tbuckley/cabot-search huggingface dataset:
Abstract 4588: Estrogen receptor alpha mediates HPV E6/E7 oncoproteins: Induced breast cells proliferation
Authors: Eva McGhee, Lucy Tran, Mengtao Li, Yong Wu, Seyung Chung, Cheryl Araniego, Karen Tate, Melanie Baker, Kamilah Evans, Mechelle Rouse, Jay Vadgama
Journal: Cancer Research (2016)

Abstract The association of human papillomavirus (HPV) with cervical cancer, head and neck cancer is well established, but the involvement of HPV E6/E7 oncoproteins in breast cancer is more contentious. Previous studies suggest that high risk HPV E6/E7 oncoproteins inactivate two tumor suppressor proteins p53 and pRb signaling and increase cell proliferation. There is cumulative evidence that high risk HPV 16 E6/E7 oncoproteins may have causal roles in some human breast cancers. Moreover, some studies have identified HPV DNA in breast tissue and breast cancer specimens. Nevertheless, the route of transmission of HPV in breast cells has not been determined, and the mechanisms by which HPV involvement in breast cancer are not known. We used a non-tumorigenic (MCF12A) epithelial breast cell line transfected with HPV 16 to elucidate the role of oncoproteins E6/E7 in pro-proliferative and anti-apoptotic signaling pathways. We also used Tamoxifen treatment, which is an antagonist of the estrogen receptor in breast tissues through its active metabolite, 4hydroxytamoxifen. We demonstrate that HPV E6/E7 transfection activates the extracellular signal-regulated kinase (ERK) MAPK pathway and Akt/PKB kinase signaling pathways through activating estrogen receptor alpha in MCF12A cells. E6/E7 oncoproteins transfection alone dramatically increases estrogen receptor alpha protein expression. Treatment with tamoxifen, an antagonist of the ER, significantly abolishes E6/E7-increase in ERK and PKB phosphorylation without altering their protein levels, suggesting that the estrogen receptor is a key mediator of HPV E6/E7 mediated ERK and Akt/PKB activation. Our current work show an insightful understanding of the molecular mechanisms of HPV-elicited Akt/PKB activation and its roles in cell proliferation and survival in normal breast epithelial cells. Therefore, these findings indicate that HPV E6/E7 oncoproteins may promote the transforming activities of high-risk HPV E6/E7 proteins and cell proliferation in breast cells. Therefore, suppression of estrogen receptor signaling networks may be used as a therapeutic strategy for HPV associated lesions and cancers such as breast metastasis. Citation Format: Eva McGhee, Lucy Tran, Mengtao Li, Yong Wu, Seyung Chung, Cheryl Araniego, Karen Tate, Melanie Baker, Kamilah Evans, Mechelle Rouse, Jay Vadgama. Estrogen receptor alpha mediates HPV E6/E7 oncoproteins: Induced breast cells proliferation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4588.
Abstract 4029: MEK pathway inhibition upregulates PD-L1 and MHC class I expression levels in head and neck squamous cell carcinoma
Authors: Seong-Ho Kang, Bhumsuk Keam, Soyeon Kim, Miso Kim, Yong-Oon Ahn, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo
Journal: Cancer Research (2016)

Abstract Background: Expression of programmed death-ligand 1 (PD-L1) and down-regulation of MHC class I are well known tumor immune evasion mechanisms. The purpose of this study is to investigate the regulation of PD-L1 and MHC class I expression in head and neck squamous cell carcinoma (HNSCC) cell lines by MEK inhibitor trametinib. Methods: Six HNSCC cell lines (SNU-1041, SNU-1066, SNU-1076, PCI-13, Detroit 562, and FaDu) were used. Trametinib was purchased from Selleckchem. Growth inhibition of trametinib was measured using MTT assay. Trametinib was dosed at 10 - 640 nM for investigating their effect on PD-L1 and MHC class I molecule expression. Changes of PD-L1 and MHC class I (including HLA-A2) expression levels were analyzed by flow cytometry after treatment with trametinib (20 nM) and/or IFN-γ (1 - 10 ng/ml). Total and phosphorylated STAT1 and STAT3 were analyzed by western blot. Results: Overall IC50 values of trametinib were over 10 μM in cell lines except SNU-1066 and Detroit 562 with IC50 values still higher than 100 nM. All the six cell lines have no upstream RAS or RAF mutation. Although trametinib treatment did not inhibit growth of these cells, it up-regulated MHC class I expression level in