tbuckley/cabot-search huggingface dataset:
Clinical pharmacokinetics (PK) and translational PK-pharmacodynamic (PD) modeling and simulation to predict antitumor response of various dosing schedules to guide the selection of a recommended phase II dose (RP2D) and schedule for the investigational agent MLN0128.
Authors: Chirag G. Patel, Mayank Patel, Arijit Chakravarty, Esha A. Gangolli, Elly Barry, Eric H. Westin, Katti Jessen, Shripad D. Chitnis, Jeffrey R. Infante, Michael S. Gordon, Teresa Macarulla, Andres Cervantes-Ruiperez, Shadia Ibrahim Jalal, Karthik Venkatakrishnan
Journal: Journal of Clinical Oncology (2013)

2567 Background: MLN0128 (INK128) is an investigational oral, potent, and highly selective inhibitor of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) currently in clinical investigation. In the phase1 study INK128-001, MLN0128 was administered once daily (QD), once weekly (QW), QDx3D/week, and QDx5D/week, with respective MTDs of 6, 40, 16, and 10 mg. To guide selection of dose/schedule for further investigation, PD modulation in skin (pS6, p4EBP1, pNDRG1, pPRAS40) was put into context of clinical PK in INK128-001. A preclinical translational dynamic-PK efficacy model was used to describe the relationship and determine PK drivers of efficacy in tumor xenograft models. This model was implemented using human PK parameters to predict tumor volume-time curves, which was utilized to help determine the optimal MLN0128 dose/schedule. Methods: Phoenix NLME v1.1 was used for compartmental modeling of clinical and preclinical PK data, and modeling the preclinical PK-efficacy relationship of MLN0128. PD activity in skin was measured by immunohistochemistry, reported as H scores. Tumor growth curves were simulated using NONMEM v7.2; predicted tumor growth curves were plotted in S-Plus v8.1. Results: Clinical skin PD data suggests exposure dependent inhibition of pS6, and p4EBP1. A two compartment PK model adequately described the PK characteristics of MLN0128 [mean (%CV) ka: ~5.305 h -1 (114), k12: ~0.490 h -1 (85), k21: ~0.67 h -1 (69), V/F: ~180 L (44), Tlag: 0.317 h (73)]. Simulation of human tumor volume-time curves suggest efficacy is dependent on schedule and that MLN0128 administered in more frequent schedules (QD, QDx5D) provides stronger antitumor effect vs less frequent schedules (QW, QDx3D). Conclusions: The results indicate that per unit MLN0128 plasma exposure, QD and QDx5D may be optimal in comparison with QDx3D and QW dosing. However, these results will also need to be put into context with the overall safety profile and respective MTDs and RP2Ds for each schedule with their resultant achievable total cycle dose by schedule. Clinical trial information: NCT01058707.
Activation and Expansion of Natural Killer (NK) Cells with Potent Cytotoxicity for Multiple Myeloma
Authors: Jumei Shi, Susann Szmania, Guido Tricot, Tarun K. Garg, Priyangi A Malaviarachchi, Amberly Moreno-Bost, Katie Stone, Fenghuang Zhan, Dario Campana, John Shaughnessy, Bart Barlogie, Frits van Rhee
Journal: Blood (2008)
Quantitative Proteomic and Transcriptomic Analysis Reveals Post-Transcriptional Regulation of Mitochondrial Biogenesis during Erythropoiesis
Authors: Xin Liu, Yuannyu Zhang, Feng Zhou, Zhen Shao, Robert Signer, Hui Cao, Zeping Hu, Ralph DeBerardinis, Jian Xu
Journal: Blood (2015)
Abstract 3232: NF-κB regulates suppression of macrophage activity during tumor initiation
Authors: Nivedita Ratnam, David Wang, Denis Guttridge
Journal: Cancer Research (2016)

Abstract Constitutive activation of NF-κB is characteristic of most cancer cells. However, how NF-κB functions during tumor initiation is not well established. Recent findings from our laboratory showed that one mechanism by which NF-κB functions to promote tumor initiation is by suppressing immune surveillance. Here we investigated how this occurs. Initiating tumors are characterized by a massive infiltration of immune cells, especially macrophages that exhibit anti-tumor activity through the secretion of pro-apoptotic factors like tumor necrosis factor (TNF) and nitric oxide (NO). Using co-culture assays with conditioned media from Ras transformed tumor cells in the presence of NF-κB, we find that the tumor cells are able to protect themselves from the pro-apoptotic activity of the macrophages by secreting a neutralizing factor. RNA sequencing analysis identified this factor as macrophage inhibitory cytokine-1 (MIC-1)/ growth and differentiation factor-15 (GDF-15). Our results show that MIC-1/GDF-15 is a direct transcriptional target of NF-κB. Furthermore, xenografts in SCID mice show delayed tumor initiation in p65+/+ Ras tumor cells that are depleted for MIC-1/GDF-15 compared to wild type p65+/+ Ras tumor cells. Moreover, we find that MIC-1/GDF-15 inactivates macrophages directly by suppressing their ability to produce TNF and NO. This suppression occurs through the inhibition of NF-κB signaling in the macrophages. Interestingly, expression of MIC-1/GDF-15 is increased in patients with pancreatic ductal adenocarcinoma. In the pancreatic cancer cell line, Panc02, we show that knocking down MIC-1/GDF-15 prevents macrophage inhibition thereby increasing their sensitivity to macrophage-mediated killing both in vitro and in vivo. Thus, NF-κB functions during pancreatic cancer initiation to suppress the anti-tumor activity of infiltrating macrophages by regulating the expression of MIC-1/GDF-15. Citation Format: Nivedita Ratnam, David Wang, Denis Guttridge. NF-κB regulates suppression of macrophage activity during tumor initiation. [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 3232.
