tbuckley/cabot-search huggingface dataset:
Abstract 759: microRNA 26a-5p inhibited stemness and enhanced the chemosensitivity of non-small cell lung cancer
Authors: Jiwoong Son, Sun Jung Kwon, In Beom Jeong, Ji Hye Kim
Journal: Cancer Research (2019)

Abstract Only a subpopulation of cells which have the ability to regulate self-renewal and differentiation of cancer cells, are able to tumorigenic capacity. This subpopulation of cells is called cancer stem cells (CSC). Cancer stem cells are also identified in lung cancer and exhibits resistance to chemotherapy, radiotherapy and targeted therapy. Therefore, the technology to control CSCs is a good strategy to overcome resistance to cancer therapy. Epithelial-mesenchymal transition (EMT) has been linked with the generation of cancer stem cells (CSCs). Recent evidence proposes that EMT-related transcriptomic alterations correlate with the acquisition of CSC phenotype. In previous study, we investigated the miRNA profiles of mesenchymal-like lung cancer cell lines to evaluate the relationship beween EMT and miRNA in non-small cell lung cancer (NSCLC). miR-26a-5p is down-regulated in mesenchymal like lung cancer cell lines. These findings suggested miR-26a-5p may be involved in cancer stemness of lung cancer cells. To test that miR-26a-5p has a role in stemness of lung cancer, we performed colony formation assay, sphere formation assay and fluorescence activated cell sorting. RNA polymerase III subunit G (POLR3G) was selected as a candidate target of miR-26a-5p related to cancer stemness. To verify that miR-26a-5p regulates POLR3G, we performed qRT-PCR, western blot and luciferase assays. Cell proliferation assay was performed to evaluate miR-26a-5p’s role of chemosensitizer. The overexpression of miR-26a-5p induced a marked reduction of the colony formation and sphere formation in non-small lung cancer cell lines. Overexpression of miR-26a-5p lead to reduction of CD133+ cells. Co-treatment with miR-26-5p and Paclitaxel treatment showed a significant reduction of growth. miR-26a-5p regulated the expression of POLR3G at the mRNA and protein levels. These data demonstrate for the first time that miR-26a-5p suppresses lung cancer stemness by repressing POLR3G expression. This provides new insight into a potential approach for the treatment of lung cancer by regulating cancer stemness. Citation Format: Jiwoong Son, Sun Jung Kwon, In Beom Jeong, Ji Hye Kim. microRNA 26a-5p inhibited stemness and enhanced the chemosensitivity of non-small cell lung 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 759.
A Correction to the Research Article Titled: “The Identification and Characterization of Breast Cancer CTCs Competent for Brain Metastasis” by L. Zhang, L. D. Ridgway, M. D. Wetzel, J. Ngo, W. Yin, D. Kumar, J. C. Goodman, M. D. Groves, D. Marchetti
Journal: Science Translational Medicine (2013)
The genetic evolution of metastatic uveal melanoma
Authors: A. Hunter Shain, Mette M. Bagger, Richard Yu, Darwin Chang, Shanshan Liu, Swapna Vemula, Jingly F. Weier, Karin Wadt, Steffen Heegaard, Boris C. Bastian, Jens F. Kiilgaard
Journal: Nature Genetics (2019)
Abstract LB-314: Fibroblast growth factor-2, derived from cancer-associated fibroblasts, stimulate proliferation and migration of human breast cancer cells though FGFR1
Authors: Jinyoung Suh, Do-Hee Kim, Hye-Kyung Na, Young-Joon Surh
Journal: Cancer Research (2019)

