tbuckley/cabot-search huggingface dataset:
Abstract 1921: Stem-like clusters of CD44+ circulating tumor cells seed metastases in breast cancer
Authors: Xia Liu, Wenjing Chen, Rokana Taftaf, Huiping Liu
Journal: Cancer Research (2017)

Abstract Background: Circulating tumor cells (CTCs) are cells shed from primary tumor and circulate in the peripheral blood. They are considered the seeds of metastasis. Compared to single CTCs, clusters of multiple CTCs possess 50 times higher metastatic capacity in mouse breast cancer models. However, the mechanisms underlying the metastatic promotion effect of CTC clusters are unclear. In addition, whether clustered CTCs have cancer stem cell (CSC) properties and what stem cell markers they express have not been determined. Methods: Immunohistochemistry (IHC) was used to detect CTCs in vascular structures, and the stem cell markers in single and clustered CTCs. Lung metastases were either monitored by bioluminescence imaging (BLI) or visualized by fluorescence microscopy. Stem cell properties were examined by mammosphere assays in vitro and tumorigenic assays in vivo. Clustering assay was performed by culturing cells in Poly-HEMA coated plates (for cell lines) or collagen-coated plates (for primary cells derived from patient-derived breast tumor xenografts, PDXs), and then monitored by IncuCyte live cell dynamic imaging. Results: CD44+ enriched circulating tumor cell (CTC) clusters were found in the lung/liver vascular structures in vivo in both metastatic breast cancer patients and PDXs that develop spontaneous lung metastases. Comparing to single CD44+ cells, clustered CD44+ cells formed more mammospheres, increased tumorigenic potential, and promoted lung colonization. Combining siRNA-mediated knockdown and CRISPR/Cas-based knockdout, we found that CD44 is required for breast tumor cell cluster formation and lung colonization upon tail vein seeding. During cluster formation, EGFR was activated, which improved both stemness and survival of clustered CTCs. Anti-EGFR antibody mimicked CD44 knockdown to inhibit cluster formation of PDX-derived tumor cells. Administration of EGFR inhibitor Erlotinib efficiently inhibited CD44+ cells-mediated spontaneous metastases to the lungs without affecting primary tumor growth. Conclusions: Our data provide new insights into the cellular and molecular mechanisms of stem-like clustered CD44+ cells-seeded metastasis, and implicate that targeting CD44+ CTC clusters by inhibition of EGFR activity could be a new therapeutic strategy to treat metastatic breast cancer. Citation Format: Xia Liu, Wenjing Chen, Rokana Taftaf, Huiping Liu. Stem-like clusters of CD44+ circulating tumor cells seed metastases in breast 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 1921. doi:10.1158/1538-7445.AM2017-1921
Abstract 5279: Association of Vitamin D deficiency with breast cancer in African-American and Hispanic women in south Los Angeles
Authors: Yanyuan Wu, Marianna Sarkissyan, Sheilah Clayton, Jay Vadgama
Journal: Cancer Research (2017)

