tbuckley/cabot-search huggingface dataset:
Abstract NTOC-116: THE TUMOUR SUPPRESSOR PROTEIN OPCML ACTS AS A SENSITIZING AGENT IN ANTI–EGFR/HER2 THERAPY AND CISPLATIN TREATMENT IN OVARIAN CANCER
Authors: E Zanini, LS Louis, J Antony, I Okon, AB McKie, C Recchi, H Gabra
Journal: Clinical Cancer Research (2017)

Abstract Ovarian cancer is a very heterogeneous disease characterised by lack of oncogene addition and occurrence of resistance to platinum-based treatment. The opioid-binding cell adhesion molecule (OPCML) is a glycosylphosphatidylinositol (GPI) anchored protein that was found to be epigenetically inactivated in 83% of ovarian cancers and demonstrated to act as a tumour suppressor gene (TSG) by negatively regulating a spectrum of receptor tyrosine kinases (RTKs), such as ErbB2/HER2, FGFR1, EphA2 and Axl, and their related downstream signalling. We propose that OPCML can sensitise cells to drugs that target these RTKs and, given the profound effect of OPCML on the AKT signaling, we also propose that OPCML can sensitize cells to platinum-based therapy. In particular, here we confirm by in vitro pull-downs and mammalian 2-hybrid studies that OPCML physically interacts with HER2 but not with EGFR. As HER2 is the obligate and preferred partner of EGFR, we propose that OPCML can sensitize cells to drugs that target either EGFR or both EGFR and HER2 when HER2 is over-expressed in the system. SK-OV-3 and OV90 cells were stably transduced to express OPCML and treated with either Erlotinib or Lapatinib for IC50 studies and analysis of the downstream signalling pathways. We found that OPCML was able to significantly sensitize only the cells with high HER2 expression (SK-OV-3) to both Erlotinib and Lapatinib. Proliferation and apoptosis assays were also carried out in OPCML-expressing SK-OV-3 cells after treatment with Cisplatin, showing how OPCML expression sensitizes the cells to the drug by increasing Caspase 3/7 activation. Overall, we show that OPCML expression is associated with a better response to two drugs that target the EGFR/HER2 system, Erlotinib and Lapatinib, when HER2 is over-expressed in the cells. Similarly, cells expressing OPCML are sensitised also to Cisplatin. These results are particularly relevant in view of the development of OPCML as a therapeutic that could prove to be an effective adjuvant to both RTK-specific and platinum-based therapies. Citation Format: Zanini E, Louis LS, Antony J, Okon I, McKie AB, Recchi C, Gabra H. THE TUMOUR SUPPRESSOR PROTEIN OPCML ACTS AS A SENSITIZING AGENT IN ANTI–EGFR/HER2 THERAPY AND CISPLATIN TREATMENT IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-116.
Evaluating the addition of bevacizumab (Bev) to endocrine therapy as first-line treatment for hormone-receptor positive (HR+)/HER2-negative advanced breast cancer (ABC): Pooled-analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials.
Authors: Miguel Martin, Sibylle Loibl, Terry Hyslop, Juan de la Haba-Rodriguez, Bahriye Aktas, Constance Cirrincione, Eva Maria Carrasco, Keyur Mehta, William Thomas Barry, Serafin Morales, Lisa A. Carey, Jose Angel Garcia Saenz, Ann Partridge, Noelia Martinez, Olwen Mary Hahn, Eric P. Winer, Angel Guerrero, Cliff Hudis, Maribel Casas, Maura N. Dickler
Journal: Journal of Clinical Oncology (2017)

