tbuckley/cabot-search huggingface dataset:
Abstract 1876: Cell cycle-dependent front polarized cell migration requires Aurora kinase A
Authors: Tony Lok Heng Chu, Lixin Zhou, Jennifer Won, Pooja Mohan, Oksana Nemirovsky, Abbas Fotovati, Torsten Nielsen, Nelly Pante, Christopher Maxwell
Journal: Cancer Research (2017)

Abstract PROBLEM- Metastasis accounts for 90% of deaths from carcinomas. BACKGROUND- To initiate migration, epithelial cells must front-rear polarize and reorganize the microtubule cytoskeleton directed toward the lamillipodia or leading edge. During mitosis, centrosome maturation, duplication, spindle pole assembly and chromosome segregation require Aurora kinase A (AURKA), which is optimally active when complexed with TPX2. Accumulating evidences identify non-mitotic functions for AURKA, such as cell migration and ciliary reorganization. Overexpression of AURKA leads to tumorigenesis in breast cancer. Mechanisms that activate non-mitotic AURKA and promote cell migration as well as metastasis are yet to be uncovered. RESULTS- In a large breast cancer tissue microarray (n= 3,175), the abundance of phosphorylated RHAMM (a substrate of AURKA) predicted overall and relapse-free survival in ER-negative, basal-subtype, and triple negative breast tumors. We studied the AURKA-TPX2-RHAMM signaling axis in mammary (MCF10A and nMUMG-FUCCI) and HeLa cells. In scratch wound assays, migratory cells were found to have front-polarized centrosomes, which correlated with G2 cell cycle phase, phosphorylated AURKA and elevated microtubule nucleation at centrosomes. Small molecule inhibition of Aurora kinase activity impaired centrosome polarity and retarded the kinetics of cell migration. In parallel, silencing RHAMM altered TPX2 location as indicated by immunofluorescence and immuno-EM, which located TPX2 to the nuclear envelope and nuclear pore basket. Nuclear import of recombinant TPX2 was attenuated in RHAMM silenced cells and nuclear envelope accumulation was elevated. CONCLUSION- The AURKA-TPX2-RHAMM axis regulates centrosome polarity, microtubule nucleation and directional cell migration while phosphorylated RHAMM predicts survival in aggressive forms of breast cancer. Citation Format: Tony Lok Heng Chu, Lixin Zhou, Jennifer Won, Pooja Mohan, Oksana Nemirovsky, Abbas Fotovati, Torsten Nielsen, Nelly Pante, Christopher Maxwell. Cell cycle-dependent front polarized cell migration requires Aurora kinase A [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 1876. doi:10.1158/1538-7445.AM2017-1876
Abstract 315: S100B regulates IL-6 signaling via the p90 ribosomal S6 kinase (RSK) in malignant melanoma
Authors: Milad J. Alasady, Kaylin A. Adipietro, Adam D. Pierce, Paul T. Wilder, Kira G. Hartman, David J. Weber, Nissim Hay
Journal: Cancer Research (2017)

Abstract S100B is a tumor marker that is highly elevated during the progression of malignant melanoma. However, the function of S100B in the progression of melanoma is not well understood. Here we propose a regulatory mechanism that defines interplay between S100B, Interleukin-6 (IL-6), STAT3, and CREB. First, we show that S100B inhibits IL-6 mRNA and protein levels, and that silencing S100B in melanoma cell lines induces the expression and secretion of IL-6. Consistent with this result, STAT3 phosphorylation and its activation occur upon S100B ablation and IL-6 production. Our data suggest that S100B exerts its effect on the IL-6 pathway via p90 ribosomal S6 kinase (RSK), leading to activation of transcription factor CREB. Elevated S100B in melanoma cells were shown to bind directly to RSK, sterically block its phosphorylation (at Thr573) and sequester RSK in the cytoplasm (Hartman et al., 2014). Silencing of S100B enables RSK nuclear translocation, which in turn elevates CREB phosphorylation and its transcriptional activity in the nucleus to induce IL-6 expression, which is consistent with these newer observations. Because IL-6 can inhibit the proliferation of melanocytes and early stage melanoma cells, we propose that the suppression of IL-6 by elevated S100B may be a mechanism for cancer cells to circumvent the inhibitory effect of IL-6 at early stages of melanoma. Additionally, the suppression of IL-6 by elevated S100B may also curb local immune response(s), which otherwise would be elevated by the secreted IL-6. Note: This abstract was not presented at the meeting. Citation Format: Milad J. Alasady, Kaylin A. Adipietro, Adam D. Pierce, Paul T. Wilder, Kira G. Hartman, David J. Weber, Nissim Hay. S100B regulates IL-6 signaling via the p90 ribosomal S6 kinase (RSK) in malignant melanoma [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 315. doi:10.1158/1538-7445.AM2017-315
National Readmission Patterns of Isolated Splenic Injuries Based on Initial Management Strategy
Authors: Graeme M. Rosenberg, Lisa Knowlton, Charlotte Rajasingh, Yingjie Weng, Paul M. Maggio, David A. Spain, Kristan L. Staudenmayer
Journal: JAMA Surgery (2017)