Abstract Background: Experimental evidence supports a protective role of Vitamin D level in breast carcinogenesis, but epidemiologic evidence is inconsistent. African Americans have high prevalence of Vitamin D deficiency and the African American women with breast cancer have the highest mortality rate. The aim of this study is to investigate the association of Vitamin D levels with breast cancer risk and disease progression in African American and Hispanic women. Methods: This is a cases-control study of 660 African American and Hispanic women with and without breast cancer in South Los Angeles. Blood samples were collected prior cancer treatment and the serum 25-hydroxyvitamin D (25(OH) D was measured by Quest Diagnostics. Information regarding BMI and clinical factors were obtained by medical record abstraction. Logistic Regression with multivariate analysis was used for determining the association of Vitamin D deficiency (&amp;lt;20ng/ml) with breast cancer. Kaplan-Meier survival analysis and Cox Regression with multivariate analysis were used to assess disease-free survival and the relative risk of disease progression. Results: Our data shows that 69.2% of African American women and 37.8% of Hispanic women suffer from Vitamin D deficiency in our cohort. African American women had significant lower level of Vitamin D3 compared with Hispanic women in all age groups. The lower Vitamin D3 level was observed among age groups of 31 to 50 in African Americans. The deficiency in Vitamin D levels was significantly associated with breast cancer in both African Americans (OR=2.5, p=0.007) and Hispanics (OR=1.9, p=0.009). Interestingly, we found that a significant association of Vitamin D deficiency with trip negative breast cancer (TNBC) in African Americans (OR=3.2, p=0.04), but not in Hispanics. The lowest Vitamin D3 level was observed in African American women with TNBC. There was no significant association of Vitamin D deficiency with tumor size, lymph node involvement and tumor stage. The deficiency of Vitamin D3 level was not associated with disease progression in this cohort of women. Conclusion: Our data suggests that a significant association of Vitamin D deficiency with breast cancer in both African Americans and Hispanics, especially more associated with type of TNBC in African American women in our cohort. Citation Format: Yanyuan Wu, Marianna Sarkissyan, Sheilah Clayton, Jay Vadgama. Association of Vitamin D deficiency with breast cancer in African-American and Hispanic women in south Los Angeles [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 5279. doi:10.1158/1538-7445.AM2017-5279
Abstract 2073: A systematic investigation of the effect of scheduling of targeted combination therapies on response and dynamics of relapse in triple negative breast cancer cells
Authors: Gauri A. Patwardhan, Vikram B. Wali, Lajos Pusztai, Christos Hatzis
Journal: Cancer Research (2017)

Abstract Cancer treatment typically involves administration of combination of targeted therapies, but initial response is often followed by disease relapse. The efficacy of a treatment regimen depends on the complex interplay between cancer growth dynamics, drug specificity and kinetics, treatment dose and its scheduling. In standard high-throughput drug screening assays, cells are treated with a single drug cocktail bolus and cell viability is assessed after 2-3 days, thus not considering treatment interactions and long-term effects. Recently we have reported a promising synergistic combination of crizotinib (ALK/MET inhibitor) and ABT-263 (BCL2/BCL-XL inhibitor) against triple negative breast cancer cells. To understand the effect of the sequence and combination doses of crizotnib and ABT-263, we designed a comprehensive experimental plan that involved a total of 567 treatment regimens by varying treatment duration with the first drug (1, 2, or 3 days), followed by drug withdrawal and recovery period (2, 5 or 10 days) and then by a second cycle of treatment and recovery periods over a 26-day period. Cell viability was assessed by the CellTiter-Glo luminescence assay. Interestingly, ABT-263 alone induced higher cytotoxicity than an equivalent dose of crizotinib, but the remaining viable cells recovered much faster after ABT-263 withdrawal than cells after crizotinib withdrawal. Furthermore, cells exposed to higher doses of ABT-263 eventually become less sensitive to crizotinib. Among sequential regimens, crizotinib followed by ABT-263 was significantly more effective than ABT-263 followed by crizotinib, and combinations that included lower doses of ABT-263 were most effective. Taken together, our results show a significant interaction between the two targeted therapies, and suggest that it may be possible to select treatment scheduling that can delay drug resistance and tumor relapse in vivo. Note: This abstract was not presented at the meeting. Citation Format: Gauri A. Patwardhan, Vikram B. Wali, Lajos Pusztai, Christos Hatzis. A systematic investigation of the effect of scheduling of targeted combination therapies on response and dynamics of relapse in triple negative breast cancer 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 2073. doi:10.1158/1538-7445.AM2017-2073
Health differentials among women aged 15–54 years in the occupied Palestinian territories: a cross-sectional study of data from the Palestinian Family Health Survey 2010
Authors: Katie Bates, Rula Ghandour, Sawsan Imseeh, Suzan Mitwalli, Shiraz Nasr, Doaa Hammoudeh, Ernestina Coast, Tiziana Leone, Rita Giacaman
Journal: The Lancet (2017)
Abstract 3399: Genomic analysis of melanoma evolution following a 30 year disease-free interval
Authors: Jerry J. Miller, Kristopher A. Lofgren, Sarah R. Hughes, Steven E. Cash, David R. Meier, Paraic A. Kenny
Journal: Cancer Research (2017)

