tbuckley/cabot-search huggingface dataset:
Abstract 3920: Tumor volume as a predictor of lymph node metastases in prostate cancer
Authors: Chidi N. Molokwu, Keith Yuen, Sanjay Addla, Rajindra Singh, Rohit Chahal
Journal: Cancer Research (2017)

Abstract Introduction: Pelvic lymph node dissection (PLND) is recommended during radical prostatectomy (RP) in patients with high risk prostate cancer (PCa). Guidelines recommend extended PLND in patients who have &amp;gt;5% probability of lymph node involvement, calculated from pre-operative parameters. PLND increases procedure time and potential morbidity to patients. Tumour size has been reported to be predictive of biochemical recurrence after RP. We analysed the utility of several parameters including tumour size in predicting lymph node metastases in order to further refine the population who require PLND during RP. Materials &amp; Methods: We maintained a prospective database of Robotic Assisted Radical Prostatectomy (RARP) from July 2012 to August 2016 consisting of a cohort of 531 patients. Patients with &amp;gt;5% calculated probability of lymph node metastasis had PLND during RARP. We performed multiple linear regression using age, PSA, D’Amico risk score, ISUP prognostic group, clinical T-stage, radiological T-stage, tumour volume, tumour volume relative to prostate size (relative tumour volume), and number of nodes excised during PLND to determine if any of these parameters could predict the presence of lymph node metastases. Results: Of the cohort of 531 patients, 154 had PLND during RARP. Of the PLND cohort, 15 (10%) had pN1 disease. Tumour volume (r2 0.044, p= 0.0098), relative tumour volume (r2 0.033, p=0.026) and number of lymph nodes excised (r2 0.046, p=0.0075) were independent predictors of pN1 disease. D’Amico risk score (r2 0.019, p=0.089) approached but did not reach statistical significance. Patients with pN1 disease all had primary tumours ≥6cc. Conclusions: In our cohort of PLND patients, tumour volume was an independent risk factor for pN1 disease. With the increasing availability of multi-parametric MRI, tumour volume can be measured pre-operatively as an adjunct to PIRADS scoring. The role of tumour volume and relative tumour volume in predicting lymph node metastasis in conjunction with other pre-operative parameters requires further investigation. The use of tumour volume in determining the need for PLND in patients undergoing RP may help to further refine the population at highest risk for pN1 disease and avoid the additional morbidity of PLND in those at low risk. In addition, our findings support the recommendation of performing an extended PLND to maximise regional lymph node clearance. Citation Format: Chidi N. Molokwu, Keith Yuen, Sanjay Addla, Rajindra Singh, Rohit Chahal. Tumor volume as a predictor of lymph node metastases in prostate 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 3920. doi:10.1158/1538-7445.AM2017-3920
Abstract 5108: Potent small molecule compounds that selectively inhibit proliferation of ABC-DLBCL cell lines
Authors: Leena Khare Satyam, Dinesh Chikkanna, Vinayak Khairnar, Manoj Pothuganti, Sunil Panigrahi, Anirudha Lakshminarasimhan, Narasimha Rao, Wesley Balasubramanian, Sandeep Patil, Sreevalsam Gopinath, Gunta Upendra, Jwala Nagaraj, Kiran Aithal, Vijay Ahuja, Sanjeev Giri, Chetan Pandit, Murali Ramachandra
Journal: Cancer Research (2017)

Abstract Diffuse large B cell lymphoma (DLBCL), which accounts for 25% of all lymphomas cases, has been classified into molecular subtypes including germinal center B cell like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal B cell lymphoma (PMBL). Among these subtypes, patients with ABC-DLBCLs have the worst prognosis because of the high chemo-resistance, and require effective therapies. Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 (MALT1) protease activity is linked to the pathogenesis of ABC-DLBCL. Therefore, a focused library of covalent compounds selected based on molecular docking on the reported crystal structure was screened for selective sensitivity to ABC-DLBCL, but not GCB-DLBCL cell lines. Optimization of initial hits resulted in the identification of lead compounds with an anti-proliferative EC50 of &amp;lt;100 nM selectively in ABC-DLBCL cell lines. Consistent with the previously reported role of MALT1 inhibitors, lead compounds also showed anti-proliferative activity in selected melanoma and NSCLC cell lines. The anti-proliferative activity of the lead compounds correlated well with the inhibition IL-6, a downstream marker of MALT1 signaling, in ABC-DLBCL cell line such as OCI-LY3. The lead compounds exhibited excellent drug-like properties including solubility, metabolic stability, lack of CYP inhibition, permeability and desired dose-dependent oral exposure in pharmacokinetic studies. In a repeated dose MTD study, the lead compounds showed good tolerability with an exposure multiple of &amp;gt;10 over cellular EC50 for up to 8 hours. The lead compounds showed dose-dependent tumor growth inhibition in a xenograft model upon oral dosing. In summary, we have identified novel and potent MALT1 inhibitors capable of selectively inhibiting proliferation of DLBCL cell lines with optimized drug-like properties including oral bioavailability. The data presented here strongly support further development of these compounds for DLBCL and other indications. Citation Format: Leena Khare Satyam, Dinesh Chikkanna, Vinayak Khairnar, Manoj Pothuganti, Sunil Panigrahi, Anirudha Lakshminarasimhan, Narasimha Rao, Wesley Balasubramanian, Sandeep Patil, Sreevalsam Gopinath, Gunta Upendra, Jwala Nagaraj, Kiran Aithal, Vijay Ahuja, Sanjeev Giri, Chetan Pandit, Murali Ramachandra. Potent small molecule compounds that selectively inhibit proliferation of ABC-DLBCL cell lines [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 5108. doi:10.1158/1538-7445.AM2017-5108
Abstract 5456: Avoiding chemotherapy resistance in squamous cell carcinomas: anticancer activities of terpenoids and their impact on the regulation of microRNAs
Authors: Camila Hernandes, Bruna da Silva, Maria de Fatima Guarrido Klingbeil, Monica Beatriz Mathor, Ana Maria Soares Pereira, Patricia Severino
Journal: Cancer Research (2017)

Abstract MicroRNAs are small noncoding RNAs that play important roles in cellular biology. They have been implicated in pharmacogenomics by down-regulating genes that are essential for drug function. In this work we verified the potential anticancer activity of the quinone methide triterpenes maytenin and 22-β-hydroxymaytenin, as well as of a quinone methide triterpene-rich extract obtained from cultivated Maytenus ilicifolia root cells, and evaluated the associated microRNA expression following half maximal inhibitory concentration (IC50) treatment. Standard selectivity index (SI) for the isolated compounds and the root cell extract was determined by the logarithmic shift in effective concentration (IC50) between cancer cell lines and oral keratinocytes. Both isolated molecules as well as the root cell extract presented pronounced antiproliferative and pro-apoptotic activities in four cell lines derived from head and neck squamous cell carcinomas, including a metastasis-derived cell line. A positive SI, with an average 2-fold increase in potency, was detected for single agents and for the extract. MicroRNA expression profiles were assessed at 24h, 48h and 72h following treatment and an average of 100 molecules presented consistent marked variation in expression levels. Considering associations of microRNAs, genes they regulate, and the drugs effects dependent on these genes, the down-regulation of miR-193a-3p and miR-21 in treated cells is of particular interest. Both microRNAs have been involved in 5-fluorouracil and cisplatin resistance, current agents of standard chemoradiotherapy for locally advanced head and neck cancer. Squamous cell carcinoma of the head and neck is one of the most common cancer types worldwide whereas treatment options based on conventional therapies or targeted therapies under development have limited efficacy. Plant-derived products are valuable sources for the development of new therapeutic options for cancer treatment or as synergistic agents in existing regular care. Citation Format: Camila Hernandes, Bruna da Silva, Maria de Fatima Guarrido Klingbeil, Monica Beatriz Mathor, Ana Maria Soares Pereira, Patricia Severino. Avoiding chemotherapy resistance in squamous cell carcinomas: anticancer activities of terpenoids and their impact on the regulation of microRNAs [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 5456. doi:10.1158/1538-7445.AM2017-5456
