may have a prominent role in the near future in many oncological applications to delivery anti-cancer drugs, helping to fight cancer in human. Citation Format: Giulio Alessandri, Valentina Coccè, Fabio Pastorino, Rita Paroni, Michele Deicas, Francesco Restelli, Carlo Tremolada, Angiola Berenzi, Eugenio Parati, Anna Teresa Brini, Giampietro Bondiolotti, Augusto Pessina, Mirco Ponzoni. Microfragmented human fat tissue is a natural scaffold for drug delivery: potential application in cancer chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2160.
Abstract 4401: Implications of STAG2 loss in Ewing sarcoma
Authors: Aparna Gorthi
Journal: Cancer Research (2019)

Abstract Ewing sarcoma is an aggressive pediatric bone and soft tissue cancer that is driven by a translocation event, predominantly involving the RNA binding protein EWSR1 and the transcription factor FLI1. The resultant fusion transcription factor EWSR1-FLI1 is a potent oncogene and drives dramatic changes in the transcriptional landscape of Ewing sarcoma. Our previous work demonstrated that EWS-FLI1 drives aberrant accumulation of R-loops, increases replication stress and suppresses homologous recombinational repair in Ewing sarcoma. Similar phenotypes were also observed with the loss of wildtype EWSR1. However, surprisingly, Ewing tumors have highly stable genomes. The most common mutation is in the STAG2 gene, a component of the cohesin ring complex. It was recently reported that STAG2-cohesin complexes not only participate in maintaining chromatin architecture but also play a key role in directing tissue-specific gene expression by interacting with transcription factors. In the present study, we evaluate the STAG2 function in R-loop metabolism, replication and repair and attempt to identify the reason for its selective loss in Ewing sarcoma. Using biochemical and biophysical experimental strategies, we observed that STAG2 and EWSR1 both bind R-loop structures with high affinity and are protective against RNaseH-mediated degradation of R-loops to significantly different degrees. We also examine the effect of STAG2 loss on R-loop accumulation and replication stress in Ewing and non-Ewing cell lines. Finally, we evaluate the correlation between STAG2 binding sites and R-loops. We propose that loss of STAG2 alleviates some of the genomic stresses experienced in Ewing sarcoma. Note: This abstract was not presented at the meeting. Citation Format: Aparna Gorthi. Implications of STAG2 loss in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4401.
Apalutamide for Metastatic, Hormone-Responsive Prostate Cancer
Authors: Laurence Klotz
Journal: New England Journal of Medicine (2019)

The Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial, the results of which are reported in this issue of the Journal,1 involved patients with metastatic, castration-sensitive prostate cancer who were randomly assigned to receive either apalutamide (240 mg per day) or placebo, both added to androgen-deprivation therapy (ADT). The trial is the latest contribution to the veritable explosion of large, prospective, randomized trials of androgen-receptor axis–targeted drugs (ARATs). These have resulted in the rapid transformation of the management of advanced prostate cancer. Docetaxel was the only effective agent for castration-resistant prostate cancer2 until 2011, when a trial of abiraterone . . .
Abstract 20594: IL-1 Pathway Inhibition Attenuates Vascular Smooth Muscle Cell Phenotypic Switching to a Macrophage-Like State During Aortic Aneurysm Formation
Authors: Morgan D Salmon, William Montgomery, Michael D Spinosa, Delphine Gomez, Gary K Owens, Ashish K Sharma, Gilbert R Upchurch, Gorav Ailawadi
Journal: Circulation (2017)

Introduction: Aortic aneurysms(AAs) are characterized by inflammation, cytokine upregulation, smooth muscle cell(SMC) modulation, macrophage activation and matrix degradation. IL-1 has been shown t...
High-throughput identification of human SNPs affecting regulatory element activity
Authors: Joris van Arensbergen, Ludo Pagie, Vincent D. FitzPatrick, Marcel de Haas, Marijke P. Baltissen, Federico Comoglio, Robin H. van der Weide, Hans Teunissen, Urmo Võsa, Lude Franke, Elzo de Wit, Michiel Vermeulen, Harmen J. Bussemaker, Bas van Steensel
Journal: Nature Genetics (2019)
Impact of vaccination on antibiotic usage: a systematic review and meta-analysis
Authors: B.S. Buckley, N. Henschke, H. Bergman, B. Skidmore, E.J. Klemm, G. Villanueva, C. Garritty, M. Paul
Journal: Clinical Microbiology and Infection (2019)

BackgroundVaccines may reduce antibiotic use and the development of resistance.ObjectivesTo provide a comprehensive, up-to-date assessment of the evidence base relating to the effect of vaccines on antibiotic use.Data sourcesOvid MEDLINE, Embase, the Cochrane Library, ClinicalTrials.gov and WHO Trials Registry.Study eligibility criteriaRandomized controlled trials (RCTs) and observational studies published from January 1998 to March 2018.ParticipantsAny population.InterventionsVaccines versus placebo, no vaccine or another vaccine.MethodsTitles, abstracts and full-texts were screened independently by two reviewers. Certainty of RCT evidence was assessed using GRADE.ResultsIn all, 4980 records identified; 895 full-text reports assessed; 96 studies included (24 RCTs, 72 observational). There was high-certainty evidence that influenza vaccine reduces days of antibiotic use among healthy adults (one RCT; n = 4253; rate reduction 28·1%; 95% CI 16·0–38·4); moderate-certainty evidence that influenza vaccines probably reduce antibiotic use in children aged 6 months to 14 years (three RCTs; n = 610; ratio of means 0·62; 95% CI 0·54–0·70) and probably reduce community antibiotic use in children aged 3–15 years (one RCT; n = 10 985 person-seasons; risk ratio 0·69, 95% CI 0·58–0·83); and moderate-certainty evidence that pneumococcal vaccination probably reduces antibiotic use in children aged 6 weeks to 6 years (two RCTs; n = 47 945; rate ratio 0·93, 95% CI 0·87–0·99) and reduces illness episodes requiring antibiotics in children aged 12–35 months (one RCT; n = 264; rate ratio 0·85, 95% CI 0·75–0·97). Other RCT evidence was of low or very low certainty, and observational evidence was affected by confounding.ConclusionsThe evidence base is poor. Although some vaccines may reduce antibiotic use, collection of high-quality data in future vaccine trials is needed to improve the evidence base.PROSPERO registrationCRD42018103881.