Abstract The rate of ultra-late recurrence (beyond 10-15 years) of cutaneous melanoma has been estimated to be between 2.0-6.9% from large case series. Two major factors complicate the interpretation of these data. Firstly, the risk of second primary melanoma is approximately 5% creating uncertainty about whether at least some of these late onset tumors might be independent of the original lesion. Secondly, in the majority of cases, the original pathology specimen is no longer available for comparative analysis. Accordingly, putative late recurrences are difficult to unambiguously distinguish from a new primary melanoma. We identified a patient with a second melanoma diagnosed after a 30 year disease-free interval, and sought to determine if this new lesion was a recurrence of the original melanoma. We report the genomic sequence analysis of the exomes of two melanoma lesions isolated from the same individual in 1985 and 2015, and their comparison to each other and to the germline DNA of the patient. Identification of many shared somatic mutations between these lesions prove a lineal relationship spanning 30 years. Unlike prior reports of ultra-late melanoma recurrence, the availability of the original tumor and the use of comprehensive genomic analysis allowed us to confirm that the second lesion is truly a recurrence. We demonstrate the acquisition of numerous additional mutations during the three decade asymptomatic period. This is, to our knowledge, the longest disease-free interval that has been rigorously confirmed in melanoma or any other solid tumor type. These data highlight the low but very long-lasting risk of recurrence in this patient population. Citation Format: Jerry J. Miller, Kristopher A. Lofgren, Sarah R. Hughes, Steven E. Cash, David R. Meier, Paraic A. Kenny. Genomic analysis of melanoma evolution following a 30 year disease-free interval [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 3399. doi:10.1158/1538-7445.AM2017-3399
Abstract 1868: Molecular imaging of human esophageal cancer for early detection
Authors: Xibo Ma, Hui Meng, Jie Tian
Journal: Cancer Research (2017)

Abstract Esophageal cancer was the sixth common cancer for incidence and ranks fourth for death rate in China, and squamous cell carcinoma is the main histological type. It is usually in an advanced stage at the time of diagnosis, resulting in an overall 5-year survival rate of &amp;lt;15%. Early detection can lead to an improvement in patient outcomes but is limited by nonspecific contrast mechanisms. As all we know, antibody and peptides establish a biological basis for image contrast, which could achieve sufficient target-to-background ratio for in vivo detection. In this paper, an EGFR antibody (Cetuximab) conjugated with an NIR dye (NIRDye800) was used for early detection of esophageal cancer. We demonstrated our technology could identify esophageal cancer in small size (&amp;lt;1 mm) and high-grade dysplasia from low-grade dysplasia. And 4.2-fold greater fluorescence intensity for esophageal cancer compared with surrounding normal esophageal tissues. No toxicity was observed in our experiments. The result indicated that this targeted, antibody-based imaging agents have great potential in early detection of esophageal cancer and other epidermal cancer. Citation Format: Xibo Ma, Hui Meng, Jie Tian. Molecular imaging of human esophageal cancer for early detection [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 1868. doi:10.1158/1538-7445.AM2017-1868
Abstract SY19-03: Inflammation-driven cancer: Host and microbial pathways
Authors: Fiona Powrie, Sarah McCuaig, Nathan West, Grigory Ryzhakov
Journal: Cancer Research (2017)

Abstract The gastrointestinal (GI) tract is home to a large number and vast array of bacteria that play an important role in nutrition, immune system development, and host defense. In inflammatory bowel disease (IBD) there is a breakdown in this mutualistic relationship, resulting in aberrant inflammatory responses that can progress to colon cancer. Our studies in model systems have implicated innate lymphoid cells and production of IL-22 as key drivers of neoplasia and cancer in the intestine. In this presentation I will discuss new checkpoints that control bacteria-driven innate inflammation in the intestine as well as the functional effects of IL-22 on intestinal epithelial cells and interactions between IL-22 signaling and oncogenic mutations. Further understanding of the interactions between host genetics, gut microbiota, and deranged inflammatory pathways will yield new approaches to patient stratification and personalized therapy. Citation Format: Fiona Powrie, Sarah McCuaig, Nathan West, Grigory Ryzhakov. Inflammation-driven cancer: Host and microbial pathways [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 SY19-03. doi:10.1158/1538-7445.AM2017-SY19-03
Discovery of Aptamer Ligands for Hepatic Stellate Cells Using SELEX
Authors: Zhijin Chen, Hao Liu, Akshay Jain, Li Zhang, Chang Liu, Kun Cheng
Journal: Theranostics (2017)