1012 Background: Data from randomized trials comparing ET v ET-Bev in 1st line HR+/HER2- ABC pts showed controversial results. We performed a pooled-analysis of two randomized trials (LEA and CALGB 40503) to refine the Bev value in this patient population. Methods: We analysed 749 ABC pts with ET (letrozole-673, tamoxifen-39, fulvestrant 250mg-37) +/- Bev. Primary objective was to compare progression-free survival (PFS). Secondary endpoints were: safety; other efficacy (overall response rate [ORR], clinical benefit rate [CBR] and overall survival [OS]) in all pts; and efficacy in de novo pts and by previous endocrine-sensitivity (-/+ 24 months [mo] without recurrence under ET in adjuvant setting). Multivariable Cox models were fitted for PFS adjusted by study co-variables and controlled for study level differences. Results: Median age was 61 years (yr) (range: 25-87); 40% had de novo ABC and 60% recurrent disease (with disease free interval of ≤ 1 yr in 5%, 1-2 yr in 7% and &gt; 2 yr in 88%); 82% of recurrent pts had previous ET sensitivity. Median PFS was 14.3 mo in the ET arm v 19 mo in the ET+Bev arm (HR 0.77; 95% CI 0.66-0.91; p&lt;0.01). ORR and CBR with ET v ET+Bev were 40 v 61% (p&lt;0.01) and 64 v 77% (p&lt;0.01). OS did not differ between arms (HR 0.96; 95% CI 0.77-1.18; p=0.68). PFS for de novo ABC pts was 14.6 and 19.3 mo in the ET and ET+Bev arms (HR 0.82; 95% CI 0.63-1.06; p=0.13). PFS differed between arms for previous sensitive pts (HR 0.68; 95% CI 0.53-0.89; p=0.004) but not for ET-resistant pts (HR 0.73; 95% CI 0.4-1.3; p=0.29). Grade 3-5 hypertension (2.2 v 20.1%), proteinuria (0 v 9.3%), cardiovascular events (0.5 v 4.2%) and liver events (0 v 2.9%) were significantly higher in the ET+Bev arm (all p&lt;0.01). Multivariable analyses showed age (p&lt;0.01), PgR status (p&lt;0.01), type of prior ET (p&lt;0.01) and treatment arm (p&lt;0.01) to be associated with PFS. Conclusions: The addition of Bev to ET increased PFS but not OS. Analyses to define subgroups with prolonged benefit from ET alone or ET-Bev are ongoing. Support: U10CA180821, U10CA180882, Breast Cancer Research Foundation, Genentech, Roche. Clinical trial information: NCT00545077 / NCT00601900.
Aromatase inhibitors in elderly patients with advanced breast cancer: An exploratory pharmacogenetic study.
Authors: Enrica Rumiato, Antonella Brunello, Selma Ahcene-Djaballah, Lucia Borgato, Milena Gusella, Felice Pasini, Pasquale Fiduccia, Alberto Amadori, Daniela Saggioro, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2014)

11058 Background: Aromatase inhibitors (AIs) are the first choice for older patients (pts) with estrogen-receptor (ER) positive advanced breast cancer (BC). Yet, response is variable and difficult to predict. Some pts exhibit very good long-lasting response whereas others rapidly progress even after initial response. Factors such as tumor subtype (i.e., luminal A vs B) or BMI have been reported to correlate with response but so far no predictive marker is available. The aim of this study was to identify gene variants associated with AIs response in elderly pts with advanced BC. Methods: Genomic DNA from peripheral blood of 55 pts with locally advanced or metastatic breast cancer was analyzed with DMET Plus GeneChip array (Affymetrix, Santa Clara, CA), appropriateness of data was evaluated with DMET Console and statistically relevant variants were assessed with DMET-Analyzer. Median age was 79 years (IQR, 73-86), all patients had ER-positive HER-2 negative BC. Clinico-pathologic factors were evaluated for their impact on response. Bivariate analysis was used with the non-parametric tests Chi-square and Fisher’s exact. Results: Pts had locally advanced (30 pts) and metastatic (25 pts) BC. All pts had ER positivity ≥70%, 31 pts had Ki67 <20%, 13 pts had grade 3 tumors. Median BMI was 26, median 17-ß-estradiol level was 80 pmol/L. Overall, 23 pts had complete or very good partial response, 28 pts partial response <50% or disease stabilization, 4 pts progressive disease as best response at 6 months. No significant correlation was observed between any of the baseline variables (tumor subtypes, BMI, Ki67, estradiol level) and response. None of the 11 aromatase gene (CYP19A1) polymorphisms present in the DMET array achieved the statistical significance. However, when considering only pts with locally advanced BC, the ABCG1 rs3788007 and UGT2A1rs4148304 were associated with objective response. The association of these variants with response was confirmed when the analysis was extended to metastatic pts. Conclusions: This exploratory study indicates DMET array as a valid approach to discover new predictive gene variants in AIs-treated elderly pts with advanced BC. Our data need to be validated in a larger cohort.
Association of MBL2 genotypes wtih infections and outcome after allogeneic stem cell transplantation
Authors: G. A. Papanicolaou, C. Mihu, K. Kadeishvili, M. Doll, D. Stokar, A. Buchbinder, K. Hsu, R. O'Reilly, E. G. Pamer, J. Satagopan
Journal: Journal of Clinical Oncology (2007)