Options for managing splenic injuries have evolved with a focus on nonoperative management. Long-term outcomes, such as readmissions and delayed splenectomy rate, are not well understood.To describe the natural history of isolated splenic injuries in the United States and determine whether patterns of readmission were influenced by management strategy.The Healthcare Cost and Utilization Project's Nationwide Readmission Database is an all-payer, all-ages, longitudinal administrative database that provides data on more than 35 million weighted US discharges yearly. The database was used to identify patients with isolated splenic injuries and the procedures that they received. Adult patients with isolated splenic injuries admitted from January 1 through June 30, 2013, and from January 1 through June 30, 2014, were included. Those who died during the index hospitalization or who had an additional nonsplenic injury with an Abbreviated Injury Score of 2 or greater were excluded. Univariate and mixed-effects logistic regression analysis controlling for center effect were used. Weighted numbers are reported.Initial management strategy at the time of index hospitalization, including nonprocedural management, angioembolization, and splenectomy.All-cause 6-month readmission rate. Secondary outcome was delayed splenectomy rate.A weighted sample of 3792 patients (2146 men [56.6%] and 1646 women [43.4%]; mean [SE] age, 48.5 [0.7] years) with 5155 admission events was included. During the index hospitalization, 825 (21.8%) underwent splenectomy, 293 (7.7%) underwent angioembolization, and 2673 (70.5%) had no procedure. The overall readmission rate was 21.1% (799 patients). Readmission rates did not differ based on initial management strategy (195 patients undergoing splenectomy [23.6%], 70 undergoing angioembolism [23.9%], and 534 undergoing no procedure [20%]; P = .33). Splenectomy was performed in 36 of 799 readmitted patients (4.5%) who did not have a splenectomy at their index hospitalization, leading to an overall delayed splenectomy rate of 1.2% (36 of 2967 patients). In mixed-effects logistic regression analysis controlling for patient, injury, clinical, and hospital characteristics, the choice of splenectomy (odds ratio, 0.93; 95% CI, 0.66-1.31) vs angioembolization (odds ratio, 1.19; 95% CI, 0.72-1.97) as initial management strategy was not associated with readmission.This national evaluation of the natural history of isolated splenic injuries from index admission through 6 months found that approximately 1 in 5 patients are readmitted within 6 months of discharge after an isolated splenic injury. However, the chance of readmission for splenectomy after initial nonoperative management was 1.2%. This finding suggests that the current management strategies used for isolated splenic injuries in the United States are well matched to patient need.
Abstract 3120: Application of a lectin as a drug carrier for glycan-targeting cancer therapy
Authors: Tatsuya Oda, Osamu Shimomura, Hiroaki Tateno, Jun Hirabayashi, Masayuki Noguchi, Shigeru Chiba, Makoto Asashima, Nobuhiro Ohkohchi
Journal: Cancer Research (2017)

Abstract Various cancers such as pancreatic ductal adenocarcinoma (PDAC) remain intractable despite recent advances in tumour-targeting antibody drugs. Although the outermost coating of every cell type is predominantly composed of cell-specific glycans, antibody strategies have hit walls of technical difficulties in intentional glycan targeting, and medico-economic burden. Lectins, proteins with glycan-binding potential, could be used as an alternative scaffold; however, the prejudice that all lectins mediate harmful haemagglutination limited its use only in experimental and diagnostic applications. Here, we show the successful in vivo application of a lectin as a drug carrier for cancer therapy. We have employed rBC2LC-N lectin since this has already shown a specific affinity between PDAC cell-surface glycans. When a lectin-drug conjugate (LecD) was developed by fusion with a bacterial exotoxin, the 50% inhibitory concentration (1.04 pg/ml=0.0195 pM) was 1000 times lower than that of conventional immunotoxins (on the order of ng/ml). In addition, we have revealed that rBC2LC-N lectin was safely administrable to mice without haemagglutination. Administration of this LecD in a PDAC mouse model of subcutaneous nodules and peritoneal dissemination, generated prominent therapeutic effects. The utilization of lectins as an in vivo drug-carrier targeting cancer glycan shows realistic potential when paired with advanced lectin engineering technologies, and their applications could be expanded by coupling with small molecule and/or nanoparticle drugs. Citation Format: Tatsuya Oda, Osamu Shimomura, Hiroaki Tateno, Jun Hirabayashi, Masayuki Noguchi, Shigeru Chiba, Makoto Asashima, Nobuhiro Ohkohchi. Application of a lectin as a drug carrier for glycan-targeting cancer 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 3120. doi:10.1158/1538-7445.AM2017-3120
A Program for the Study of Cancer of the Stomach
Authors: Carl Voegtlin
Journal: JNCI Journal of the National Cancer Institute (1941)

