tbuckley/cabot-search huggingface dataset:
Abstract 5924: Necrotic cells promote microglia infiltration in glioblastoma through regulating MCP-1 and MIP-3α expression
Authors: Yieun Jung, So-Hee Ahn, Hyunju Park, Jiwoo Lim, Jihee Lee Kang, Youn-Hee Choi, Eun Ju Kim
Journal: Cancer Research (2017)

Abstract Glioblastoma multiform (GBM), a grade IV astrocytoma, is most lethal and common adult primary intracranial tumor. GBM is characterized by diffuse infiltration into normal brain parenchyma, rapid growth and the presence of necrosis and microglia/macrophage infiltration. Among these properties of GBM, necrosis has been implicated to be a strong predictor of poor prognosis; however, the effect of necrosis on GBM progression is poorly understood at present. In this study, we examined the effect of necrosis on glioblastoma cells by exploring molecular mechanisms underlying gene expression and chemokine expression. Data obtaining from chemokine array and ELISA showed that CRT-MG human gliomablastoma cells secreted several chemokines including MCP-1 and MIP-3α in response to necrotic cells. Expression levels of mRNA and protein of MCP-1 and MIP-3α were also increased by treatment with necrotic cells in CRT-MG in a dose-dependent manner. Necrotic cells induced NF-κB/AP-1 activation and their binding to the MCP-1 and MIP-3α promoter, leading to enhanced MCP-1 and MIP-3α production in GBM cells. Finally, transwell migration assay showed that incubation with necrotic cells significantly enhanced the migration of microglia. Our data demonstrate that when GBM cells are exposed to and stimulated by necrotic cells, the expression and secretion of MCP-1 and MIP-3α are enhanced in GBM cells and microglia infiltration/migration to the tumor site are facilitated. Citation Format: Yieun Jung, So-Hee Ahn, Hyunju Park, Jiwoo Lim, Jihee Lee Kang, Youn-Hee Choi, Eun Ju Kim. Necrotic cells promote microglia infiltration in glioblastoma through regulating MCP-1 and MIP-3α expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5924. doi:10.1158/1538-7445.AM2017-5924
Abstract LB-310: PYK2 as a therapeutic target for pancreatic cancer
Authors: Jing Hu, Chenxi Gao, Guangming Chen, Xuan Gao, Dennis H. Zhang, Shih-Fan Kuan
Journal: Cancer Research (2017)

Abstract Since nearly 100% of pancreatic ductal adenocarcinoma (PDAC) carried mutational activation of KRAS, KRAS and its effectors are theoretically ideal candidates for PDAC therapeutic intervention. Unfortunately, attempts to directly inhibit oncogenic KRAS or known RAS effector pathways have been either unsuccessful or proven ineffective. As a result, there is significant interest in identifying novel downstream effectors of oncogenic KRAS signaling that could be amenable to pharmacologic intervention. Our results suggest that PYK2 (proline-rich tyrosine kinase 2, a non-receptor cytoplasmic tyrosine kinase) is a novel downstream mediator of mutant KRAS signaling and a new actionable therapeutic target for PDAC. Specifically, our studies revealed: (1) mutant KRAS activated PYK2 gene transcription in a YAP1 (Yes-associated protein 1)-dependent manner. Hippo pathway effector YAP1 is a transcription cofactor and a powerful downstream effector of mutant KRAS in PDAC. (2) PYK2 levels were drastically elevated in mouse PanINs (pancreatic intraepithelial neoplasia) and human PDAC tissues. (3) Functionally, Whole-body deletion of PYK2, even heterozygous deletion, remarkably suppressed PanIN formation and progression to PDAC in the Pdx1-Cre KRASG12D mice model. Further, knockdown of PYK2 abrogated tumor growth in a PDAC cell line xenograft model, indicating that PYK2 is required for PDAC maintenance. (4) Mechanistically, PYK2 directly phosphorylated β-catenin at tyrosine (Y) 654 to promote the Wnt/β-catenin pathway and increased RelA/p65 phosphorylation at serine (S) 536 to promote the NF-κB pathway in PDAC cells. Because both pathways are essential for PDAC development in mice, we propose that PYK2 contributes to PDAC through upregulating Wnt/β-catenin and NF-κB pathways. Overall, our study has revealed that PYK2 is a new actionable target for treating PDAC. Citation Format: Jing Hu, Chenxi Gao, Guangming Chen, Xuan Gao, Dennis H. Zhang, Shih-Fan Kuan. PYK2 as a therapeutic target for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-310. doi:10.1158/1538-7445.AM2017-LB-310