Abstract Cancer-associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. CAFs are distinct from normal fibroblasts for their overexpression of α-smooth muscle actin (α-SMA) and fibroblast activating protein. Recent studies suggest that CAFs play an important role in proliferation and migration of cancer cells through crosstalk with them. In the present study, we investigated the role for CAFs in breast cancer progression and underlying molecular mechanisms. We found the increased expression of α-SMA in human breast tumor tissues compared with normal adjacent tissues. In particular, α-SMA was highly expressed in the most of estrogen receptor (ER)-negative tumor tissues. When ER-negative breast cancer MDA-MB-231 cells and MDA-MB-468 cells were treated with the CAF-conditioned medium (CM), the cell viability was significantly elevated. In addition, MDA-MB-231 cells exhibited elevated expression of proliferative and invasive genes when incubated with CAFs. Notably, fibroblast growth factor-2 (FGF2) expression was correlated with the presence of CAFs. We noticed that mRNA level of FGF2 in CAFs as well as the concentration of FGF2 in CAF-CM was higher than that in normal fibroblasts. FGF2 exerts its biological effects by binding to FGF receptor 1 (FGFR1). In the breast cancer tissue microarray, 42% ER-negative patients co-expressed FGF2 and FGFR1 proteins, whereas only 19% ER-positive patients co-expressed those proteins. While the expression of FGFR1 was up-regulated in breast cancer cells, another major FGF2-corresponding receptor FGFR2 was barely expressed.This prompted us to explore FGF2-FGFR1 signaling in the context of paracrine communication. CAF-stimulated MDA-MB-231 cell migration and invasion as well as FGFR1 signaling activation were abolished when FGF2-neutralizing antibody was added to the CAF-CM. In a xenograft mouse model, co-injection of shmock-MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced tumor growth, which suggests that stromal-derived FGF2 enhances tumor formation through activation of FGFR1 in cancer cells. Furthermore, FGF2 promotes nuclear localization of FGFR1 which might be associated with cancer cell proliferation and migration. In conclusion, secretion of FGF2 by CAFs stimulates proliferation and migration of breast cancer cells through interaction with FGFR1 which may contribute to human breast cancer progression. Citation Format: Jinyoung Suh, Do-Hee Kim, Hye-Kyung Na, Young-Joon Surh. Fibroblast growth factor-2, derived from cancer-associated fibroblasts, stimulate proliferation and migration of human breast cancer cells though FGFR1 [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-314.
Abstract 2222: Progastrin a new biomarker for hepatocellular cancer patient follow-up
Authors: Alexandre Prieur, Marie Dupuy, Dominique Joubert, Eric Assenat
Journal: Cancer Research (2019)

Abstract Background and aims: Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) patient follow-up, even though around 30% of HCC do not express AFP and its capacity to reliably monitor treatment efficacy is questioned. Interestingly, progastrin, a direct target of the oncogenic Wnt/beta-catenin pathway that is commonly activated in HCC, is secreted as such from tumor cells of various origin, from the very first steps of tumorigenesis. Here, we show the first study evaluating the potency of blood progastrin levels to monitor treatment efficacy and compared it with AFP. Methods: Progastrin was quantified in the blood of 87 patients with HCC (focal (n=23), locally advanced (n=49) or metastatic (n=19). AFP was available in 79 patients. The cancerREAD technology (CE marked since 2017) specifically designed to detect progastrin with a high sensitivity and not any maturation products such as gastrin or gastrin glycine extended was used to assay progastrin in the blood. Patients received a systemic (nevaxar, tepotinib, regorafenib, nivolumab, anti FGR, or carbozantinib) and/or a local treatment. Variations in the levels of progastrin and AFP were analyzed in relationship with evolution of the disease: progression, decrease, stable, in remission, without taking into account the different treatment regimens. Results: Progastrin was detected in 80% of the patients (cut-off value 1 pM, range 0 to 75.9 pM, mean value +/- SE 16.29 +/-1.97 pM). Patients in remission had a significantly lower blood progastrin compared to focal (p=0.019), locally advanced (p=0.0001) or metastatic HCC (p=0.015) (Focal 16.96 +/- 4.82 pM; locally advanced 18.57 +/- 2.75 pM; metastatic 17.81 +/- 4.9 pM; in remission 4.89 +/- 1.05 pM). AFP was above 10 ng/ml (a common threshold value) in 59.4% of the samples; levels of progastrin were not statistically correlated with those of AFP. Blood samples for follow-up of treatment were available for 48 patients. Compared to AFP, progastrin was a better biomarker of the evolution of the disease in 35.1% of the patients. Both biomarkers were equivalent in 32.4% and none were good in 10.8%. AFP was better than progastrin only in 21.6%. Conclusion: Thus, and for the first time, we showed that not only progastrin is a better blood biomarker than AFP to detect HCC but also is better for the follow-up of HCC patients, whatever the treatment of the patient. This is the first study that shows the potential of progastrin (alone or in combination with AFP) as a tool for follow-up of cancer treatment efficacy. Citation Format: Alexandre Prieur, Marie Dupuy, Dominique Joubert, Eric Assenat. Progastrin a new biomarker for hepatocellular cancer patient follow-up [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 2222.
Abstract 283: Combination treatment of PARP and SRC inhibitors in BRCA2 mutated prostate cancer
Authors: Nabeela Khan, Goutam Chakraborty, Subhiksha Nandakumar, Ying Z. Mazzu, Mohammad Atiq, Yuki Yoshikawa, Gwo-Shu Mary Lee, Philip Kantoff
Journal: Cancer Research (2019)

