tbuckley/cabot-search huggingface dataset:
Abstract S6-04: The PI3K inhibitor, taselisib, has enhanced potency in PIK3CA mutant models through a unique mechanism of action
Authors: LS Friedman, KA Edgar, K Song, S Schmidt, DS Kirkpatrick, L Phu, MA Nannini, R Hong, E Cheng, L Crocker, A Young, D Sampath
Journal: Cancer Research (2017)

Abstract Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutational activation of the PIK3CA gene. The dysregulation of this pathway has been implicated in tumor cell growth and survival, thus PI3K is a promising therapeutic target with multiple inhibitors in clinical trials. Taselisib (GDC-0032), a novel, oral, selective inhibitor of p110alpha, sparing inhibition of p110beta, is more potent against cancer cells bearing mutations in the PIK3CA gene than those with wildtype PIK3CA. The mechanism leading to this enhanced mutant selectivity is revealed in these preclinical studies. Uniquely among PI3K inhibitors, taselisib has a gain of potency in PIK3CA mutant SW48 isogenic cells compared to wildtype SW48 parental cells. Pathway inhibition and increased apoptosis are associated with the enhanced activity observed in PIK3CA mutant cells. In PIK3CA mutant cell culture-derived and patient-derived xenograft (PDX) models taselisib induces tumor regressions. In comparison to other clinical-stage PI3K inhibitors, taselisib confers superior anti-tumor activity in PIK3CA mutant xenografts when treated at a Maximum Tolerated Dose (MTD) in vivo. We have discovered that taselisib has a dual mechanism of action, both blocking kinase signaling and inducing down-regulation of the mutant p110alpha protein level in a dose-dependent and time-dependent manner. Taselisib treatment leads to the specific degradation of mutant p110alpha without significant change in wildtype p110alpha protein in cultured cells and in mutant xenograft models including PDX. Other clinical PI3K inhibitors, including PI3Kalpha selective and pan-PI3K inhibitors are unable to induce degradation of mutant p110 alpha. The taselisib-induced degradation of mutant p110a protein is ubiquitin-mediated and proteasome-dependent. These unique mechanistic effects of taselisib are most pronounced when comparing signaling suppression and p110a protein levels at 24 hours vs. 1 hour of drug exposure in PIK3CA mutant cell lines. This discovery indicates that PI3K inhibitors which trigger degradation of mutant p110a protein can more effectively suppress the signaling pathway in response to feedback, and may result in greater activity and improved therapeutic index. Citation Format: Friedman LS, Edgar KA, Song K, Schmidt S, Kirkpatrick DS, Phu L, Nannini MA, Hong R, Cheng E, Crocker L, Young A, Sampath D. The PI3K inhibitor, taselisib, has enhanced potency in PIK3CA mutant models through a unique mechanism of action [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S6-04.
Acidosis Acts through HSP90 in a PHD/VHL-Independent Manner to Promote HIF Function and Stem Cell Maintenance in Glioma
Authors: Alina Filatova, Sascha Seidel, Nuray Böğürcü, Sabine Gräf, Boyan K. Garvalov, Till Acker
Journal: Cancer Research (2016)

Hypoxia is a common feature of solid tumors, which controls multiple aspects of cancer progression. One important function of hypoxia and the hypoxia-inducible factors (HIF) is the maintenance of cancer stem-like cells (CSC), a population of tumor cells that possess stem cell-like properties and drives tumor growth. Among the changes promoted by hypoxia is a metabolic shift resulting in acidification of the tumor microenvironment. Here, we show that glioma hypoxia and acidosis functionally cooperate in inducing HIF transcription factors and CSC maintenance. We found that these effects did not involve the classical PHD/VHL pathway for HIF upregulation, but instead involved the stress-induced chaperone protein HSP90. Genetic or pharmacologic inactivation of HSP90 inhibited the increase in HIF levels and abolished the self-renewal and tumorigenic properties of CSCs induced by acidosis. In clinical specimens of glioma, HSP90 was upregulated in the hypoxic niche and was correlated with a CSC phenotype. Our findings highlight the role of tumor acidification within the hypoxic niche in the regulation of HIF and CSC function through HSP90, with implications for therapeutic strategies to target CSC in gliomas and other hypoxic tumors. Cancer Res; 76(19); 5845-56. ©2016 AACR.
Simulating the cost-effectiveness of lung cancer screening by low-dose CT scan in Canada.
Authors: John R. Goffin, William M Flanagan, Anthony Miller, Fei Fei Liu, Sonya Cressman, Natalie Fitzgerald, Sharon Fung, Michael Wolfson, William K. Evans
Journal: Journal of Clinical Oncology (2013)