Abstract 767: Breast cancer in sub-Saharan Africa: a histopathologic review from a tertiary hospital in Northern Nigeria
Authors: Saad A. Ahmed, Balarabe Kabir, Nasiru Abubakar
Journal: Cancer Research (2017)

Abstract Introduction: Breast cancer is the commonest cancer in women world-wide, however, there are discrepancies in the incidence among different geographical regions. The highest incidence rate is in North American, Northern and Western European, while the lowest rate is found among Asian and sub-Sahara African women. Breast cancer is undoubtedly heterogeneous in terms of its presentation, morphology and molecular profiles. Studies from the developing countries suggested that there are differences between the biology of BC in the developing and developed countries. Methods: This is a retrospective histopathologic review of breast cancer cases between 1st January 2003 and 31st December 2015 from the Ahmadu Bello University Teaching Hospital Zaria - Nigeria. Results: A total of 784 breast cancer cases were seen during the study period and majority of the cases (99.4%) were females. The prevalence of breast cancer was found to be 12.6%. Triple-negative breast cancers (TNBC) constitute 67.7% of cases. The mean age was 45.8 ±12.0 years and the youngest patient was 18 years while the oldest was 90 years. Out of the 784 cases, 208 were mastectomies while the remaining were incisional, trucut needle and excisional biopsies. Infiltrating ductal carcinoma NST was the most common histologic variant seen (94.7%) and most of these cases (59.1%) were Grade II tumors. The Nottingham Prognostic Index (NPI) shows that 91.4% of the cases have NPI Score of ≥3.5 with attendant poor 5-year survival rate. Conclusion: This study found that breast cancer is common and affects mostly women in fifth decade of life. There is a high TNBC among the population studied and therefore androgen receptor profile and genomic studies may be useful to determine the course of therapy. Note: This abstract was not presented at the meeting. Citation Format: Saad A. Ahmed, Balarabe Kabir, Nasiru Abubakar. Breast cancer in sub-Saharan Africa: a histopathologic review from a tertiary hospital in Northern Nigeria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 767. doi:10.1158/1538-7445.AM2017-767
Subgroup analyses of the effectiveness of oral glucosamine for knee and hip osteoarthritis: a systematic review and individual patient data meta-analysis from the OA trial bank
Authors: Jos Runhaar, Rianne M Rozendaal, Marienke van Middelkoop, Hans J W Bijlsma, Michael Doherty, Krysia S Dziedzic, L Stefan Lohmander, Timothy McAlindon, Weiya Zhang, Sita Bierma Zeinstra
Journal: Annals of the Rheumatic Diseases (2017)

Objective To evaluate the effectiveness of oral glucosamine in subgroups of people with hip or knee osteoarthritis (OA) based on baseline pain severity, body mass index (BMI), sex, structural abnormalities and presence of inflammation using individual patient data. Methods After a systematic search of the literature and clinical trial registries, all randomised controlled trials (RCTs) evaluating the effect of any oral glucosamine substance in patients with clinically or radiographically defined hip or knee OA were contacted. As a minimum, pain, age, sex and BMI at baseline and pain as an outcome measure needed to be assessed. Results Of 21 eligible studies, six (n=1663) shared their trial data with the OA Trial Bank. Five trials (all independent of industry, n=1625) compared glucosamine with placebo, representing 55% of the total number of participants in all published placebo-controlled RCTs. Glucosamine was no better than placebo for pain or function at short (3 months) and long-term (24 months) follow-up. Glucosamine was also no better than placebo among the predefined subgroups. Stratification for knee OA and type of glucosamine did not alter these results. Conclusions Although proposed and debated for several years, open trial data are not widely made available for studies of glucosamine for OA, especially those sponsored by industry. Currently, there is no good evidence to support the use of glucosamine for hip or knee OA and an absence of evidence to support specific consideration of glucosamine for any clinically relevant OA subgroup according to baseline pain severity, BMI, sex, structural abnormalities or presence of inflammation.