Journal Article A Program for the Study of Cancer of the Stomach Get access Carl Voegtlin Carl Voegtlin chief National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 1, Issue 4, February 1941, Pages 539–558, https://doi.org/10.1093/jnci/1.4.539 Published: 01 February 1941
A rapid reduction of Bcr/Abl transcripts is associated with an early cytogenetic response to Glivec (STI571) in chronic myeloid leukemia in chronic phase: a study of the Italian cooperative study group on CML
Authors: G Martinelli, F Pane, G Saglio, D Alberti, M Amabile, E Ottaviani, M Intrieri, F Salvatore, M Tiribelli, G Rosti, A De Vivo, F Bonifazi, E Trabacchi, S Bassi, D Russo, N Testoni, D Ruggeri, C Zardini, B Giannini, S Buonamici, M Baccarani, S Tura
Journal: Blood (2001)
Abstract 2233: The fatty acid amide hydrolase inhibitor URB937 ameliorates radiation-induced lung injury in a mouse model
Authors: Rui Li, Jianxin Xue, You Lu
Journal: Cancer Research (2017)

Abstract Radiation-induced lung injury (RILI) is a common and potentially serious complication from radiotherapy to the thoracic region. In the current study, we examined the potential protective effects of URB937, an inhibitor of fatty acid amide hydrolase in a mouse model of RILI. Here we challenged male C57BL/6 mice with irradiation (16Gy to the thoracic region), and then injected intraperitonealy either URB937 (1 mg/kg) or vehicle three times a week for 30 days. Mice were sacrificed at either the end of treatment or120 days from irradiation to evaluate the extent of RILI and mice survival. Potential effects of URB937 on irradiation induced tumor growth inhibition were also evaluated. We found URB937 increased endocannabinoids in the lungs, attenuated the extent of RILI, prolonged the survival,inhibited mice developed pathological alterations of pneumonitis and lung fibrosis. Irradiation-induced increases of proinflammatory and profibrotic cytokines were decreased, including interleukin-1β, interleukin-6, tumor necrosis factor-α, transforming growth factor-β1 in plasma and lung tissue. Moreover, malondialdehyde in plasma and inflammation cells in bronchoalveolar lavage fluid were lower in mice treated with irradiation plus URB937. URB937 did not affect tumor growth inhibition caused by irradiation. These results suggested that inhibiting fatty acid amide hydrolase through URB937 could ameliorate the RILI, without affecting the efficacy of irradiation on tumor control. Note: This abstract was not presented at the meeting. Citation Format: Rui Li, Jianxin Xue, You Lu. The fatty acid amide hydrolase inhibitor URB937 ameliorates radiation-induced lung injury in a mouse model [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 2233. doi:10.1158/1538-7445.AM2017-2233
Abstract 351: mTOR-ERK co-targeting strategies for head and neck cancer therapy
Authors: Zhiyong Wang, Esteban Delgado, Kosuke Yamaguchi, Ramiro Iglesias-Bartolomé, Panomwat Amornphimoltham, Alfredo Molinolo, Qianming Chen, J.Silvio Gutkind
Journal: Cancer Research (2017)