27PD Plasma miRNA-based signatures to predict 3-year postoperative recurrence risk for patients with stage II and III gastric cancer
Authors: X. Liu, X. Zhang, Z. Zhang, J. Chang, Z. Wu, C. Wang, Z. Sun, X. Ge, R. Geng, W. Tang, C. Dai, Y. Lin, M. Sun, W. Jia, W. Xue, Y. Hu, J. Li
Journal: Annals of Oncology (2015)
Loss of NR4A1 Accelerates the Development of Aggressive Lymphomas in Myc Induced Cancerogenesis
Authors: Kerstin Wenzl, Katharina Troppan, Beata Pursche, Marco Bischof, Christine Beham-Schmid, Hildegard T. Greinix, Peter Neumeister, Alexander JA Deutsch
Journal: Blood (2015)
Engineered gadolinium-doped carbon dots for magnetic resonance imaging-guided radiotherapy of tumors
Authors: Fengyi Du, Lirong Zhang, Li Zhang, Miaomiao Zhang, Aihua Gong, Youwen Tan, Jiawen Miao, Yuhua Gong, Mingzhong Sun, Huixiang Ju, Chaoyang Wu, Shenqiang Zou
Journal: Biomaterials (2016)
R-DHAP Immuno-Chemotherapy Is An Effective Remission-Induction Treatment for Fludarabine Refractory CLL Patients and Allows the Majority to Proceed to Allogeneic Stem Cell Transplantation. Results of the Planned Interim Analysis of the Dutch-Belgian Prospective Multicenter HOVON88 Trial,
Authors: Michel Van Gelder, Wendim Ghidey, Martine ED Chamuleau, Jan J Cornelissen, Ka Lung Wu, Mels Hoogendoorn, S. M. G. J. Daenen, Eefke Petersen, Marinus H. J. van Oers
Journal: Blood (2011)
Abstract 3400: An angiogenesis gene signature points to active TGF-beta/JAK signaling pathways in a subset of human pancreatic ductal adenocarcinoma cancer patients that are distinct from pathways in pancreatic neuroendocrine tumors
Authors: Kelly E. Craven, Jesse Gore, Julie L. Wilson, Murray Korc
Journal: Cancer Research (2016)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC), which comprises 85% of pancreatic cancers, is the 4th leading cause of cancer death in the United States with a 5-year survival of 7%. While human PDACs (hPDACs) are hypovascular, they also overexpress a number of angiogenic growth factors and receptors. Additionally, the use of anti-angiogenic agents in murine models of PDAC leads to reduced tumor volume, tumor spread, and microvessel density, and improved survival. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful in hPDAC. On the other hand, pancreatic neuroendocrine tumors (PNETs) account for only 2% of pancreatic tumors, yet they are very vascular and classically angiogenic, respond to anti-angiogenic therapy, and confer a better prognosis than PDAC even in the metastatic setting. By analyzing the recently expanded TCGA (The Cancer Genome Atlas) dataset, we report here that an angiogenesis gene signature is present in ∼35% of PDACs and is mostly distinct from an angiogenesis signature present in PNETs. Additionally, principal component analysis (PCA) of the entire or angiogenic PDAC and PNET transcriptomes from TCGA indicates that there are large differences in gene expression between these two tumor types. For example, PDACs exhibit a transcriptome that reflects active TGF-β signaling, and up-regulation of several pro-inflammatory genes, including members of JAK signaling pathways. Functionally, targeting the TGF-β type I receptor (TβRI) kinase with SB505124 and JAK1-2 with ruxolitinib blocks proliferative cross-talk between human pancreatic cancer cells and human endothelial cells. Tumors from the KRC (oncogenic Kras, deleted Rb1) PDAC mouse model show superior enrichment and differential expression of the angiogenic gene signature compared to tumors from the KPC (oncogenic Kras, mutated Trp53) PDAC mouse model. Moreover, treatment of KRC and KPC mice with ruxolitinib suppresses murine PDAC progression in KRC mice but not in KPC mice. These findings