Abstract Background: Recently, poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) have shown promise in metastatic castration resistant prostate cancers (mCRPC) patients harboring DNA repair defects due to mutations of BRCA1/2 and ATM. Despite responses, resistance is common and treatment modalities for PARPi-resistant patients are limited. We hypothesized that combining PARPi with other agents in BRCA2 altered tumors would create synergy and greater response rate and durability. Methods: We established a transcriptomic profile associated with genomic deletion of BRCA2 (homozygous and heterozygous) using publicly available datasets from mCRPC patient tumors. To identify the significantly unregulated oncogenic signaling pathways associated with BRCA2 loss, we used gene-set enrichment analysis (GSEA). We also analyzed this transcriptomic profile by Toppgene suite to identify potential drug targets for BRCA2 deleted tumors. We used experimental human prostate cancer cell lines to validate our current observations from human clinical datasets and pathway analysis. Results: Our GSEA analysis showed significant enrichment of the SRC signaling pathway in BRCA2-altered tumors, and based on the Toppgene suite, we also identified dasatinib (pharmacological inhibitor of SRC) as a potential agent for BRCA2-deleted tumors. Similarly, we observed significant up regulation of SRC phosphorylation in human prostate cancer cells (LNCaP-abl and PC3M) that harbor genomic deletion of BRCA2. We performed cell growth assays in these BRCA2 deleted cells treated with PARPi (olaparib, talazoparib), and dasatinib alone or in combination and calculated drug synergy based on the Chou-Talay Method. PC3M and LNCaP-abl prostate cancer cell lines showed different sensitivities to olaparib and talazoparib. We used olaparib for PC3M and talazoparib for LNCaP-abl cells. Co-administration of the PARPi and SRCi showed significant synergy in both cell lines compared to either inhibitors alone. We will develop the rationale for combining PARPi and SRCi in CRPC patients who harbor defects of BRCA2 after completion of our study in xenograft models. Conclusion: Our study reveals the synergistic effect of PARPi and SRCi in prostate cancer cell lines. We believe this shows great potential for future clinical trials in patients with mCRPC harboring BRCA2 deletions. Citation Format: Nabeela Khan, Goutam Chakraborty, Subhiksha Nandakumar, Ying Z. Mazzu, Mohammad Atiq, Yuki Yoshikawa, Gwo-Shu Mary Lee, Philip Kantoff. Combination treatment of PARP and SRC inhibitors in BRCA2 mutated prostate 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 283.
Prognostic Significance of Ki67 Expression By Immunohistochemistry (IHC) on Bone Marrow Biopsy in Newly Diagnosed Multiple Myeloma
Authors: Myra M Robinson, Shebli Atrash, Taylor Brown, Jared G Block, Edward H Lipford, Elton T Smith, Reed Friend, Amanda Aneralla, Alankrita Taneja, Qing Zhang, David M Foureau, Chelsea Sprouse, Ami Ndiaye, James T Symanowski, Belinda Rene Avalos, Edward A Copelan, Peter M. Voorhees, Saad Z Usmani, Manisha Bhutani
Journal: Blood (2017)
Staphylococcus aureus internalization in mast cells in nasal polyps: Characterization of interactions and potential mechanisms
Authors: Stephen M. Hayes, Timothy C. Biggs, Simon P. Goldie, Philip G. Harries, Andrew F. Walls, Raymond N. Allan, Sylvia L.F. Pender, Rami J. Salib
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 2182: Preclincial in vitro and in vivo combination therapies for mutant IDH1R132 tumors with BAY 1436032
Authors: Stefan Kaulfuss, Julia Zaman, Anuhar Chaturvedi, Holger Hess-Stumpp, Jennifer Höde, Ricarda Biber, Renan Borowicz, Michael Heuser, Andreas von Deimling, Stefan Pusch
Journal: Cancer Research (2019)