Abstract Despite therapeutic advances in the past decade, head and neck squamous cell carcinoma (HNSCC) continues to be a major public health concern. Although recent studies of human cancer genomes identified remarkable complexity of genomic alterations in HNSCC, surprisingly, most aberrations have fallen within key driver signaling pathways. Among them, PI3K/AKT/mTOR pathway is most frequently activated in over 80% of the HNSCC patients. We showed that the majority of HNSCC lesions exhibit high levels of phosphorylated ribosomal S6 protein (pS6), key downstream target of the AKT-mTOR pathway, and that inhibition of mTOR by the use of rapamycin causes a rapid decrease in the level of pS6 and the apoptotic death of HNSCC tumor xenografts, thereby causing tumor regression. Our initial studies identified the AKT-mTOR pathway as a potential therapeutic target for HNSCC and provided strong rational to initiate multiple clinical trials. Indeed, inhibitors of PI3K/AKT/mTOR block mTOR activity and exert a beneficial response in HNSCC patients. However, therapeutic resistance was evidenced in several trials, which might be due to the activation of adaptive survival signaling in tumor cells. To explore the therapeutic option that can overcome the resistance, we performed a synthetic lethality screen in HNSCC cell lines using shRNA libraries. We found that multiple molecules involved in ERK pathway were highly represented. Furthermore, treating HNSCC cell lines harboring activated mTOR with small molecule inhibitors that target PI3K/AKT/mTOR pathway can sequentially induce ERK activation, which is consistent with the findings observed in numerous clinical trials. We demonstrated that co-targeting mTOR and ERK using trametinib, a MEK1/2 inhibitor or cetuximab, an EGFR monoclonal antibody, exhibited the synergistic effect by sensitizing HNSCC to priming with the mTOR inhibitor. Specifically, mTOR-ERK co-targeting prevented the growth of HNSCC tumor xenografts by decreasing cell proliferation, reducing lymphangiogenesis and activating apoptosis. In addition, we have recently used a phosphoproteomics approach to identify the molecular mechanisms of ERK feedback activation caused by PI3K/AKT/mTOR inhibition. Overall, our promising findings from these preclinical studies suggest that the use of mTOR-ERK co-targeting strategies may provide the novel alternative approach to achieve durable responses (cure) in HNSCC cancer patients. Citation Format: Zhiyong Wang, Esteban Delgado, Kosuke Yamaguchi, Ramiro Iglesias-Bartolomé, Panomwat Amornphimoltham, Alfredo Molinolo, Qianming Chen, J.Silvio Gutkind. mTOR-ERK co-targeting strategies for head and neck cancer 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 351. doi:10.1158/1538-7445.AM2017-351
Long-term outcomes of dasatinib-induced pulmonary arterial hypertension: a population-based study
Authors: Jason Weatherald, Marie-Camille Chaumais, Laurent Savale, Xavier Jaïs, Andrei Seferian, Matthieu Canuet, Hélène Bouvaist, Pascal Magro, Anne Bergeron, Christophe Guignabert, Olivier Sitbon, Gérald Simonneau, Marc Humbert, David Montani
Journal: European Respiratory Journal (2017)

This study aimed to describe the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib.21 incident, right heart catheterisation-confirmed cases of dasatinib-induced PAH were identified from the French Pulmonary Hypertension Registry. Clinical and haemodynamic variables were compared from baseline to last follow-up (median (range) 24 (1-81) months).Median age was 52 years and 15 patients were female (71%). 19 patients received dasatinib for chronic myelogenous leukaemia for a median (range) duration of 42 (8-74) months before PAH diagnosis. No bone morphogenic protein receptor-2 (BMPR2) mutations were found in the 10 patients tested. Dasatinib was uniformly discontinued and 11 patients received PAH medications. Four patients died during follow-up. New York Heart Association functional class improved from 76% in class III/IV to 90% in class I/II (p<0.01). Median (range) 6-min walk distance improved from 306 (0-660) to 430 (165-635) m (p<0.01). Median (range) mean pulmonary arterial pressure improved from 45 (30-70) to 26 (17-50) mmHg (p<0.01) and pulmonary vascular resistance from 6.1 (3.2-27.3) to 2.6 (1.2-5.9) Wood units (p<0.01). Patients treated with PAH medications had worse baseline haemodynamics but similar long-term outcomes to untreated patients. PAH persisted in 37% of patients.Dasatinib-induced PAH frequently improves after discontinuation but persisted in over one-third of patients, therefore systematic follow-up is essential.
Mitochondrial alkaline pH-responsive drug release mediated by Celastrol loaded glycolipid-like micelles for cancer therapy
Authors: Yanan Tan, Yun Zhu, Yue Zhao, Lijuan Wen, Tingting Meng, Xuan Liu, Xiqin Yang, Suhuan Dai, Hong Yuan, Fuqiang Hu
Journal: Biomaterials (2017)
Abstract 5843: Role of CDK9 inhibition as a sensitizer to radiation in esophageal adenocarcinoma: In vitro and in vivo efficacy study
Authors: Omkara Lakshmi M. Veeranki, Rashmi Dokey, Alicia Mejia, Zhimin Tong, Jianhu Zhang, Yawei Qiao, Pankaj Kumar Singh, Riham Katkhuda, Barbara Minoo, Jaime Rodriguez Canales, Steven Lin, Sunil Krishnan, Dipen Maru
Journal: Cancer Research (2017)