6550 Background: The National Lung Screening Trial (NLST) demonstrated that low-dose CT screening diminishes the risk of death among smokers. A cost-effectiveness analysis was undertaken in the context of the Canadian publically funded healthcare system. Methods: Microsimulation of CT screening was undertaken using the Cancer Risk Management Model, which incorporates demographic data, cancer risk factors, cancer registry data, diagnostic and treatment algorithms and health utilities. Simulations were performed at the individual level for a cohort incepted during the period 2012-2032. The criteria for the screen-eligible population, CT scan test characteristics, and screened cohort outcomes were derived from NLST and Canadian data. The baseline screening scenario was annual CT screening for ≥30 pack-year smokers, age 55 to 74. Simulation assumed 60% of the eligible population participates by 10 years, 70% adhere to the screening regimen, and smoking cessation rates are unchanged. One-way sensitivity analyses were performed. Costs and life-years lived were discounted at 3% annually. Results: Compared to no screening, annual screening results in incremental system costs of $2.97 billion (Cdn), 149,000 life-years saved (LYS) or 55,000 quality-adjusted life-years saved (QALYS), an incremental cost-effectiveness ratio (ICER) of $19,900/LYS, and $53,700/QALYS. With participation rates from 40% to 80%, ICER /QALYS remained within the range of $53,700 to $58,200. Increases in screening adherence from 50% through 90% increased the ICER /QALY from $50,400 to $58,800. Higher rates of smoking cessation led to improvements in ICER /QALY (150% of background cessation rate of 3.2-5.3%, $47,000; 200%, $41,500; 300%, $32,900). A system of biennial screening had a net cost of $1.81 billion, resulting in an ICER of $19,600 /LYS, and $54,800 /QALYS. Conclusions: Screening for lung cancer with low-dose CT scans could be cost-effective, but requires substantial system costs. The smoking cessation rate greatly impacts the ICER and a cessation program should be considered if screening is implemented. Compared to annual screening, biennial screening costs less and produces a similar ICER. Further analyses will be detailed.
Herpes Zoster Mandibularis
Authors: Tania Afonso, Romeu Pires
Journal: New England Journal of Medicine (2016)

A 70-year-old man presented with a 2-day history of facial edema, rash along the left lower jaw, and plaque that covered two thirds of the left half of his tongue. He had had pain, otalgia, and glossodynia 3 days before the outbreak of the rash.
Applying clinical process analysis in patient access.
Authors: Gina Aranzamendez, Courtney Barnes, Eric Enriquez, Beverly A Hayes, Valerie Haywood, Laurie Kaufman, Doris Quinn, Duke Rohe
Journal: Journal of Clinical Oncology (2014)

214 Background: Patient access is the entry point for new and established patient registration and scheduling process. It serves as the doorway in aligning the need of the patients to the vision of the organization, ensuring financial viability of all parties involved. The increasing demands for regulatory requirements, changes in reimbursement policies, technological and medical advancement, and steep competition, patient access becomes a vital improvement initiative in many healthcare organizations. In FY 2013, our group, the Clinical Process Analysis (CPA) team was tasked to assess the patient access work processes of our clinic areas. Methods: Through a series of structured group interview meetings, the interdisciplinary team (frontline staff, clinical leadership and financial teams) reflects and articulates their current work processes. These work processes are translated into an electronic process map, inclusive of the activities, job roles, estimated times, probabilities, and opportunities for improvement (OFIs). With these elements, CPA delivers a visual display of current work processes which can be utilized for onboarding, visualization of OFIs, and calculation of direct labor cost. A completion of a facilitated PDSA project further infuses the science of improvement. Results: Six centers completed the CPA projects since September 2013. 98 OFIs identified with 91% identified as efficiency and timely issues. 10 PDSA projects initiated, 50% reached completion and 50% are in progress. Clinical teams continue to work on the improvement projects even after the facilitation were completed. Conclusions: Drawing from system thinking and Time-Driven Activity-Based Costing (TDABC) methodology, CPA provides a comprehensive analysis of the current work flow. This allows for both a clinic specific and institutional comparative analysis for identification, implementation and improvement plan. Through facilitation of an interdisciplinary team, from frontline to leadership, process realities are visualized and work-list of opportunities for improvement are identified and worked on. This enables a quality improvement culture of providers and staff to drive quality and financial improvement.
NHS funding in England: money’s too tight to mention
Authors: Jennifer Dixon, Will Warburton
Journal: BMJ (2016)