Abstract Background: Isocitrate dehydrogenase (IDH) mutations are drivers of different tumors. The IDH1R132 mutation is frequently found in glioma (80%), chondrosarcoma (CS, 45%), intrahepatic cholangiocarcinoma (ICC, 20%), acute myeloid leukemia (AML, 7%), and with low incidences in other solid tumors. Although clinical therapies of mutant IDH inhibition were recently approved for the treatment of AML, few patients benefit from a single therapy with a mutant IDH inhibitor and most of them relapse. Here we report preclinical in vitro and in vivo data on combination therapies of the mIDH1R132 inhibitor BAY 1436032 with standard of care chemotherapies. Methods: in vitro: The sarcoma cell line HT1080 (IDH1R132C), together with two IDH1 wildtype sarcoma cell lines, the SW1353 (IDH2R172S) and SW872 (IDHwt) cell lines, were treated with BAY 1436032 alone and in combination with different standard of care drugs. in vivo: The patient derived xenograft (PDX) ICC model LIXFC2084 (IDH1R132L), the melanoma PDX model MEXF1341 (IDH1R132C) (MEXF1341), the PDX AML model 13PB020 (IDH1R132C) and a sarcoma cell line derived xenograft model HT1080 (IDH1R132C) were included. All models were treated with BAY 1436032 alone and in combination with different standard of care (SOC) drugs. Results: The in vitro treatment with BAY 1436032 unexpectedly increased growth in HT1080 (IDH1R132C) cells with no effect to the control cell lines SW1353 and SW872. In contrast, in vivo, combination of BAY1436032 with everolimus had additive anti-tumor efficacy and was synergistic with cisplatin or the MEK inhibitor refametinib in the treatment of HT1080 xenografts. The combination of BAY 1436032 and refametinib was also additive in the treatment of a melanoma xenograft with IDH1R132C mutation. Another additive efficacy of BAY 1436032 and gemcitabine or cisplatin could be observed in an ICC xenograft model and further in the combination with everolimus in the same model. The combination of BAY 1436032 together with azacitidine in a PDX AML model was also synergistic. Conclusion: These results highlight the combinatorial potential of the mIDH1R132 inhibitor BAY 1436032 with standard of care therapy and the importance of microenvironmental factors, which has to be taken into account when dealing with mutant IDH tumors. Citation Format: Stefan Kaulfuss, Julia Zaman, Anuhar Chaturvedi, Holger Hess-Stumpp, Jennifer Höde, Ricarda Biber, Renan Borowicz, Michael Heuser, Andreas von Deimling, Stefan Pusch. Preclincial in vitro and in vivo combination therapies for mutant IDH1R132 tumors with BAY 1436032 [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 2182.
Regulation of cell cycle and androgen receptor by brefeldin A in androgen-responsive prostate cancer cells
Authors: Robert B. Simon, Shahrad Aynehchi, Hiroshi Tazaki, Muhammad S. Choudhury, Masafumi Oyama, Sensuke Konno
Journal: Cancer Research (2005)

4423  Purpose: To study the mechanism by which an antibiotic brefeldin A (BFA) inhibits proliferation of androgen-responsive prostatic cancer LNCaP cells, focusing on cell cycle and androgen receptor (AR). Materials and Methods: Androgen-mediated cellular events in LNCaP cells were induced using 5α-dihydrotestosterone (DHT) as an androgenic mediator. Effect of BFA on DHT-stimulated cell growth was first assessed, and its regulatory mechanism(s) was further explored by examining cell cycle and AR activity/expression using flow cytometry, AR binding assay, and Western blot analysis. Results: DHT (1 nM) stimulated LNCaP cell growth by ∼37% above control; however, BFA (30 ng/ml) was capable of completely inhibiting such DHT-stimulated proliferation. Cell cycle analysis showed that this growth inhibition was associated with ∼75% reduction in the cell number in the S phase, indicating a blocking of G1-S phase transition. Such a G1 growth arrest was confirmed by a drastic (>80%) down-regulation of specific G1 cell cycle regulators (CDK2, CDK4 and cyclin D1). BFA-induced growth inhibition was also accompanied by a profound (∼90%) loss in AR activity, resulting from a reduction in AR protein expression, revealed by Western blots.Conclusion: This study shows that BFA is capable of completely inhibiting androgen-stimulated LNCaP proliferation, demonstrating its antiproliferative activity. The mode of such inhibitory action of BFA appears to involve a G1 cell cycle arrest as well as the down-regulation of AR activity/expression. Thus, BFA appears to be an effective agent to regulate the growth of hormone-dependent prostate cancer cells.
Abstract 16948: Left Ventricular Longitudinal Strain is Preserved by Lifelong Exercise Training in Healthy Seniors
Authors: Erin Howden, Graeme Carrick-Ranson, Naoki Fujimoto, Tom Sarma, Shige Shibata, Benjamin Levine
Journal: Circulation (2013)