suggest that targeting both TGF-β and JAK signaling in the 35% of PDAC patients whose cancers exhibit an angiogenesis gene signature should be explored in the clinic and that this could lead to improved responses to anti-angiogenic therapy in PDAC. Citation Format: Kelly E. Craven, Jesse Gore, Julie L. Wilson, Murray Korc. An angiogenesis gene signature points to active TGF-beta/JAK signaling pathways in a subset of human pancreatic ductal adenocarcinoma cancer patients that are distinct from pathways in pancreatic neuroendocrine tumors. [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 3400.
Abstract 4942: Towards a screening blood test for esophageal adenocarcinoma
Authors: Alok K. Shah, Virendra Joshi, Kim-Anh Le Cao, David C. Whiteman, Andrew P. Barbour, Michelle M. Hill
Journal: Cancer Research (2016)

Abstract BACKGROUND: The incidence of esophageal adenocarcinoma (EAC) has been rapidly increasing globally. The majority of EAC cases are diagnosed at late stages leading to poor 5-year survival of &amp;lt;20%. Monitoring programs for patients with the metaplastic condition, Barrett's esophagus (BE) involves endoscopy with biopsy. However, the cost-effectiveness is limited by the low rate of progression to cancer and expense of the method. Our research program aims to improve the cost-effectiveness of screening by developing a blood test to select patients for endoscopy/biopsy. Using our integrated lectin magnetic bead array (LeMBA) glycoprotein biomarker pipeline [1, 2] with Australian cohorts for the discovery and qualification phases, we identified serum lectin-glycoprotein biomarker candidates which can distinguish EAC from BE and healthy controls [3]. Here, we report the performance of these biomarker candidates in an independent patient cohort from the Ochsner Health System, New Orleans, USA. APPROACH &amp; METHODOLOGY: Serum samples were collected from consenting patients undergoing endoscopy (Control - 16, BE - 13, and EAC - 10). The control group consisted of all patients not classified as BE with or without dysplasia, or EAC. LeMBA-MRM-MS was performed using 4 different lectins with different glycan specificities; AAL (Fucoseα1-2, -3, -6 linked glycan), EPHA (bisecting GlcNAc), JAC (Galα1-6GalNAc and Galβ1-3GalNAc), NPL (Manα1-6Man). Statistical analysis was performed using Shiny MixOmics as previously described [3]. RESULTS &amp; DISCUSSION: Several lectin-protein candidate biomarkers cross-validated in the USA cohort. Most notably, differentially glycosylated complement component C9 is highly diagnostic in both cohorts, achieving area under the receiver operating curve (AUROC) of 0.74 (AAL-C9) to 0.90 (JAC-C9) as a single marker. Complement C9 binding to all four monitored lectins were increased 1.4 to 1.8 fold in EAC, compared to either BE or controls. Another consistent biomarker is gelsolin, with its binding to EPHA and NPL lectin significantly decreased in EAC, compared to either BE or controls. Hence, glycosylated C9 and gelsolin show promise as potential serum biomarkers for EAC screening, and will be further evaluated in prospective cohorts. REFERENCES: [1] Loo et al., J Proteome Res 9, 5496-5500 (2010); [2] Choi et al., Electrophoresis 32, 3564-3575 (2011); [3] Shah et al., Molecular &amp; Cellular Proteomics 14:3023-39 (2015). Citation Format: Alok K. Shah, Virendra Joshi, Kim-Anh Le Cao, David C. Whiteman, Andrew P. Barbour, Michelle M. Hill. Towards a screening blood test for esophageal adenocarcinoma. [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 4942.
HCRN GU14-188: Neoadjuvant pembrolizumab (P) and gemcitabine (G) with or without cisplatin (C) in muscle invasive urothelial cancer (MIUC).