7100 Background: Low MBL2 concentration and MBL2 genotype variants have been associated with an increased risk of infection. Our objective was to correlate MBL2 genotypes with specific infections and outcome of HSCT. Methods: 125 non- consecutive, non-selected HSCT were examined. Patients were classified as high or low risk group based on status of underlying disease. Antifungal prophylaxis consisted of fluconazole 400 mg daily. Patients on steroids received mould prophylaxis. There was no routine antibacterial prophylaxis. Microbiologically confirmed infections were recorded. Genotype was determined by PR-Melting Curve Analysis on blood or buccal swab specimens. MBL genotype was classified as wild-type: A/A (MBL-sufficient, MBL-S) or variant-type: A/O, O/O (MBL deficient, MBL- D). Patients were followed for up to 2 years. Analyses of categorical variables were performed using the Fisher exact test and the Log-Rank test for time to event. Results: Seventy-one (58.2%) patients were homozygous for wild-type MBL2 (AA), 43 (35.3%) were heterozygous (A/0) and 8 (6.5%) were homozygous for variant genotypes (OO). MBL-D group had higher incidence of fungal infections (20% vs 7%, p=0.05), and in particular Aspergillosis (12% vs 3%, p=0.05). MBL-D was associated with a trend for higher rates of bacterial infections (63% vs 46%, p=0.10) and total number of bacterial infections (p=0.10). Rates of respiratory and enteric viral infections or CMV were similar in MBL-D and MBL-S groups (41% vs 38%, p=0.9 and 58% vs. 54% p=1.0 respectively). Patients with MBL-D genotype were at a disadvantage in relapse-free (RFS) and overall survival (OS), (p&lt;0.01 and p=.08). This disadvantage was also observed when stratified by disease risk groups. The estimated 2-year relapse-free survival rate was 30% compared to 53% for MBL-D vs. MBL-S patients (p&lt;0.01). Conclusions: 1) Patients with variant MBL genotype (MBL-D) had a trend for increased incidence and number of bacterial infections. 2) MBL-D genotype and graft versus host disease were risk factors for aspergillosis. 3) MBL-D genotype was associated with worse overall survival and relapse free survival post HSCT. These data suggest that MBL-D patients have impaired immune function compared with MBL-S patients and is consistent with animal data. [Table: see text]
Scientific literature's open sesame?
Authors: T. Delamothe
Journal: BMJ (2003)

How could you make the results of the world's original biomedical research freely available to anyone who wanted them? This question remained hypothetical until the arrival of the world wide web, which allows distribution of material at only a fraction of the cost of distribution on paper. But publishing peer reviewed original research has some costs that the internet cannot magic away. Recently, a way to meet those costs has become clear. The goal of original research being free to everybody everywhere could be very close.