all cells. Furthermore, trametinib enhanced exogenous IFN-γ-induced MHC class I up-regulation in four out of six cell lines. Mechanistically, trametinib treatment increased phosphorylated STAT1 levels by IFN-γ in all cells, and subsequent total STAT1 levels in two out of six cell lines. Interestingly, trametinib treatment directly phosphorylated STAT3 although total STAT3 level was not changed. Either trametinib alone or with IFN-γ induce PD-L1 expression, but the effect was various in these cells. These results imply that blockade of MAPK pathway may alternatively activate JAK/STAT pathway in HNSCC cells, and MHC class I and PD-L1 expression levels were changed as the results Conclusion: Our results suggest that MEK pathway is closely related with regulation of PD-L1 and MHC class I expression. Up-regulated levels of PD-L1 and MHC class I by inhibiting MEK pathway suggest a possible synergistic role of MEK inhibitor with anti-PD-1/PD-L1 immunotherapy in HNSCC. Citation Format: Seong-Ho Kang, Bhumsuk Keam, Soyeon Kim, Miso Kim, Yong-Oon Ahn, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo. MEK pathway inhibition upregulates PD-L1 and MHC class I expression levels in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4029.
Case 54-1966
Authors: Martin J. Wohl, Benjamin Castleman
Journal: New England Journal of Medicine (1966)

Presentation of Case First admission. A seventy-four-year-old man was admitted to the hospital because of hematuria.Two years previously nocturia developed. On the morning of admission he was able to void only a small volume of urine and then passed a blood clot, at which time he experienced a dull, steady pain in the suprapubic region. During the next few hours he repeatedly voided small amounts of urine containing blood clots.Four years before entry a physician found that he had hypertension; the blood pressure had been normal on previous examinations. He had had intermittent claudication for several years. . . .
The Combination of Entospletinib and Vincristine Demonstrates Synergistic Activity in a Broad Panel of Hematological Cancer Cell Lines and Anti-Tumor Efficacy in a DLBCL Xenograft Model
Authors: Mark Joseph Axelrod, Peter Fowles, Jeff Silverman, Astrid Clarke, Jennifer Tang, Emma Rousseau, Heather Kay Webb, Julie Di Paolo
Journal: Blood (2015)
The Rhesus Monkey Connectome Predicts Disrupted Functional Networks Resulting from Pharmacogenetic Inactivation of the Amygdala
Authors: David S. Grayson, Eliza Bliss-Moreau, Christopher J. Machado, Jeffrey Bennett, Kelly Shen, Kathleen A. Grant, Damien A. Fair, David G. Amaral
Journal: Neuron (2016)
Abstract 4244: Comparison of different ALK tests in non-small cell lung cancer (NSCLC) patients treated with crizotinib and their clinical outcome
Authors: Anthonie J. van der Wekken, Thijo JN Hiltermann, Wim Timens, Ed Schuuring, Harry JM Groen
Journal: Cancer Research (2015)

Abstract Background: The screening algorithm for detection of ALK-rearranged NSCLC is still under investigation. The Break-Apart ALK FISH is the standard diagnostic test for the treatment with crizotinib. However, immunohistochemistry (IHC) with different antibodies shows excellent results when compared to ALK FISH. The efficacy of crizotinib is studied in relation to ALK FISH. We compared IHC outcome and the number of ALK breaks estimated with FISH with clinical outcome. Methods: Patients treated with crizotinib who had biopsies with sufficient tumor tissue were selected. Tumour response was assessed by CT using RECIST. Fluorescence in situ hybridization (FISH) was performed with Vysis LSI ALK Break Apart FISH Probe KIT (Abbott Molecular) and immunohistochemistry with Ventana ALK IHC Kit using D5F3 antibody. Results: Twenty one patients with NSCLC were selected, median (range) age 54 yrs (21-75); 19 had adenocarcinoma, 2 had large-cell carcinoma. We confirmed the presence of EML4-ALK fusions in all samples either by FISH or IHC. Median percentage of ALK breaks was 47% (6-76). Tumour response occurred in 12 pts having a median of 51 (6-76) breaks and 9 non-responders having a median of 27 (15-64) breaks. Of the 12 responders, 8 pts had positive IHC (67%), 3 were negative and 1 was not done; the FISH negative, IHC positive patient was one of the responders. Of the 9 non-responders 2 had positive IHC (22%), 3 negative (33%), and 1 was equivocal