Insulin like growth factor II receptor (IGFIIR) is a transmembrane protein overexpressed in activated hepatic stellate cells (HSCs), which are the major target for the treatment of liver fibrosis.In this study, we aim to discover an IGFIIR-specific aptamer that can be potentially used as a targeting ligand for the treatment and diagnosis of liver fibrosis.Systematic evolution of ligands by exponential enrichment (SELEX) was conducted on recombinant human IGFIIR to identify IGFIIR-specific aptamers.The binding affinity and specificity of the discovered aptamers to IGFIIR and hepatic stellate cells were studied using flow cytometry and Surface Plasmon Resonance (SPR).Aptamer-20 showed the highest affinity to recombinant human IGFIIR protein with a K d of 35.5 nM, as determined by SPR.Aptamer-20 also has a high affinity (apparent K d 45.12 nM) to LX-2 human hepatic stellate cells.Binding of aptamer-20 to hepatic stellate cells could be inhibited by knockdown of IGFIIR using siRNA, indicating a high specificity of the aptamer.The aptamer formed a chimera with an anti-fibrotic PCBP2 siRNA and delivered the siRNA to HSC-T6 cells to trigger silencing activity.In Vivo biodistribution study of the siRNA-aptamer chimera also demonstrated a high and specific uptake in the liver of the rats with CCl 4 -induced liver fibrosis.These data suggest that aptamer-20 is a high-affinity ligand for antifibrotic and diagnostic agents for liver fibrosis.
Should This Patient Receive an Antidepressant?
Authors: Risa B. Burns, Gerald W. Smetana, Roscoe Brady
Journal: Annals of Internal Medicine (2017)

Depression is a major public health problem and a common cause of disability. To help physicians choose among available treatment options, the American College of Physicians recently issued a guideline titled “Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients with Major Depressive Disorder.” The evidence review done for the guideline found no statistically significant difference in the efficacy of second-generation antidepressants (SGAs) versus most other treatments for this disorder. However, rates of adverse events and discontinuation were generally higher in patients treated with SGAs. This Beyond the Guidelines reviews the guideline and includes a discussion between 2 experts on how they would apply it to a 64-year-old man with depression who is reluctant to begin medication. They review the data on which the guideline is based, discuss the limitations of applying the data to real-world settings, review how they would incorporate patient preferences when making treatment decisions, and outline options for patients in whom first-line therapy has failed.
Abstract 881: CD44-specific supramolecular hydrogels for fluorescence molecular imaging of EMT induced BRAF &amp;lt;V600E&amp;gt; mutant thyroid cancer cells
Authors: Hyung Kwon Byeon, Minhee Ku, Yeon Ju Yang, Min Hee Cho, Yoojung Oh, Jae Wook Kim, Myung Jin Ban, Ji-Hoon Kim, Da Hee Kim, Joo Hyun Kim, Jaemoon Yang, Yoon Woo Koh
Journal: Cancer Research (2017)