Currently subscribers to journals, mostly academic libraries, pay for access to scientific information. In the new model, authors (or, more likely, those who employ them or fund their research) would pay the costs of peer reviewing and electronically disseminating their articles. This one off processing charge would ensure that the article was freely available to all, forever. Journals' estimates of how much this article processing charge would need to be to cover their costs vary between $500 (£314) and $1800 per article.1 In disciplines where authors already pay submission and page charges the change would be small.

Experiments with the “author pays” model are already under way. Over the past two years, the publisher BioMed Central has set up 90 electronic journals adopting this model. The two new journals planned by the Public Library of Science (a pressure group set up to promote open access to the world's primary research literature) will be funded this …
Nut allergy guidelines discourage complete avoidance
Authors: Anne Gulland
Journal: BMJ (2017)

Patients with peanut or tree nut allergy should not be advised to avoid all nuts, the first single guidance on managing and preventing nut allergy recommends.

The guidelines,1 drawn up by the British Society for Allergy and Clinical Immunology (BSACI), state that, while complete nut avoidance is the safest approach and results in few adverse reactions, this is difficult to achieve and can result in a severely restricted diet. They advise that patients should continue to eat nuts that they know are safe …
Palbociclib exposure-response analyses in second-line treatment of hormone-receptor positive advanced breast cancer (ABC).
Authors: Wan Sun, Yanke Yu, Justin Hoffman, Nicholas C. Turner, Massimo Cristofanilli, Diane Dan Wang
Journal: Journal of Clinical Oncology (2017)

1053 Background: Palbociclib (PAL) is an oral inhibitor of cyclin-dependent kinases 4 and 6 approved for ABC. Exposure-response analyses for efficacy and safety endpoints were performed to evaluate the current PAL clinical dosing regimen (125 mg daily, 3 weeks on and 1 week off) and dose modification strategy in 2nd-line ABC. Methods: The present analyses used data from PALOMA3, a phase 3 study comparing the safety and efficacy of fulvestrant plus either PAL or placebo in 2nd-line ABC patients (PTs). A Bayesian pharmacokinetic (PK) analysis was conducted to estimate PAL PK parameters for individual PTs. Average concentration of PAL over the entire treatment (C avg ) was derived from average daily dose intensity divided by post hoc estimates of clearance for each PT. Time varying C avg (C avgt ) was also derived to account for dose modifications up to each observation point. Kaplan-Meier method and the Cox proportional hazards model were employed to explore relationship between progression-free survival (PFS) and C avg , C avgt , as well as other prognostic factors. A semi-mechanistic PK-pharmacodynamic (PD) model was built to quantify the relationship between PAL concentration and absolute neutrophil count (ANC). Results: The median PFS for low and high PAL exposure groups divided according to C avg were similar (9.47 and 10.9 months, respectively) and significantly higher than that of the control arm (4.57 months). While C avgt was found to be a significant predictor for PFS in univariate analysis (P-value &lt; 0.05), this relationship was not significant in the multivariate analysis where other significant prognostic factors were also included. The PK-PD analysis for safety endpoint indicated higher PAL concentrations were associated with lower ANC, which is consistent with the fact that ANC profiles were well managed by dose modification strategies, i.e., dose interruption, delay and reduction. Conclusions: The analysis results suggested PTs were benefited similarly from fulvestrant plus PAL treatment with manageable safety profile, supporting a favorable benefit-risk profile of PAL under the current dosing regimen and dose modification strategy in 2 nd -line ABC. Funding: Pfizer Inc. Clinical trial information: NCT01942135.
In Vivo Evidence of in Situ Cell Death Preferentially Occurring in CLL Patients with Minimal Lymphocytosis By the Diminished BCL2 and Loss of T Cell Support after Ibrutinib Treatment
Authors: Shih-Shih Chen, Steven Ham, Priyadarshini Ravichandran, Ileana D'Aloisio, Emily Kate Butera, Romi Lyallpuri, Yasmine Kieso, Jacqueline C. Barrientos, Kanti R Rai, Jan Burger, Nicholas Chiorazzi
Journal: Blood (2016)
Preclinical development, primary and secondary phrmacodynamics, of the CD19/CD3 Tandab (AFM11).
Authors: Eugene Zhukovsky, Stefan Knackmuss, Uwe Reusch, Claudia Wall, Kristina Ellwanger, Ivica Fucek, Carmen Burkhardt
Journal: Journal of Clinical Oncology (2014)