Abstract 500: Impairment of DNA double strand break repair in human primary alveolar type II cells in emphysema
Authors: Beata Kosmider, Liudmila Vlasenko, Nathaniel Marchetti, Sudhir Bolla, Chenna Mandapati, Nathaniel Xander, Gerard Criner, Karim Bahmed
Journal: Cancer Research (2017)

Abstract Rationale Emphysema is caused by the destruction of alveolar wall septa. The major risk factor for this disease is cigarette smoke and effective therapies are very limited. Alveolar type II (ATII) cells are in the gas exchange portion of the lung. They make and secrete pulmonary surfactant, and proliferate to restore the epithelium after damage to the more sensitive alveolar type I cells. Methods Control ATII cells were isolated from deidentified control non-smoker and smoker organ donors whose lungs were not suitable for transplantation and donated for medical research. Furthermore, as a unique approach, we have developed a new method on how to isolate ATII cells from excess tissue from lung transplants obtained from patients with emphysema using magnetic microbeads. We determined DNA damage, DNA repair, oxidative stress, injury, and inflammation in human primary ATII cells isolated from these individuals in comparison with controls. Results Our data indicates high oxidative stress in human ATII cells induced by cigarette smoke extract in vitro as measured by 4-HNE staining by immunocytofluorescence. We also observed DNA double strand breaks, high DNA damage, and low DNA repair in these cells. Moreover, we found greater proinflammatory response as determined by IL-8 and IL-6 levels by ELISA. Furthermore, ATII cells obtained from patients with emphysema had greater injury compared to cells obtained from control non-smokers and smokers. Conclusion Our results indicate oxidative ATII cell damage induced by cigarette smoke and in emphysema. Observed DNA damage/repair imbalance may contribute to cell death in this disease. The study of ATII cell injury may improve our knowledge on this disease pathogenesis and may lead to novel therapeutic strategies to slow the progression of emphysema. Note: This abstract was not presented at the meeting. Citation Format: Beata Kosmider, Liudmila Vlasenko, Nathaniel Marchetti, Sudhir Bolla, Chenna Mandapati, Nathaniel Xander, Gerard Criner, Karim Bahmed. Impairment of DNA double strand break repair in human primary alveolar type II cells in emphysema [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 500. doi:10.1158/1538-7445.AM2017-500
Abstract 4332: Interactome between vascular endothelial cells and Proneural glioma stem cells protects seeds for GBM recurrence from radiation therapy
Authors: Soniya Bastola, Marat S. Pavlyukov, Shinobu Yamaguchi, Jun Wang, Svetlana Komarova, Harley I. kornblum, Ichiro Nakano
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) is the most aggressive form of intracranial tumors. Despite multimodal treatment strategies that include surgical resection, radiation and chemotherapy, most patients survive for less than two years. GBM cells tend to invade into adjacent normal brain tissues and therefore, cannot be completely resected by surgery. These remaining tumor cells are the “seeds” to escape post-surgical therapies, thereby giving rise to recurrent tumors during or after treatment. The exact mechanisms by which these seeds contain pre-existing resistant cells, and/or gain resistance to therapy remain elusive. Recent findings demonstrated that communication between normal and GBM cells play physiological roles in tumor initiation and progression. Here, we aim to determine how vascular endothelial (VE) cells affect GBM recurrence in response to radiotherapy. To this end, we first assessed the effect of secreted factors from VE cells on patient-derived GBM neurospheres in vitro by using their conditioned medium (CM). GBM neurospheres promoted their growth with CM from VE cells. qPCR and FACS exhibited that the CM treatment preferentially protected CD133+ population in GBM neurospheres that otherwise