and 3 not done. Median PFS for positive IHC is 7.9 mo (95% CI., 5.5 - 10.3) and for negative IHC 1.6 mo (1.3 - 1.8), n = 17, p&amp;lt;0.0001. OS survival data are 6.5 mo (95% CI., 0 - 17.8) and 18.3 mo (95% CI., 11.1 - 25.6) respectively, n = 17 p = 0.052. PFS above 30% number of breaks was 7.0 mo (95% CI., 1.8 - 12.2) versus PFS below is 1.8 mo (95% CI., 0.7 - 2.9), n = 21, p = 0.05. OS survival data are 4.1 mo (95% CI., 0 - 9.3) and 16.1 mo (95% CI., 9.0 - 23.2) respectively, n = 21 p = 0.003. Therefore PFS and OS is more prolonged in those tumors who have ALK breaks above 30%. IHC difference are only significant for PFS. Conclusions: Both ALK FISH and IHC identify NSCLC patients who benefit from crizotinib treatment. Patients with ALK breaks above 30% have a better PFS and OS. IHC only differentiates for PFS. Citation Format: Anthonie J. van der Wekken, Thijo JN Hiltermann, Wim Timens, Ed Schuuring, Harry JM Groen. Comparison of different ALK tests in non-small cell lung cancer (NSCLC) patients treated with crizotinib and their clinical outcome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4244. doi:10.1158/1538-7445.AM2015-4244
98P BRCA1 methylation in triple-negative breast cancer
Authors: A. Kawachi, E. Okochi-Takada, T. Shimoi, A. Shimomura, M. Kodaira, M. Yunokawa, K. Yonemori, C. Shimizu, Y. Fujiwara, T. Ushijima, K. Tamura
Journal: Annals of Oncology (2015)
Abstract 338: A novel small molecule inhibitor of the Notch transcription activation complex
Authors: Rajwinder Lehal, Viktoras Frismantas, Sylvain Loubéry, Viktoria Reinmuller, Gerardo Turcatti, Marcos Gonzalez-Gaitan, Jean-Pierre Bourquin, Freddy Radtke
Journal: Cancer Research (2016)

Abstract NOTCH signaling is a developmental pathway known to play critical roles during embryonic development as well as for the regulation of self-renewing tissues. Aberrant activation of NOTCH signaling leads to deregulation of the self-renewal process resulting in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion and metastasis, all of which are hallmarks of cancer. Over activation of NOTCH in human cancers can be a consequence of over expression of NOTCH ligands/receptors, GOF mutations in NOTCH receptors as well as chromosomal translocations leading to constitutive activation of the pathway. Given the importance of Notch signaling in human cancers, several therapeutic approaches have been utilized to block NOTCH signaling. Two of these strategies are; a) the use of monoclonal blocking antibodies (Mabs) against NOTCH ligands and receptors and b) the use of small molecule γ-secretase inhibitors (GSIs). However, these approaches can only be effective if tumor cells express full-length ligand or receptor molecules. On the contrary, in human cancers harbouring NOTCH gene fusion due to chromosomal translocations, the use of Mabs and GSIs will have very limited clinical benefits. A third, yet not fully explored approach could be the blockage of NOTCH signalling by targeting the most downstream event in the NOTCH cascade i,e NOTCH transcriptional activation complex using small molecule inhibitors. Here we report discovery and identification of a novel, orally-active small molecule inhibitor, named CB-103, of the NOTCH pathway that blocks NOTCH signaling by targeting the NOTCH transcriptional activation complex in the nucleus. CB-103 has shown the ability to block NOTCH signalling in human cancer cell lines, induce neurogenic phenotype in drosophila, induce muscle cell differentiation and inhibit NOTCH dependent cellular processes in mice. In addition, CB-103 exhibit anti-tumor efficacy in a xenograft model of human triple negative breast cancer resistant to GSIs and Mabs against NOTCH ligands/receptors. Furthermore, CB-103 has shown a remarkable activity in PDX models of human T-ALL harbouring activation of the NOTCH pathway. Additional studies are underway on several analogs of CB-103 to determine ADME/PK/PD profile and nominate a development candidate for further clinical development of this novel inhibitor of the NOTCH pathway. Citation Format: Rajwinder Lehal, Viktoras Frismantas, Sylvain Loubéry, Viktoria Reinmuller, Gerardo Turcatti, Marcos Gonzalez-Gaitan, Jean-Pierre Bourquin, Freddy Radtke. A novel small molecule inhibitor of the Notch transcription activation complex. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 338.