What prospects for better quality care in the NHS?

The NHS in England is halfway through its tightest ever decade of funding growth. If plans set out in the spending review last autumn hold true to 2020, real term growth in the NHS will average around 1% a year over this decade—relative to the long term average of just under 4%. This is equivalent to just 0.3% growth in spending per head of population.

The pips are squeaking. In 2015-16, NHS provider organisations were £2.8bn (€3.32bn; $3.69bn) in the red, with more than two thirds of NHS trusts not balancing their books. Recently published accounts show the Department of Health overspent the total health budget (excluding capital) by £207m.1 This is despite the fact that growth in health spending was “frontloaded”—higher allocations in 2015-16 and 2016-17 before dropping from 2017-18 to 2020-21.2 “Brexit” could introduce additional risks to even this historically low rate of funding increase. Uncertainty after the EU referendum has threatened the stability …
Abstract 2851: EGFR-TERT cooperation in the development of EGFR-TKI treatment induced pulmonary fibrosis
Authors: Rongrong Wei, Wanqing Liu
Journal: Cancer Research (2016)

Abstract Background: Previous studies have shown that epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer can lead to the development of pulmonary fibrosis (PF). In other studies, it has been shown that reduced telomerase reverse transcriptase (TERT) function increases susceptibility to PF. In this work, we hypothesize that TERT is associated with the pathogenesis of EGFR-TKI induced PF via important signaling pathways. Methods: HCC827 cells (EGFR L858R) was treated with gefitinib and TERT expression level was detected following the treatment. To investigate the molecular changes following gefitinib treatment, we also performed a 84-TF qPCR- microarray and a qPCR microarray for 84-key secreted proteins of cytokines and chemokines. The level of interleukin-6(IL-6) was further measured with ELISA in cell medium following the gefitinib treatment. Fibrogenic markers were detected after co-culturing HCC827 with lung fibroblast IMR-90 cells. Results: TERT gene expression was significantly decreased over 90% after gefitinib treatment. Early growth response protein 1(EGR-1) and E2F transcription factor 1(E2F1) were significantly down-regulated as major TFs that are responsive to gefitinib treatment. Both EGR-1 and E2F1 have been shown to regulate TERT expression in previous studies. In addition, TFs including JUN and most REL members involved in the NF-κB pathway, were significantly up-regulated after gefitinib treatment, which are known to lead to the activation of the senescence-associated secretory phenotype (SASP) pathway. IL-6 mRNA as well as protein secretion were both significantly up-regulated after gefitinib treatment. After co-culturing HCC827 and IMR-90 for 7 days and treating with gefitinib, the growth of IMR-90 cells were increased compare to the control group. Fibrogenic markers, e.g. COL1A1 (Collagen, Type I, Alpha 1), α-SMA (alpha smooth muscle actin), FSP-1(Fibroblast-specific protein 1), etc. were all up-regulated. Conclusion: Our data suggest that EGFR inhibition leads to lung epithelial cell senescence via inhibiting TERT function and activating of the SASP pathway, which further activates fibroblasts and induces fribrogenesis. Continued studies are warranted to further understand the molecular signaling in this mechanism. Citation Format: Rongrong Wei, Wanqing Liu. EGFR-TERT cooperation in the development of EGFR-TKI treatment induced pulmonary fibrosis. [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 2851.
Abstract 3816: Reactive oxygen species and ERK2 phosphorylation are required for NSC59984 to induce mutant p53 protein degradation and restore p53 signaling
Authors: Shengliang Zhang, Lanlan Zhou, David Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2016)