Introduction: Left ventricular (LV) systolic strain may be a more sensitive indicator of cardiac adaptation to exercise training than traditional indices of LV systolic function like ejection fract...
Clinical outcome for patients with metastatic colorectal cancer (mCRC) enrolled in phase I clinical trials: Single institution experience.
Authors: Umang Shah, Gopichand Pendurti, Umang Swami, Yijuan Hou, Mohammad Haroon Ghalib, Imran Chaudhary, Sridhar Mani, Sanjay Goel, Santiago Aparo
Journal: Journal of Clinical Oncology (2013)

e13550 Background: Phase I studies are a fundamental step in anti-cancer drug development. Prior meta-analysis looking at phase I studies showed an overall response rate (ORR) of 10.6 % and grade 4 toxicity rate of 14.3 %, and specifically, patients (pts) with mCRC enrolled in phase I trials had an ORR of 1.3 %. Herein, we report the results of a 12-year experience from our institution. Methods: Records from pts with metastatic colorectal adenocarcinoma enrolled in phase I studies at our institution from January 1999 to December 2010 were reviewed. Recorded data included treatment related responses, survival times and adverse events (AE). Kaplan-Meier analysis, t-test and X 2 tests were used to analyze data. A Cox proportional-hazard model using clinical parameters at enrolment was used to predict survival. Results: Our cohort included 141 pts with mCRC (83% colon and 17% rectum) enrolled in 25 unique phase I trials. Median patient age at enrolment was 59 years, 66% were female and 81% had an ECOG PS of 0-1. Pts received a median of 3 lines of chemotherapy prior to enrolment. The median overall survival (OS) was 8.9 months. The ORR was 4.2%. The clinical benefit rate (ORR or stable disease for ≥ 4 months) was 22%. Univariate analysis showed that being female (P=0.02), Hb &lt;12 g/dL (P=0.01), Alb &lt; 4 g/dL (P=&lt;0.001), Alkaline phosphatase &gt; 150 U/L (P=&lt;0.001) and LDH ≥ 300 U/L (P=&lt;0.001) were independently associated with shorter survival. Multivariate analysis showed that females (HR of 2.81 95% CI 1.71-4.59, p= &lt;0.001), Hb ≥ 12 g/dL (1.67, 95%CI 1.03-1.71, p=0.04), Alb &lt; 4 g/dL (HR 2.51, 95% CI 1.59-3.98, p= &lt;0.001) and LDH ≥300 U/L (HR 2.59, 95% CI 1.65-4.03, p= &lt;0.001) were associated with shorter survival. Grade 3/4 non-hematological and hematological AE were seen in 25% and 45% of patients, respectively. Conclusions: This cohort of pts that received a median of 3 prior lines of therapy had a median OS and ORR of 8.9 months and 4.2%, respectively. These findings are similar to the ones reported in the recent phase III trial using regorafenib. Interestingly, multivariate analysis showed that a Hb of ≥ 12g/dL was associated with worse survival, in agreement with prior reports in which red cell growth factors were used.
An image-based deep learning framework for individualising radiotherapy dose: a retrospective analysis of outcome prediction
Authors: Bin Lou, Semihcan Doken, Tingliang Zhuang, Danielle Wingerter, Mishka Gidwani, Nilesh Mistry, Lance Ladic, Ali Kamen, Mohamed E Abazeed
Journal: The Lancet Digital Health (2019)

Radiotherapy continues to be delivered uniformly without consideration of individual tumor characteristics. To advance toward more precise treatments in radiotherapy, we queried the lung computed tomography (CT)-derived feature space to identify radiation sensitivity parameters that can predict treatment failure and hence guide the individualization of radiotherapy dose.We used a cohort-based registry of 849 patients with cancer in the lung treated with high dose radiotherapy using stereotactic body radiotherapy. We input pre-therapy lung CT images into a multi-task deep neural network, Deep Profiler, to generate an image fingerprint that primarily predicts time to event treatment outcomes and secondarily approximates classical radiomic features. We validated our findings in an independent study population (n = 95). Deep Profiler was combined with clinical variables to derive iGray, an individualized dose that estimates treatment failure probability to be <5%.Radiation treatments in patients with high Deep Profiler scores fail at a significantly higher rate than in those with low scores. The 3-year cumulative incidences of local failure were 20.3% (95% CI: 16.0-24.9) and 5.7% (95% CI: 3.5-8.8), respectively. Deep Profiler independently predicted local failure (hazard ratio 1.65, 95% 1.02-2.66, p = 0.04). Models that included Deep Profiler and clinical variables predicted treatment failures with a concordance index of 0.72 (95% CI: 0.67-0.77), a significant improvement compared to classical radiomics or clinical variables alone (p = <0.001 and <0.001, respectively). Deep Profiler performed well in an external study population (n = 95), accurately predicting treatment failures across diverse clinical settings and CT scanner types (concordance index = 0.77 [95% CI: 0.69-0.92]). iGray had a wide dose range (21.1-277 Gy, BED), suggested dose reductions in 23.3% of patients and can be safely delivered in the majority of cases.Our results indicate that there are image-distinct subpopulations that have differential sensitivity to radiotherapy. The image-based deep learning framework proposed herein is the first opportunity to use medical images to individualize radiotherapy dose.