were depleted by irradiation treatment. Furthermore, RNA sequencing of VE cells and A2B5-expressing GBM stem-like cells directly isolated from GBM and epilepsy patients demonstrated that only tumor-derived VE cells and GBM stem-like cells express a high level of a secreted factor Endocan (ESM1) and its receptor CD11a, respectively. Preferential expression of CD11a in perivascular GBM cells was also confirmed by immunocytochemistry. Further, we found that recombinant Endocan is able to promote GBM neurosphere growth in vitro after irradiation and protected them from irradiation-induced aggressive mesenchymal transition of these cells. Taken together, these results demonstrate a potential role of a crosstalk between peri-vascular GBM stem-like cells and their adjacent VE cells, via the ligand-receptor interaction mechanism. This interactome network may help Proneural GBM stem cells to escape from radiation therapy, thereby reinitiating the tumor as recurrence via an Endocan-CD11a signaling. Hence, targeting Endocan in endothelial cells or CD11a in GBM cells may have potential as a novel efficacious strategy for preventing recurrence. Citation Format: Soniya Bastola, Marat S. Pavlyukov, Shinobu Yamaguchi, Jun Wang, Svetlana Komarova, Harley I. kornblum, Ichiro Nakano. Interactome between vascular endothelial cells and Proneural glioma stem cells protects seeds for GBM recurrence from radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4332. doi:10.1158/1538-7445.AM2017-4332
Abstract 2320: Cucurbitacin D induces cell cycle arrest and apoptosis by inhibiting STAT3 and NF-κB signaling in doxorubicin-resistant human breast carcinoma (MCF7/ADR) cells
Authors: Jin Mo Ku, Se Hyang Hong, Myeong-Sun Kim, Hyo In Kim, Soo-Yeon Kang, Kangwook Lee, Yu-Jeong Choi, Chunhoo Cheon, CHING WEN HUANG, Youme Ko, Yui Sasaki, Sohyeon Kang, Ji Hye Kim, Hye Sook Seo, Tai Young Kim, Yong Cheol Shin, Seong-Gyu Ko
Journal: Cancer Research (2017)

Abstract Objective: We examined whether cucurbitacin D affects doxorubicin resistance of MCF7/ADR breast cancer cells. Methods: Cell viability was measured by MTT assay. Levels of p-STAT3, p-NF-κB, IκB, and caspases were measured by western blot analysis. Nuclear staining of Stat3 and NF-κB was measured by immunocytochemistry. STAT3 and NF-κB transcriptional activity was detected by STAT3 and NF-κB luciferase reporter gene assays. Analysis of cell cycle arrest was performed by flow cytometry. Induction of apoptosis by cucurbitacin D was measured by annexin VFITC/PI assay. Results: More than 90% of MCF7/ADR cells lived upon treatment with doxorubicin for 24 h. However, upon treatment with cucurbitacin D, cell death was more than 60%. Co-administration of cucurbitacin D and doxorubicin induced apoptosis, G2/M cell cycle arrest, and inhibited upregulated Stat3 by doxorubicin on MCF7/ADR cells. Additionally, cucurbitacin D led to an increase in the IκBα level in the cytosol and a decrease in the p-NF-κB level in the nucleus. Finally, cucurbitacin D inhibited translocation of Stat3 and NF-κB and decreased transcriptional activity in the nucleus. Conclusion: Cucurbitacin D decreases cell proliferation and induces apoptosis by inhibiting Stat3 and NF-κB signaling in doxorubicin-resistant breast cancer cells. Cucurbitacin D could be used as a useful compound to treat Adriamycin-resistant patients. Note: This abstract was not presented at the meeting. Citation Format: Jin Mo Ku, Se Hyang Hong, Myeong-Sun Kim, Hyo In Kim, Soo-Yeon Kang, Kangwook Lee, Yu-Jeong Choi, Chunhoo Cheon, CHING WEN HUANG, Youme Ko, Yui Sasaki, Sohyeon Kang, Ji Hye Kim, Hye Sook Seo, Tai Young Kim, Yong Cheol Shin, Seong-Gyu Ko. Cucurbitacin D induces cell cycle arrest and apoptosis by inhibiting STAT3 and NF-κB signaling in doxorubicin-resistant human breast carcinoma (MCF7/ADR) cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2320. doi:10.1158/1538-7445.AM2017-2320
Abstract 710: Identification of autoantibody to ECH1 &amp; HNRNPA2B1 as potential biomarkers in the early detection of lung cancer