e19546 Background: AFM11 is a bispecific TandAb molecule that recruits T cells (via an anti-CD3 domain) to CD19+ tumor cells (via an anti-CD19 domain). Due to the lack of a relevant species, the nonclinical pharmacology program of AFM11 required extensive primary and secondary pharmacodynamic studies in vitro. Methods: The affinity, target specificity, and species specificity of AFM11 to its target antigens, CD3 and CD19, were characterized employing FACS assays. Cytotoxicity was tested on a panel of lymphoma and leukemia cell lines. Cytokine release in AFM11-stimulated PBMC cultures was quantified employing Luminex technology. Results: AFM11 has affinity to human CD3 in the sub-nanomolar and to human CD19 in the low nanomolar ranges. Staining patterns of AFM11 on the full FDA and EMA tissue panel from 3 non-related donors corresponded to those seen with control antibodies directed against either CD3 or CD19. In vitro, AFM11 induces specific and selective killing of CD19+ target cells by T cells with an EC50 of 1 - 2 pM. Secondary pharmacodynamic properties of AFM11 were investigated in several in vitro systems including the ability to induce cytokine release and proliferation of human PBMC. For the assessment of cytokine release,in vitro PBMC cultures from 7 donors were stimulated with AFM11 or the reference anti-CD3 antibody, OKT3. The dose-response profiles of most cytokines produced in response to AFM11 was similar to that of OKT3, although the absolute amounts of the cytokines induced by AFM11 were substantially lower than those mediated by OKT3. Spiking of PBMC cultures with CD19+ Raji tumor cells increased the amounts of the cytokines induced by AFM11, whereas B cell-depletion of PBMC cultures abolished release. Thus, AFM11-mediated cross-linking of CD19+ cells and CD3+T cells (and not cross-linking of CD3 on the T cell surface) is the trigger for cytokine release. AFM11 expression is performed in a mammalian CHO cell system that employs fed batch fermentation in a single-use bioreactor at 500L scale, followed by an established downstream process. Stability testing, according to the ICH guidelines, indicates a stable drug product. Conclusions: Phase I clinical studies with AFM11 will commence in the first half of 2014.
Multicolor Flow Cytometry and Multi-Gene Next Generation Sequencing Are Complimentary and Highly Predictive for Relapse in Acute Myeloid Leukemia Following Allogeneic Hematopoietic Stem Cell Transplant
Authors: Bartlomiej M Getta, Sean Devlin, Molly A. Maloy, Abhinita Mohanty, Maria Arcila, Martin S. Tallman, Ross L. Levine, Sergio A. Giralt, Mikhail Roshal
Journal: Blood (2016)
Abstract AP15: MODULATION OF OXIDATIVE STRESS AND SUBSEQUENT INDUCTION OF APOPTOSIS AND ENDOPLASMIC RETICULUM STRESS ALLOWS CITRAL TO DECREASE CANCER CELL PROLIFERATION
Authors: Arvinder Kapur, Mildred Felder, Lucas Fass, Justanjot Kaur, Austin Czarnecki, Kavya Rathi, San Zeng, Kathryn Kalady Osowski, Colin Howell, May P. Xiong, Rebecca J. Whelan, Manish S. Patankar
Journal: Clinical Cancer Research (2017)