Authors: Christopher J. Hoimes, Robert Abouassaly, Joel N. Saltzman, Mark T. Fleming, Jean H. Hoffman-Censits, Tara Byrd, Cheryl Eitman, Michele Snyder-Willis, Jodi O'Neill, Lisa Wood, Robin Elliott, Matthew M. Cooney
Journal: Journal of Clinical Oncology (2016)

TPS4578 Background: Neoadjuvant chemotherapy (NAC) with C prior to cystectomy prolongs survival and increases the cure rate in MIUC. Most MIUC patients, however, are not cured with NAC or are cisplatin ineligible. Both G and C have favorable immunomodulatory activity with ability to increase antigen presentation, inhibit and reduce myeloid derived suppressor cells, and prevent PD-1 dependent CD4+ T cell tolerization. Single agent PD-1 antagonism with P has been shown to have activity in metastatic urothelial cancer. Hoosier Cancer Research Network (HCRN) GU14-188 is a phase Ib/II trial (NCT02365766) evaluating tolerability and efficacy of the combination of G and P with or without C in cisplatin -eligible and –ineligible MIUC patients. Methods: Up to 12 subjects will be enrolled on the Phase Ib portion of the trial performed in a standard 3+3 design where a recommended phase II dose of P will be found or stopped due to pre-specified dose limiting toxicities (DLT). An additional 70 subjects that are either cisplatin eligible or ineligible will be treated on a phase II portion and treated with GC+P (cisplatin eligible) or GP (cisplatin ineligible). Eligible subjects include those with clinical stage II or III bladder or upper tract disease with urothelial or mixed variant histology. GC is given every 21 days for 4 cycles; G is given on a 28 day cycle for 3 cycles. All patients receive overlapping therapy with P every 3 weeks for a total of five doses, followed by consolidation extirpative surgery. Primary endpoint is the pathologic muscle invasive response rate (PaIR, p ≤ T1) and will be reported for the cisplatin –eligible and –ineligible cohorts. Secondary endpoints include relapse free survival and overall survival. Exploratory immune and histopathologic aims are also being performed. Clinical trial information: NCT02365766.
Bacterial microbiota of the upper respiratory tract and childhood asthma
Authors: Martin Depner, Markus J. Ege, Michael J. Cox, Sarah Dwyer, Alan W. Walker, Lena T. Birzele, Jon Genuneit, Elisabeth Horak, Charlotte Braun-Fahrländer, Hanna Danielewicz, Raina M. Maier, Miriam F. Moffatt, William O. Cookson, Dick Heederik, Erika von Mutius, Antje Legatzki
Journal: Journal of Allergy and Clinical Immunology (2016)
Dietary saturated fat and monounsaturated fat have reversible effects on brain function and the secretion of pro-inflammatory cytokines in young women
Authors: Julie A. Dumas, Janice Y. Bunn, Joshua Nickerson, Karen I. Crain, David B. Ebenstein, Emily K. Tarleton, Jenna Makarewicz, Matthew E. Poynter, Craig Lawrence Kien
Journal: Metabolism (2016)
Chemotherapy treatment patterns by site of care (SOC): A comparison of the physician office versus hospital outpatient setting.