Abstract Tumor suppressor p53 is mutated in over 50% of human cancers. p53 mutation abolishes wild-type p53 function and also endows mutant p53 with a gain-of-function (GOF) that drives tumor growth and drug resistance. Targeting mutant p53 is an attractive strategy for cancer therapy. We recently reported (Zhang et al., Cancer Research, 2015) a small-molecule NSC59984 with dual capabilities to restore p53 signaling and destabilize mutant p53 protein (depleting GOF). We now demonstrate the role of reactive oxygen species (ROS) and ERK2 in the mechanism of action of NSC59984. We observe a sustained-phosphorylation of ERK2 in cancer cells treated with NSC59984. Blockade of ERK2 rescues mutant p53 from NSC59984-mediated degradation, and inhibits restoration of p53 signaling in mutant p53-expressing cells. Thus, sustained ERK2 phosphorylation is required for NSC59984-induced degradation of mutant p53 protein, and depletion of mutant p53 contributes to the restoration of p53 pathway. NSC59984 induces MDM2 phosphorylation that correlates with ERK2 phosphorylation. The effect of NSC59984 on MDM2 phosphorylation is blocked by U0126 and knockdown of ERK2. NSC59984-mediated mutant p53 protein degradation is inhibited by MDM2 knockdown, and enhanced by MDM2 overexpression. Thus, ERK2-dependent MDM2 phosphorylation is a major determinant of NSC59984-mediated mutant p53 degradation. We investigated the role of ROS in the effect of NSC59984 on ERK2 phosphorylation. ROS is induced by NSC59984 and a decrease in ROS by NAC inhibits NSC59984-induced ERK2 phosphorylation, and mutant p53 protein degradation. Increased ROS by BSO treatment enhances the NSC59984 effect on ERK2 phosphorylation, mutant p53 protein degradation and restoration of p53 signaling. We conclude that ROS is required for NSC59984 to sustain ERK2 phosphorylation, which, in turn, is required for NSC59984-induced mutant p53 protein degradation via MDM2. The combination of NSC59984 and BSO synergistically induces cell death in colorectal cancer cells. ROS and ERK2 are two important factors required for NSC59984 to degrade mutant p53 protein, restore p53 signaling and induce cell death. These results provide a rationale for clinical testing of NSC59984 in tumors with high ROS. Citation Format: Shengliang Zhang, Lanlan Zhou, David Dicker, Wafik S. El-Deiry. Reactive oxygen species and ERK2 phosphorylation are required for NSC59984 to induce mutant p53 protein degradation and restore p53 signaling. [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 3816.
Phase I pharmacokinetics and metabolic pathway of belinostat in patients with hepatocellular carcinoma.
Authors: L. Wang, B. C. Goh, T. W. Lwin, H. Lee, S. L. Chan, R. S. Lim, A. T. Chan, W. Yeo
Journal: Journal of Clinical Oncology (2010)