Associations Between Ventilator Bundle Components and Outcomes
Authors: Michael Klompas, Lingling Li, Ken Kleinman, Paul M. Szumita, Anthony F. Massaro
Journal: JAMA Internal Medicine (2016)

Ventilator bundles, including head-of-bed elevation, sedative infusion interruptions, spontaneous breathing trials, thromboprophylaxis, stress ulcer prophylaxis, and oral care with chlorhexidine gluconate, are ubiquitous, but the absolute and relative value of each bundle component is unclear.To evaluate associations between individual and collective ventilator bundle components and ventilator-associated events, time to extubation, ventilator mortality, time to hospital discharge, and hospital death.This retrospective cohort study included all 5539 consecutive patients who underwent mechanical ventilation for at least 3 days from January 1, 2009, to December 31, 2013, at Brigham and Women's Hospital.Head-of-bed elevation, sedative infusion interruptions, spontaneous breathing trials, thromboprophylaxis, stress ulcer prophylaxis, and oral care with chlorhexidine.Hazard ratios (HRs) for ventilator-associated events, extubation alive vs ventilator mortality, and hospital discharge vs hospital death. Effects were modeled using Cox proportional hazards regression and Fine-Gray competing risk models adjusted for patients' demographic characteristics, comorbidities, unit type, severity of illness, recent procedures, process measure contraindications, day-to-day markers of clinical status, and calendar year.Of 5539 consecutive patients undergoing mechanical ventilation, 3208 were male (57.9%), 2331 female (42.1%), and the mean (SD) age was 61.2 (16.1) years. Sedative infusion interruptions were associated with less time to extubation (HR, 1.81; 95% CI, 1.54-2.12; P < .001) and a lower hazard for ventilator mortality (HR, 0.51, 95% CI, 0.38-0.68; P < .001). Similar associations were found for spontaneous breathing trials (HR for extubation, 2.48; 95% CI 2.23-2.76; P < .001; HR for mortality, 0.28; 95% CI, 0.20-0.38; P = .001). Spontaneous breathing trials were also associated with lower hazards for ventilator-associated events (HR, 0.55; 95% CI, 0.40-0.76; P < .001). Associations with less time to extubation were found for head-of-bed elevation (HR, 1.38, 95% CI, 1.14-1.68; P = .001) and thromboembolism prophylaxis (HR, 2.57; 95% CI, 1.80-3.66; P < .001) but not ventilator mortality. Oral care with chlorhexidine was associated with an increased risk for ventilator mortality (HR, 1.63; 95% CI, 1.15-2.31; P = .006), and stress ulcer prophylaxis was associated with an increased risk for ventilator-associated pneumonia (HR, 7.69; 95% CI, 1.44-41.10; P = .02).Standard ventilator bundle components vary in their associations with patient-centered outcomes. Head-of-bed elevation, sedative infusion interruptions, spontaneous breathing trials, and thromboembolism prophylaxis appear beneficial, whereas daily oral care with chlorhexidine and stress ulcer prophylaxis may be harmful in some patients.