Authors: Sari Hopson, Adrianne Casebeer, Stephen Stemkowski, Andrew M. Howe, Brian Barnett, Jeffrey Patton, Art Small, Anthony Masaquel
Journal: Journal of Clinical Oncology (2015)

e17670 Background: First line chemotherapy regimens for a variety of cancer types have been found to differ by site of care. This is the first study to explore differences in treatment patterns between patients receiving chemotherapy or biologic therapy for six types of cancer at physician offices (PO) and hospital outpatient (HO) centers in a primarily Medicare population. Methods: Humana, Inc. commercial and Medicare claims data from 2007-2013 were used to identify continuously enrolled patients first diagnosed with early stage (esBC) and metastatic (mBC) breast, colorectal (mCRC), and lung (mLC) cancers, as well as non-Hodgkin’s Lymphoma (NHL) or chronic lymphocytic leukemia (CLL), 180 days prior and up to 120 days post-index infusion. Infusions were categorized using site of care coding. Regimen class was determined by therapy given on date of first eligible infusion, as were length of therapy (LOT) in days and number of infusions (NI). Results are descriptive and unadjusted for patient characteristics. P-values are from the Wilcoxon test. Results: Mean LOT in days and mean NI were significantly higher in PO vs. HO for this mostly (80%) Medicare population. For esBC (n = 2,784) LOT and NI were greater in PO (HO 55 vs PO 61.1, p = .04 and HO 21.1 vs 23.0, p = .04) for taxanes w/o anthracyclines and LOT was longer in PO for anthracyclines w/o taxanes (HO 71.5 vs PO 81.7, p < 0.001 ). In the PO, for mBC (n = 1,602) taxanes w/o anthracyclines had longer LOT (HO 88.6 vs PO 104.9, p = .02) and greater NI (HO 7.5 vs PO 9.3, p = .02). For mCRC, oxaliplatin w/o bevacizumab had greater NI in PO (HO 10.5 vs PO 12.5, p = 0.03, n = 476). For mLC (n = 3,199) biologic therapy LOT was longer (HO 61.9 vs PO 189.9, p = .02) with greater NI (HO 3.8 vs 10.6, p = .03) in PO. For NHL/CLL (n = 1,859), LOT was longer (HO 77.3 vs PO 147.6, p < 0.001) in PO for cytotoxics only. Conclusions: There are significant differences in LOT for some chemotherapy regimen classes by site of care in a mostly Medicare population. Where differences were observed, patients in the PO had longer LOT and greater NI. These analyses are observational and did not adjust for patient characteristics. Future analysis will compare cost, quality, survival and risk adjusted outcomes.
Worsening renal function and outcome in heart failure patients with reduced and preserved ejection fraction and the impact of angiotensin receptor blocker treatment: data from the <scp>CHARM</scp>‐study programme
Authors: Kevin Damman, Scott D. Solomon, Marc A. Pfeffer, Karl Swedberg, Salim Yusuf, James B. Young, Jean L. Rouleau, Christopher B. Granger, John J.V. McMurray
Journal: European Journal of Heart Failure (2016)
Abstract 4069: The carcinogenic effects of electronic cigarettes in oral cancer
Authors: Avinaash Korrapati, Vicky Yu, Maarouf A. Saad, Mehran Rahimy, Yinan Xuan, Angela Zou, Aswini Krishnan, Kevin Brumund, Weg M. Ongkeko
Journal: Cancer Research (2016)

Abstract Alcohol consumption, tobacco use, and human papillomavirus infection have been well-established as the primary risk factors for head and neck squamous cell carcinoma (HNSCC). However, the surge in popularity of e-cigarettes (e-cigs) has prompted speculation of e-cig use potentially emerging as a new risk factor. With previous research on the safety of e-cigs still collectively inconclusive, a comprehensive study of the carcinogenicity of these devices remains urgently necessary. We therefore investigated the potential genotoxic, cytotoxic, and invasive and migratory effects of e-cig vapor exposure on human epithelial cells. A panel of normal epithelial and head and neck cancer cell lines was treated with 0.5%, 1.0%, and 2.0% by volume e-cig vapor from two popular e-cig brands, over periods ranging from 24 hours to 4 weeks. Neutral comet assay and immunostaining for γ-H2AX foci revealed significant induction of DNA double-stranded breaks (up to 3-fold increase, p &amp;lt; 0.05) in cell lines incubated with both nicotinized and nicotine-free e-cig vapor. To evaluate the cytotoxicity of e-cigarettes, trypan blue exclusion and clonogenic assays were performed following short-term e-vapor exposure. Our results indicate that in epithelial cells, short-term treatment induces up to a 5-fold increase in cell death without nicotine, and up to a 10-fold increase with nicotine as compared to untreated controls (p &amp;lt; 0.001). We subsequently assessed the effects of e-cigarettes on HNSCC progression and metastatic potential through exposure of established HNSCC cell lines to e-cigarette vapor. Wound healing assays revealed increased migration of HNSCC cells following e-cigarette treatment, with significant upregulation of key EMT-promoting genes observed via qRT-PCR. We will next examine the effects of long-term (6-9 months) e-cig vapor exposure in vivo using mouse models. Mouse oral epithelium will be harvested for histologic analysis and sequenced to determine the mutagenic potential of long-term e-cig vapor exposure. Nevertheless, our present findings based on short-term e-vapor exposure alone already pose alarming implications for the carcinogenic effects of e-cigarette use. Citation Format: Avinaash Korrapati, Vicky Yu, Maarouf A. Saad, Mehran Rahimy, Yinan Xuan, Angela Zou, Aswini Krishnan, Kevin Brumund, Weg M. Ongkeko. The carcinogenic effects of electronic cigarettes in oral cancer. [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 4069.