2585 Background: Metabolic inactivation of several hydroxamic acid-derived histone deacetylase inhibitors (HDACi) involves glucuronidation. Vorinostat, a pan-HDACi, undergoes glucuronidation by UGT2B17. We studied the pharmacokinetics and metabolic pathway of belinostat (PXD101). Methods: In vitro glucuronidation of belinostat was investigated; plasma pharmacokinetics of belinostat was studied in a phase I study in patients with hepatocellular carcinoma. Seventeen patients were treated with belinostat at escalating doses of 600 (n = 3), 900 (n = 3), 1,200 (n = 6), 1,400 (n = 5) mg/m2 daily by intravenous infusion over 30 minutes for 5 days every 21 days; blood was drawn on day 1 before infusion, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5, and 24 hours after the start of infusion, plasma was isolated for determination of belinostat and identification of its metabolites using LC-MS/MS. Pharmacokinetics of belinostat was studied using noncompartmental methods. Results: Using a panel of 12 UGT isoforms, UGT1A1 was found to be the predominant enzyme for glucuronidation of belinostat with one-third of unmetabolized belinostat left after 1 h incubation at 37 °C. Belinostat glucuronide had no activity against HONE1 cell line at 10 μ M, compared to an IC50 of 1.59 ± 0.90 μ M for belinostat. Belinostat AUC increased linearly with dose, with a mean clearance of 34.34 ± 10.56 L/h/m2 and terminal half-life of 2.94 ± 0.48 h. Five metabolites in human plasma were identified. Glucuronidation was the most significant pathway of belinostat metabolism; 2 alternate biotransformation pathways involved methylation to methylated belinostat and reduction of hydroxamic group to its corresponding belinostat amide. In addition, two minor metabolites were found to be belinostat N-glucoside and belinostat acid. Belinostat glucuronide increased in levels shortly after administration, reaching the maximum concentration at 1 h from start of infusion. Conclusions: Phase II biotransformation played a key role on belinostat disposition, with UGT 1A1 likely involved in the major pathway. Further studies should explore the role of common polymorphisms of UGT1A1 on belinostat disposition and pharmacodynamics. No significant financial relationships to disclose.
Adult Matched Sibling Blood Cell Transplants (BCT) after Myeloablative Conditioning Incorporating Daily Intravenous (IV) Busulfan (BU) and Low-Dose Antithymocyte Globulin (ATG): Outcomes with Particular Respect to Transplant-Related Mortality (TRM) in 140 Patients.
Authors: James A. Russell, Ahsan M. Chaudhy, Oluyeme Jeje, Diana Quinlan, Douglas Stewart, Donald Morris, Nizhar J. Bahlis, Lynne Savoie, Christopher B. Brown, Loree Larratt, Michelle Geddes, A. Robert Turner
Journal: Blood (2004)
Abstract 1934: MicroRNA-383 located in frequently deleted chromosomal locus 8p22 regulates prostate cancer stem cell marker CD44
Authors: Nathan Bucay, Kiran Sekhon, Varahram Shahryari, Yozo Mitsui, Guoren Deng, Z. Laura Tabatabai, Shahana Majid, Soichiro Yamamura, Rajvir Dahiya, Yuichiro Tanaka, Sharanjot Saini
Journal: Cancer Research (2016)

Abstract A major genomic alteration in prostate cancer (PCa) is frequent loss of chromosome (chr) 8p with a common region of loss of heterozygosity (LOH) at chr8p22 locus. Genomic studies implicate this locus in the initiation of clinically significant PCa and with progression to metastatic disease. However, the genes within this region have not been fully characterized to date. Here we demonstrate for the first time that a microRNA component of this region -miR-383- is frequently downregulated in prostate cancer, plays a critical role in determining tumor initiating potential and is involved in prostate cancer metastasis via direct regulation of CD44, a ubiquitous marker of PCa tumor initiating cells (TICs)/ stem cells. Expression analyses of miR-383 in PCa clinical tissues established that low miR-383 expression is associated with poor prognosis. Functional data suggests that miR-383 regulates PCa tumor initiating/ stem-like cells via CD44 regulation. Ectopic expression of miR-383 inhibited tumor initiating capacity of CD44+ PCa cells. Also, ‘anti-metastatic’ effects of ectopic miR-383 expression were observed in a PCa experimental metastasis model. In view of our results, we propose that frequent loss of miR-383 at chr8p22 region leads to tumor initiation and prostate cancer metastasis. Thus, we have identified a novel finding that associates a long observed genomic alteration to PCa stemness and metastasis. Our data suggests that restoration of miR-383 expression may be an effective therapeutic modality against PCa relapse and metastasis. Importantly, we identified miR-383 as a novel PCa diagnostic biomarker with potential that outperforms that of serum PSA. Citation Format: Nathan Bucay, Kiran Sekhon, Varahram Shahryari, Yozo Mitsui, Guoren Deng, Z. Laura Tabatabai, Shahana Majid, Soichiro Yamamura, Rajvir Dahiya, Yuichiro Tanaka, Sharanjot Saini. MicroRNA-383 located in frequently deleted chromosomal locus 8p22 regulates prostate cancer stem cell marker CD44. [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 1934.