Authors: Liping Dai, Jitian Li, Jun-Chieh J. Tsay, Xiao Wang, John S. Munger, Harvey Pass, William N. Rom, Eng M. Tan, Jian-Ying Zhang
Journal: Cancer Research (2017)

Abstract Background: Identification of biomarkers for early detection of lung cancer (LC) may lead to more effective treatment and reduction of mortality. Methods: Serological proteome analysis (SERPA) was used to identify proteins around 34 kDa, which had been previously recognized by autoantibody in sera from LC patients. We have validated autoantibody response in sera from 90 LC patients, 89 normal controls by using immunoassay. Another independent cohort of 25 LC patients with 219 serial serum samples and 56 matched normal controls were examined to evaluate whether the autoantibody can be detected in the preclinical stage. Results: The proteins with molecular weight of 34 kDa were identified as ECH1, GAPDH and HNRNPA2B1. In the validation study, autoantibody to ECH1 achieved an area under the curve (AUC) of 0.799 with sensitivity of 62.2% and specificity of 95.5% in discriminating LC from normal individuals, and showed negative correlation with tumor size (rs=0.-256, p=0.023). Autoantibody to HNRNPA2B1 performed an AUC of 0.874 with sensitivity of 72.2% and specificity of 95.5%, and showed negative correlation with lymph node metastasis (rs=0.-279, P=0.012). By using longitudinal preclinical samples, autoantibody to ECH1 showed an AUC of 0.763 with sensitivity of 60.0% and specificity of 89.3% in distinguishing LC with matched normal controls, and elevated autoantibody levels could be detected greater than two years prior to LC diagnosis. Conclusions: ECH1 and HNRNPA2B1 are autoantigens that elicit autoimmune responses in LC and can be used as potential biomarkers for the early detection of LC. Funding support: This work was supported by the National Natural Science Foundation of China (81672917, 81372371) and the National Institutes of Health (SC1CA166016 and U01CA086137). Citation Format: Liping Dai, Jitian Li, Jun-Chieh J. Tsay, Xiao Wang, John S. Munger, Harvey Pass, William N. Rom, Eng M. Tan, Jian-Ying Zhang. Identification of autoantibody to ECH1 &amp; HNRNPA2B1 as potential biomarkers in the early detection of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 710. doi:10.1158/1538-7445.AM2017-710
Abstract 456: Functional analysis of DEC1 and DEC2 in cancer metabolism
Authors: Fuyuki Sato, Yasueru Muragaki
Journal: Cancer Research (2017)

Abstract Basic helix-loop-helix (bHLH) transcription factor DEC1 (bHLHE40/Stra13/Sharp2) and DEC2 (bHLHE41/Sharp1) are clock genes that show a circadian rhythm in various tissues. However, the function of DEC1 and DEC2 in metabolism has not been poorly understood. AMP-activated protein kinase (AMPK) activity plays important roles in the metabolic process and circadian rhythm. However, how circadian rhythm of phosphorylation of AMPK (pAMPK) is regulated has been yet understood. The aim of this study is to investigate whether there is a direct correlation between DEC1 and DEC2 expression and AMPK activity in normal and cancer cells. There was an inverse relationship between DEC1 expression and AMPK activity. DEC1 protein and pAMPK showed a circadian rhythm in the mouse liver with different peak levels. Knocking down DEC1 expression increased pAMPK, whereas overexpression of DEC1 decreased it. DEC1 bound to the E-box of the LKB1 promoter, decreased LKB1 activity and total protein levels. In addition, pAMPK immunoreactivity was strongly detected in the liver and lung of DEC2 knockout mice compared with that of wild-type mice. Interestingly, medium change induced the circadian rhythm of DEC2, but not DEC1 in cancer cells. We conclude that DEC1 and DEC2 negatively regulates AMPK activity via LKB1, and play important roles in cancer cell metabolism. Citation Format: Fuyuki Sato, Yasueru Muragaki. Functional analysis of DEC1 and DEC2 in cancer metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 456. doi:10.1158/1538-7445.AM2017-456