Abstract 1888: 3D matrix confinement triggers vascular mimicry through a conserved migratory and transcriptional response
Authors: Daniel Ortiz, Brian Tsui, Tyler Goshia, Colleen Ricker, Hannah Carter, Stephanie I. Fraley
Journal: Cancer Research (2017)

Abstract An initial step in solid tumor metastasis involves the migration of tumor cells through extracellular matrix. Several cancer cell migration strategies exist in vivo, and the local properties of collagen fibers are implicated in modulating migration behaviors. Yet, individual tumor cells also display heterogeneity in their intrinsic ability to migrate and metastasize. It remains unclear to what extent intrinsic and extrinsic heterogeneity contribute to the emergence of distinct migration phenotypes and whether certain migration phenotypes contribute more to metastasis than others. To study this, we generated 3D collagen matrices of varying densities and monitored single cancer cell migration in these matrices with time-lapse microscopy. We observed a collagen density threshold at 2.5mg/ml, above which 86% of MDA-MB-231 breast cancer cells transition from single mesenchymal migration to collective cell migration, with a 50% increase in persistence after cell division. After seven days, these collectively migrating cells created networks coated with basement membrane molecules resembling a clinical phenotype known as vascular mimicry (VM).The remaining 14% of cells migrated randomly and eventually formed spheroids. HT-1080 fibrosarcoma cells also responded similarly, migrating persistently and forming cellular networks. Next we sought to identify the physical feature of high-density collagen driving VM. Neither hypoxia or matrix stiffness was sufficient to induce VM. However, PEG-induced matrix confinement triggered VM network formation. RNA sequencing revealed collectively migrating cells up-regulated a conserved transcriptional program significantly enriched for annotations of vascular development and motility regulation processes. This gene module predicted survival in human tumor transcriptome datasets. Our results suggest that the VM phenotype arises in a subpopulation of cells from a conserved transcriptional and migratory response to confinement in 3D collagen. Note: This abstract was not presented at the meeting. Citation Format: Daniel Ortiz, Brian Tsui, Tyler Goshia, Colleen Ricker, Hannah Carter, Stephanie I. Fraley. 3D matrix confinement triggers vascular mimicry through a conserved migratory and transcriptional response [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 1888. doi:10.1158/1538-7445.AM2017-1888
Abstract 4747: Subcutaneous fat predict outcome in head and neck cancer
Authors: Ngan M. Tsang
Journal: Cancer Research (2017)

Abstract Background: Previous studies have shown that body mass index (BMI) is linked to survival in cancer patients. Our objective was to analyze whether body composition before treatment can predict outcomes in patients with head-and neck cancer. Methods: All 881 patients with loco-regional head-and -neck cancer treated with curative-intent RT during 2005 to 2012 were retrospectively studied. Body composition analyses by using pre-RT CT images acquired for RT simulation. We compared subcutaneous adipose tissue (SAT) index and muscle index by measuring cross-sectional area of tissues at level of the third thoracic vertebrae (T3) in both genders. Overall survival (OS), loco-regional control (LRC), and distant metastasis-free survival (DFS) were analyzed by body composition index that divided into two groups based on values higher and lower than the median. The median follow-up was 4.68 years. Results: SAT index in female patients was significantly higher than that in male (p &amp;lt;0.001). The median SAT index and muscle index for female were 15.25 cm2/m2 (range, 0.93-88.09 cm2/m2) and 34.3 cm2/m2 (range, 14.78-73.05 cm2/m2), and for male were 6.19 cm2/m2 (range, 0.21-40.48 cm2/m2) and 51.74 cm2/m2 (range, 8.03-89.06 cm2/m2). The 5-year and 10-year OS, LRC and DFS were 66.3%, 57.6%, 73.4%, 71.4%, 83%, and 82.1%. Higher pre-treatment SAT index was associated with longer OS (HR = 0.616; P = 0.001) and DFS (HR = 0.649; P = 0.015) and a trend towards longer LRC (HR = 0.772; P = 0.066). Pre-treatment muscle index was also a significant predictor of OS (HR = 0.662; P = 0.006) and LRC (HR = 0.684; P = 0.029). Conclusion: SAT index and muscle index of T3 level obtained from CT images appear to predict outcomes in patients with curative head-and-neck cancers. Note: This abstract was not presented at the meeting. Citation Format: Ngan M. Tsang. Subcutaneous fat predict outcome in head and neck 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 4747. doi:10.1158/1538-7445.AM2017-4747