Abstract Previously, the authors have identified that the acquired drug resistance to BRAF inhibitor, PLX4032 in BRAF (V600E) mutant anaplastic thyroid cancer promotes not only tumor progression and proliferation, but also migration and invasion of cancer through upregulated epithelial-to-mesenchymal transition (EMT). The underlying mechanism to the acquired resistance to BRAF inhibition involves c-Met-mediated reactivation of PI3K/AKT pathway. Therefore combinatorial dual targeted therapy of BRAF and c-Met inhibition has shown to reverse EMT and show maximal antitumor effect. Previously, the authors have developed a novel in vivo imaging strategy using CD44-targetable near-infrared (NIR)-sensitive supramolecular hydrogels (NIRSHs) for the recognition of CD44-expressing cancer cells. In the present study, we applied this NIR-sensitive molecular imaging probe in detecting the upregulated EMT changes in PLX4032-treated 8505C cells. The CD44-targetable NIRSHs were fabricated by polyplexing Cy5.5-conjugated polyethyleimine and hyaluronic acid in an aqueous medium. Ectopic xenograft mouse models were prepared by injecting 8505C cells at the flank of male athymic nude BALB/c mice, aged 6 weeks. After confirming tumor formation at 3 weeks post-injection, the mice were randomly divided into four groups and were each treated under different conditions; DMSO, PLX4032, PHA665752, PLX4032 and PHA665752. After 3 weeks, the pre-established NIRSH probes were injected and confirmed by IVIS imaging. The injected NIRSH probes showed highest uptake in the PLX4032 single treatment group and lowest uptake in the PLX4032 and PHA665752 combination group. Sizes of tumor were verified by MRI which showed correlations with the NIRSH fluorescence imagings. The results suggest that CD44-targetable NIRSHs imaging shows potential as a non-invasive in vivo imaging tool in detecting the increased invasion potential of cancer cells and monitoring appropriate therapeutic effects. Citation Format: Hyung Kwon Byeon, Minhee Ku, Yeon Ju Yang, Min Hee Cho, Yoojung Oh, Jae Wook Kim, Myung Jin Ban, Ji-Hoon Kim, Da Hee Kim, Joo Hyun Kim, Jaemoon Yang, Yoon Woo Koh. CD44-specific supramolecular hydrogels for fluorescence molecular imaging of EMT induced BRAF &amp;lt;V600E&amp;gt; mutant thyroid cancer 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 881. doi:10.1158/1538-7445.AM2017-881
Abstract 3254: Identification of potent anti-tumor agents from the LOPAC library using a unified 2D/3D cell culture screening approach
Authors: Viswanath Das, Tomáš Fürst, Soňa Gurská, Petr Džubák, Marián Hajdúch
Journal: Cancer Research (2017)

Abstract Two-dimensional (2D) cultures of immortalized cancer cells have played a significant role cancer drug discovery and development process for decades. However, the limitations imposed by the long-term cultures of cancer cell lines are becoming increasingly apparent only recently. Therefore, there is a general shift towards three-dimensional (3D) cell cultures, which effectively mimic tumor complexities, for lead optimization and to accelerate translation research. 3D cell cultures not only model the in vivo architecture of tumors, but 3D-derived cells also retain numerous signatures of cancer stem cells compared to parental cells in 2D. In this study, using a unified 2D and 3D cell culture screening approach, we screened the LOPAC library from Sigma-Aldrich as a proof-of-concept study. The drug screening was performed using parental colorectal cancer HCT116 cells as a model cell line. 3D-derived cultures were generated from multicellular spheroids of HCT116 cells. Additionally, utilizing lightsheet fluorescence microscopy (LSFM), we studied the tissue penetration of drugs in spheroids of HCT116 and cells expressing hypoxia-inducible factor-1α (HIF-1α). We identified cc. 200 compounds from the LOPAC library that showed increased activity in 3D-derived cultures. A dose–response relationship study of top 20% compounds further confirmed the preferential activity of these drugs in 3D than 2D cultures. Next, studies in spheroid cultures resulted in the identification of five lead compounds with potent spheroid-size reducing effects. Three of these compounds were kinase inhibitors, one HIF-1α inhibitor, and one interestingly, a monoamine oxidase inhibitor. LSFM studies in HCT116-HIF-1α spheroids showed that two kinase inhibitors and the HIF-1α inhibitors significantly altered spheroid hypoxia, and presumably spheroid growth. We believe that this proof-of-concept study will further highlight the advantages of a combined 2D/3D screening approach for drug discovery and development, and consequently enable downstream testing at reduced cost. Citation Format: Viswanath Das, Tomáš Fürst, Soňa Gurská, Petr Džubák, Marián Hajdúch. Identification of potent anti-tumor agents from the LOPAC library using a unified 2D/3D cell culture screening approach [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 3254. doi:10.1158/1538-7445.AM2017-3254