Abstract 5008: Elucidating HER2 molecular heterogeneity of circulating tumor cells among breast cancer patients
Authors: Man Chun Leong, Tse Hui Lim, Chye Ling Tan, Yong Wei Chua, Elaine Hsuen Lim, Kiley Wei Jen Loh, Guek Eng Lee, Rebecca Dent, Raymond Chee Hui Ng, Andrew Wu, Wan-Teck Lim, Alvin Soon-Tiong Lim, Yoon-Sim Yap
Journal: Cancer Research (2016)

Abstract Background: HER2-positive tumors are often associated with poor prognosis, chemo-resistances and some patients eventually develop refractory disease during HER2 targeted therapy. While different mechanisms of trastuzumab resistance are being identified in recent years, contribution of confounding factors such as inherent genomic heterogeneity, equivocal HER2 amplifications and presence of chromosome 17 polysomy has been less understood thus far. In this pilot study, we aim to examine HER2 heterogeneity in CTCs obtained from breast cancer patients in the Asian population setting. Methods: CTCs were enriched from blood samples using a label-free spiral microfluidics-based ClearCell® FX system. A total of 26 samples were collected from patients diagnosed with HER2 positive (17/26) and HER2 negative (9/26) breast cancer. The enriched CTCs were analyzed using conventional diagnostic modalities (fluorescence in-situ hybridisation (FISH) and immunocytochemistry) to examine HER2 status. Concordance rate between CTCs and matched primary tumor was evaluated. Results: HER2-positive CTCs were successfully identified in 14 out of 17 HER2+ patients (82.4%); HER2 gene amplification and chromosome 17 polysomy were observed in 10(58.8%) and 13(76.5%) patients respectively. HER2+ CTC counts ranged from 2 to 30 cells from 7.5ml blood (median: 4 HER2+ CTCs/7.5ml). HER2 amplification was not observed in any of the 9 patients with HER2-negative tumors, though 5 out of 9 patients (55.6%) were identified with CTCs harbouring gain in chromosome 17 (median: 2 HER2+ CTCs/7.5ml). A “false positive” cut-off of more than 2 cells/7.5ml blood were established using receiver operating characteristic (ROC) curve analysis and a concordance rate of approximately 70% between paired tumor tissue and CTC among the 26 patients. Immunofluorescence labelling of CTCs with cytokeratin, CD45 and HER2 antibodies further revealed heterogeneity in HER2 expression on CTCs. Conclusion: CTCs capture the heterogeneity of breast cancer, and could potentially overcome limitations of tissue biopsy which are site specific. HER2- patients, as confirmed by tissue biopsy, with HER2+ CTCs pose interesting questions while determining treatment regime. Citation Format: Man Chun Leong, Tse Hui Lim, Chye Ling Tan, Yong Wei Chua, Elaine Hsuen Lim, Kiley Wei Jen Loh, Guek Eng Lee, Rebecca Dent, Raymond Chee Hui Ng, Andrew Wu, Wan-Teck Lim, Alvin Soon-Tiong Lim, Yoon-Sim Yap. Elucidating HER2 molecular heterogeneity of circulating tumor cells among breast cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5008.
Abstract 4199: Acidic pH-targeted nanorods facilitate detection of orthotopic pancreatic tumors via multispectral optoacoustic tomography
Authors: Matthew Zeiderman, Kelly M. McMasters, Phillip Chuong, Lacey R. McNally
Journal: Cancer Research (2016)

Abstract We present a precision cancer nanomedicine based on acidic pH targeted chitosan coated mesoporous silica coated gold nanorods (CMGs) designed for multispectral optoacoustic tomography (MSOT). We have conjugated pH-sensitive variant 7 pHLIP peptide to the CMGs (V7-CMG) to provide targeting specificity to the acidic tumor microenvironment. For treatment and detection of resistant malignancies such as pancreatic cancer, such targeting modalities may help to improve treatment and enhance tumor detection. The V7-CMGs provide the ideal contrast and targeting specificity necessary for MSOT imaging of retroperitoneal orthotopic pancreatic tumors. The pH-sensitivity of the targeting pHLIP peptide and chitosan coating makes the particles suitable for simultaneous in vivo tumor imaging and drug delivery. In vitro studies confirm the pH-sensitivity of CMG drug release and tumor cell specific nano-cargo delivery. Citation Format: Matthew Zeiderman, Kelly M. McMasters, Phillip Chuong, Lacey R. McNally. Acidic pH-targeted nanorods facilitate detection of orthotopic pancreatic tumors via multispectral optoacoustic tomography. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4199.
C/EBPβ expressed By Bone Marrow Mesenchymal Stromal Cells Is Indispensable For Precursor B-Cell Lymphopoiesis
Authors: Satoshi Yoshioka, Yasuo Miura, Hisayuki Yao, Masaki Iwasa, Atsushi Sato, Asumi Yokota, Terutoshi Hishita, Tatsuo Ichinohe, Hideyo Hirai, Akifumi Takaori-Kondo, Taira Maekawa
Journal: Blood (2013)