The research agenda for trauma critical care
Authors: Karim Asehnoune, Zsolt Balogh, Giuseppe Citerio, Andre Cap, Timothy Billiar, Nino Stocchetti, Mitchell J. Cohen, Paolo Pelosi, Nicola Curry, Christine Gaarder, Russell Gruen, John Holcomb, Beverley J. Hunt, Nicole P. Juffermans, Mark Maegele, Mark Midwinter, Frederick A. Moore, Michael O’Dwyer, Jean-François Pittet, Herbert Schöchl, Martin Schreiber, Philip C. Spinella, Simon Stanworth, Robert Winfield, Karim Brohi
Journal: Intensive Care Medicine (2017)
Abstract 1169: mtTERT promoter as a target for treatment of glioblastoma
Authors: Saumya R. Bollam, Harshil D. Dhruv, Hyun-Jin Kang, Sen Peng, Vijay Gokhale, Laurence Hurley, Michael Berens
Journal: Cancer Research (2017)

Abstract Approximately 86% of GBM tumors exhibit mutation at -124 or -146 bases upstream of the ATG start site in the transcription activating promoter region of Human telomerase reverse transcriptase (hTERT). Mutation in the promoter region of hTERT impairs repression, leading to overexpression of hTERT; inappropriate hTERT is associated with oncogenesis, tumor maintenance, and resistance to apoptosis. We surveyed long-term glioma cell lines and glioma PDX models for mt-hTERT; mRNA and protein expression of hTERT were assessed by qPCR and western blot. The -124 and -146 mutations are located in the major 5-12 G-quadruplex and result in misfolding of the silencer element and consequent over-expression of hTERT. Using a diverse small molecule library, we identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, TG-4260, which binds to the 26 mer base-pair heteroduplex loop, which is the nucleation site for cooperative folding of the major 5-12 G-quadruplex. The chaperone effect of TG-4260 corrects DNA hTERT G-quadruplex misfolding resulting from the somatic mutations and restores the silencer function of the G-quadruplex thereby reducing hTERT activity. TG-4260 directly decreases the transcription activity of the WT and the −124, −124/125, −138/139, and −146 mutants to a similar extent and suppresses the downstream gene BCL2, which activates caspase-3 and produces cell-cycle arrest, leading to cell death. Finally, TG-4260 significantly inhibits telomerase and shortens telomere length after five days of treatment and induces a senescence-like phenotype. This is the first example of the use of a pharmacoperone molecule to correct the misfolding of a DNA G-quadruplex element resulting from mutations in an early folding intermediate. Finally, we screened GBM cell models against a novel small molecule inhibitor that interferes with mutated hTERT promoter and demonstrated that TG-4260 selectively suppresses glioma cell viability without affecting non-transformed normal human astrocytes. Citation Format: Saumya R. Bollam, Harshil D. Dhruv, Hyun-Jin Kang, Sen Peng, Vijay Gokhale, Laurence Hurley, Michael Berens. mtTERT promoter as a target for treatment of glioblastoma [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 1169. doi:10.1158/1538-7445.AM2017-1169
Abstract 2886: CD44/SMURF1 signaling maintains cancer stem cell-like invasive cells in head and neck squamous cell carcinoma
Authors: Ali Khammanivong, Raj Gopalakrishnan, Erin B. Dickerson
Journal: Cancer Research (2017)

Abstract Head and neck squamous cell carcinoma (HNSCC) is highly invasive and resistant to therapies, where treatments often result in high rates of failure and disease recurrence. A subpopulation of tumor-initiating cancer stem cells (CSC) is thought to be responsible for metastatic invasion and drug resistance in many types of cancer, including HNSCC. CD44 is a known CSC marker in HNSCC but its role in maintaining CSC populations is not well understood. We previously reported that SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) inhibition of bone morphogenetic protein (BMP) signaling is essential for maintaining a CD44-high CSC-like population in HNSCC. In this study, we sought to determine how CD44, a