Abstract Preoperative chemoradiation in neoadjuvant setting is the standard of care for loco-regional esophageal adenocarcinoma (EAC). However, less than 30% of patients develop complete pathological response indicating need for newer therapeutic strategies. Cyclin dependent kinase 9 (CDK9) is found to be over expressed in EAC compared to Barrett’s esophagus. Our previous studies demonstrated strong antitumor effects on inhibition of CDK9 in EAC both in vitro and in vivo. Here we report augmented tumor regression in irradiated xenografts on combination with Flavopiridol, a well-established clinically used CDK inhibitor, compared to single modality treatments. In vitro studies indicate that Flavopiridol could radiosensitize FLO-1 and SKGT4 EAC cells with sustained 53BP1 foci especially in SKGT4 cells. Flavopiridol and BAY1143572, a more selective inhibitor of CDK9, could radiosensitize additional EAC radiation sensitive and resistant cell lines (SKGT4-R, OE-33 and OE-33-R) as analyzed by MTT assay, apoptosis, formation of 53BP1 foci and clonogenic assay. Flavopiridol and BAY1143572 showed a radio-synergistic action by downregulating MCL-1 and Axl. In conclusion, the radio-sensitizing capacities of CDK9 inhibitors presented here suggest that their adjuvant administration might improve EAC therapy. Note: This abstract was not presented at the meeting. Citation Format: Omkara Lakshmi M. Veeranki, Rashmi Dokey, Alicia Mejia, Zhimin Tong, Jianhu Zhang, Yawei Qiao, Pankaj Kumar Singh, Riham Katkhuda, Barbara Minoo, Jaime Rodriguez Canales, Steven Lin, Sunil Krishnan, Dipen Maru. Role of CDK9 inhibition as a sensitizer to radiation in esophageal adenocarcinoma: In vitro and in vivo efficacy study [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 5843. doi:10.1158/1538-7445.AM2017-5843
Abstract 60: Reducing toxicity of antibody-drug conjugates through modulation of pharmacokinetics
Authors: Jessica Simmons, Francisco Zapata, Haley Neff-Laford, Joshua Hunter, Julia Cochran, Patrick Burke, Robert P. Lyon
Journal: Cancer Research (2017)

Abstract Antibody-drug conjugates (ADCs) continue to emerge as effective therapeutics in a variety of oncology indications. Research on ADCs has revealed that the physicochemical properties of the drug-linker component can exert a significant impact on the disposition of the ADCs, particularly at higher levels of drug loading. We have recently reported (Nature Biotechnology 33, 733-735 (2015); Molecular Cancer Therapeutics, manuscript accepted) that these properties can be modulated through the judicious incorporation of small, discrete PEG chains of varying lengths into a monomethyl auristatin E (MMAE) drug-linker. Homogeneous DAR 8 ADCs prepared with these drug-linkers using native cysteine conjugation display a continuum of pharmacokinetic behaviors that mirror the length of the incorporated PEG chain. We selected four of these drug-linkers that span the range of observed pharmacokinetics and used them as model compounds to evaluate the impact of ADC clearance on the concentration profile of released MMAE in normal tissues and consequent toxicology in the Sprague-Dawley rat. Faster clearing ADCs (prepared with drug-linkers containing very short or no PEG modifier) produced higher tissue MMAE Cmax values at early post-dose time points relative to slower clearing ADCs that incorporate longer PEG chains. This finding indicates that MMAE concentrations in tissues are proportional to the rate at which the ADC is catabolized, a process which converts the conjugated payload into free drug. Faster clearing ADCs also exhibited diminished tolerability, with greater histologic depletion of bone marrow and more dramatic decreases and/or delayed recovery in select peripheral hematology parameters. These results provide a strategy for reducing the non-antigen-mediated toxicity of ADCs through modulation of pharmacokinetics. Citation Format: Jessica Simmons, Francisco Zapata, Haley Neff-Laford, Joshua Hunter, Julia Cochran, Patrick Burke, Robert P. Lyon. Reducing toxicity of antibody-drug conjugates through modulation of pharmacokinetics [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 60. doi:10.1158/1538-7445.AM2017-60