Abstract The monoterpenoid, citral, when delivered through PEG-b-PCL nanoparticles inhibits in vivo growth of 4T1 breast tumors. Here, we show that citral inhibits proliferation of multiple human cancer cell lines. In p53 expressing ECC-1 and OVCAR-3 but not in p53-deficient SKOV-3 cells, citral induces G1/S cell cycle arrest and apoptosis as determined by Annexin V staining and increased cleaved caspase3 and Bax and decreased Bcl-2. In SKOV-3 cells, citral induces the ER stress markers CHOP, GADD45, EDEM, ATF4, Hsp90, ATG5, and phospho-eIF2α. The molecular chaperone 4-phenylbutyric acid attenuates citral activity in SKOV-3 but not in ECC-1 and OVCAR-3 cells. In p53-expressing cells, citral increases phosphorylation of serine-15 of p53. Activation of p53 increases Bax, PUMA, and NOXA expression. Inhibition of p53 by pifithrin-α, attenuates citral-mediated apoptosis. Citral increases intracellular oxygen radicals and this leads to activation of p53. Inhibition of gluthatione synthesis by L-buthionine sulfoxamine increased potency of citral. Pretreatment with N-acetylcysteine decreases phosphorylation of p53 in citral-treated ECC-1 and OVCAR-3. These results define a p53-dependent, and in the absence of p53, ER stress-dependent mode of action of citral. This study indicates that citral in PEG-b-PCL nanoparticle formulation should be considered for treatment of breast and other tumors. Citation Format: Arvinder Kapur, Mildred Felder, Lucas Fass, Justanjot Kaur, Austin Czarnecki, Kavya Rathi, San Zeng, Kathryn Kalady Osowski, Colin Howell, May P. Xiong, Rebecca J. Whelan, Manish S. Patankar. MODULATION OF OXIDATIVE STRESS AND SUBSEQUENT INDUCTION OF APOPTOSIS AND ENDOPLASMIC RETICULUM STRESS ALLOWS CITRAL TO DECREASE CANCER CELL PROLIFERATION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP15.
Comprehensive study of the drug delivery properties of poly( l -lactide)-poly(ethylene glycol) nanoparticles in rats and tumor-bearing mice
Authors: Vladimir Shalgunov, Daria Zaytseva-Zotova, Arkadi Zintchenko, Tatiana Levada, Yuri Shilov, Dmitry Andreyev, Dzhangar Dzhumashev, Evgeny Metelkin, Alexandra Urusova, Oleg Demin, Kevin McDonnell, Greg Troiano, Stephen Zale, Elmira Safarovа
Journal: Journal of Controlled Release (2017)

Nanoparticles made of polylactide-poly(ethylene glycol) block-copolymer (PLA-PEG) are promising vehicles for drug delivery due to their biodegradability and controllable payload release. However, published data on the drug delivery properties of PLA-PEG nanoparticles are heterogeneous in terms of nanoparticle characteristics and mostly refer to low injected doses (a few mg nanoparticles per kg body weight). We have performed a comprehensive study of the biodistribution of nanoparticle formulations based on PLA-PEG nanoparticles of ~ 100 nm size at injected doses of 30 to 140 mg/kg body weight in healthy rats and nude tumor-bearing mice. Nanoparticle formulations differed by surface PEG coverage and by release kinetics of the encapsulated model active pharmaceutical ingredient (API). Increase in PEG coverage prolonged nanoparticle circulation half-life up to ~ 20 h in rats and ~ 10 h in mice and decreased retention in liver, spleen and lungs. Circulation half-life of the encapsulated API grew monotonously as the release rate slowed down. Plasma and tissue pharmacokinetics was dose-linear for inactive nanoparticles, but markedly dose-dependent for the model therapeutic formulation, presumably because of the toxic effects of released API. A mathematical model of API distribution calibrated on the data for inactive nanoparticles and conventional API form correctly predicted the distribution of the model therapeutic formulation at the lowest investigated dose, but for higher doses the toxic action of the released API had to be explicitly modelled. Our results provide a coherent illustration of the ability of controllable-release PLA-PEG nanoparticles to serve as an effective drug delivery platform to alter API biodistribution. They also underscore the importance of physiological effects of released drug in determining the biodistribution of therapeutic drug formulations at doses approaching tolerability limits.