receptor for hyaluronic acid (HA) that constitutes a major component of the tumor stroma, is involved in the regulation of SMURF1 and the maintenance of a HNSCC CSC phenotype. CSC-like cells were enriched from HNSCC cell lines as CD44-high cells. CD44 signaling was stimulated by exogenous HA treatment and inhibited by CD44 knockout (KO) using an inducible CRISPR/Cas9 system. We then assessed changes in SMURF1 protein level, BMP signaling, transwell migration, Matrigel colony formation, and invasion through three-dimensional organotypic culture (OTC) following CD44 modulation. CD44-high cells were found to have increased extracellular HA production. Treatment with exogenous HA reduced BMP signaling, as determined by a reduction in phospho-SMAD1/5/8 levels, and increased transwell migration of CD44-high cells. CD44-KO reduced SMURF1 protein expression and inhibited Matrigel colony formation of an invasive and recurrent HNSCC-derived CD44-high cells but only partially reduced colony formation of a less-invasive cell line derived from a primary HNSCC. Knockout of CD44 expression showed a slight reduction in transwell migration of invasive cells. CD44-high cells also recapitulated an invasive and CSC-like growth pattern in OTC assays. In contrast, CD44-KO inhibited OTC invasion and the epithelial-to-mesenchymal transition (EMT) phenotype, resulting in increased apical epithelial growth and differentiation. CD44 reconstitution appeared to restore the invasive and EMT phenotype. Based on our current findings, CD44 may be crucial for maintaining an anchorage-independent and invasive phenotype of HNSCC but plays a minor role in carcinoma cell migration. Citation Format: Ali Khammanivong, Raj Gopalakrishnan, Erin B. Dickerson. CD44/SMURF1 signaling maintains cancer stem cell-like invasive cells in head and neck squamous cell carcinoma [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 2886. doi:10.1158/1538-7445.AM2017-2886
Abstract 1051: Preclinical analyses of synergistic effect of eribulin and paclitaxel for triple-negative breast cancer
Authors: Takaaki Oba, Ken-ichi Ito
Journal: Cancer Research (2017)

Abstract Purpose: There is an urgent need to develop novel therapeutic strategies for triple negative breast cancer (TNBC). To explore the antitumor effect of combination of eribulin (ERI) and paclitaxel (PTX) for TNBC, we conducted preclinical experiments. Materials &amp; methods: Combinational effects of ERI and PTX were analyzed both in vitro and in vivo using two TNBC cell lines (MDA-MB-231, Hs578T). Results: When ERI was added simultaneously with PTX to TNBC cells, the sensitivity to PTX was increased synergistically. On the other hand, synergistic increase of sensitivity to ERI was observed in the presence of PTX. When the TNBC cells were treated with each drug subsequently, pretreatment with ERI for 96 hours enhanced the sensitivity to PTX administrated subsequently. In contrast, pretreatment of TNBC cells with PTX enhanced the sensitivity to the subsequently administrated ERI. When the TNBC cells were treated with ERI, the expression of epithelial marker, E-cadherin was increased, while the expression of mesenchymal markers, pSmad2, ZEB1, Slug, and vimentin were decreased. In contrast, when the cells were treated with PTX, the expressions of mesenchymal markers were increased. When epithelial-mesenchymal transition (EMT) was induced by TGF-β in the TNBC cells, the sensitivity to ERI was enhanced, while TGF-β receptor inhibitor (LY2157299) reduced the sensitivity to ERI. Furthermore, knockdown of ZEB1 by small interfering RNA conferred resistance to ERI in both TNBC cell lines. In the mouse xenograft model bearing MDA-MB-231, ERI plus PTX combination therapy significantly inhibited tumor growth compared with either PTX or ERI monotherapy. Furthermore, prior treatment with ERI significantly enhanced the antitumor activity of PTX in the mouse xenograft model. Conclusions: Our findings demonstrate an EMT-mediated synergistic antitumor effect by combination of two tubulin inhibitors. This combination therapy may serve as a novel therapeutic strategy for TNBC. Citation Format: Takaaki Oba, Ken-ichi Ito. Preclinical analyses of synergistic effect of eribulin and paclitaxel for triple-negative 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 1051. doi:10.1158/1538-7445.AM2017-1051