tbuckley/cabot-search huggingface dataset:
Abstract 2041: Quantitative phosphoproteomic analysis of EphA2 signaling in PC-3 prostate cancer cells
Authors: Carolin Offenhäuser, Keyur A. Dave, Buddhika A. Jayakody, Jeffrey J. Gorman, Andrew W. Boyd
Journal: Cancer Research (2015)

Abstract The receptor tyrosine kinase EphA2 is frequently upregulated in cancer, where it plays an intriguing dichotomous role that may lend itself to therapeutic intervention. However, much remains to be understood about how ephrin-mediated activation of EphA2 signaling can reverse its tumour-promoting ligand-independent effects and instead inhibit migration and invasion. We used quantitative phosphoproteomics to analyze EphA2 signaling in PC-3 prostate cancer cells with the aim to further elucidate its downstream signaling and pinpoint phosphorylation-dependent cellular processes that may explain its dichotomous role. Stable isotope labeling by amino acids in cell culture (SILAC) combined with liquid chromatography-coupled mass spectrometry (LC-MS/MS) was used to quantify changes in relative phosphosite abundance in response to EphA2 activation. We identified 113 significantly regulated phosphosites comprising 73 phosphoproteins, including many novel and several previously described downstream effector proteins of EphA2 signaling. More than two thirds of the regulated phosphosites showed reduced phosphorylation in response to EphA2 activation. This is consistent with EphA2 activation inhibiting oncogenic signaling pathways, including Akt and ERK-MAPK signaling. Protein association analysis using the STRING database showed that a large proportion of these differentially regulated proteins are downstream targets of Akt and ERK-MAPK, respectively. Gene ontology enrichment analysis found our dataset to be strongly enriched in proteins associated with the cytoskeleton and its regulation. Overall, our data suggest that diminished phosphorylation of cytoskeletal regulators downstream of Akt and ERK-MAPK signaling may be a major mechanism by which stimulation of EphA2 can alter cell morphology and inhibit cell motility. Citation Format: Carolin Offenhäuser, Keyur A. Dave, Buddhika A. Jayakody, Jeffrey J. Gorman, Andrew W. Boyd. Quantitative phosphoproteomic analysis of EphA2 signaling in PC-3 prostate cancer cells. [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 2041. doi:10.1158/1538-7445.AM2015-2041
Abstract 635: Development of anti-cancer ADCs with Concortis’ C-and K-lock technology
Authors: Gang Chen, Tong Zhu, Dylan Deng, Hong Zhang, David Miao
Journal: Cancer Research (2015)

Abstract Antibody-Drug Conjugation (ADC) is a rapidly growing area and has been widely explored for cancer therapy. In the past decade, numerous progresses have been reported on the identification of proper antibodies, targets validation, discovery of novel payloads, improvement of linkers, as well as the development of new coupling techniques. We have developed novel conjugation methods, C-lock, K-lock and the combination of the two. C-LockTM conjugation method utilizes a novel linker chemistry to re-connect the reduced disulfide bonds between antibody heavy and light chains, and in the meantime, to introduce a drug to each disulfide bond. While K-LockTM conjugation method is a linker-controlled conjugation technology highly selective on 1 or 2 particular sites among 80-90 Lys side chains of an antibody. The generated ADCs have fewer regioisomers and lower DAR (Drug-Antibody Ratio) while maintaining comparable potency to ADCs from regular conjugation methods. Further purification will give rise to site-specific homogeneous products without needs for cell engineering or enzymatic modification steps. The lead ADCs generated by these technologies showed improved activity both in vitro and in vivo in relevant tumor models, and also exhibited less toxicity compared to commercial standard. To pursue to the next level, we are currently developing dual drug ADCs which have two different payloads conjugated to single antibody; as well as bi-specific ADCs with either single or dual drug conjugations (2nd generation or ADC-2X). Initial results indicated that these ADCs showed improved activity and specificity in relevant tumor cell lines compared to 1st generation ADCs. Detailed results will be reported. All these data proved that our ADC technologies are unique and superior in antibody drug conjugation and are promising for anti-cancer drug development. Citation Format: Gang Chen, Tong Zhu, Dylan Deng, Hong Zhang, David Miao. Development of anti-cancer ADCs with Concortis’ C-and K-lock technology. [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 635. doi:10.1158/1538-7445.AM2015-635
A population-based study of glioblastoma multiforme (GBM) in the new stupp paradigm: Have we improved outcome?
Authors: Z. Lwin, D. MacFadden, A. AL-Zahrani, E. Atenafu, B. Miller, C. Menard, N. Laperriere, W. P. Mason
Journal: Journal of Clinical Oncology (2011)

2012 Background: Current standard of care for newly diagnosed GBM includes trimodality treatment followed by six cycles of adjuvant temozolomide (TMZ). We analysed the uptake of standard of care in a real-world setting, and compared outcome to updated controlled clinical trial data. Methods: All GBM patients registered with Cancer Care Ontario between 2004-2008 were identified. Those who were >= 16 years age, newly diagnosed, treated at our institution, had confirmed pathology, complete records and imaging,were included. Demographics, planned and delivered treatments, total cycles of adjuvant TMZ, toxicity and outcome were captured. For survival analysis patients were stratified by age, ECOG, and treatment modalities, including total cycles of TMZ delivered. Descriptive statistics were used for early progressors and long term survivors. Kaplan-Meier curves, log-rank test and Cox proportional hazards model were used for survival analyses. To compare outcome from our population database to published data from controlled clinical trials, patients were stratified into radiotherapy (RT) only group or concurrent chemoradiation (CRT) followed by TMZ. At a median follow-up of 28 months, we compared our outcome data to updated EORTC 22981/26981 NCIC CE. 3 results. Results: 517 patients were identified and 433 included for analysis. Majority were male (63%), ECOG 0-1 (66%), and <=65 years(55%). 44% received CRT followed by TMZ, 13% had CRT only, 30% had RT only and 13% had best supportive care. 35% had >6 cycles of TMZ, 10% were early progressors (<3 months from completing CRT) and 9% survived beyond 2 years. In the entire cohort poor ECOG or older age demonstrated inferior survival (p<0.0001, p=0.0003 respectively). In a multivariate analysis CRT followed by TMZ predicted superior survival (p<0.0001). Comparison of our results to EORTC 22981/26981 NCIC CE. 3 data showed median survival was 15.8 months vs. 14.6 months, 2 year survival rate for CRT plus TMZ was 35% vs. 26%, and for RT alone 0% vs. 10%, respectively. Conclusions: Our results show that only < 50% of GBM patients complete standard of care in the real-world setting and prognosis remains dismal for patients who do not receive CRT.
Assessment of Anti-Asparaginase (ASNase) Antibodies (Ab) and ASNase Activity after Suspected Clinical Allergy.
Authors: Prakash N. Tiwari, Monica Zielinski, John J. Quinn, Stuart E. Siegel, Paul S. Gaynon, Peter Wakamatsu, Nita L. Seibel, Vassilios I. Avramis
Journal: Blood (2006)
Abstract 2021: Integrin-alpha 8 as a potential therapeutic target in multiple myeloma early relapse
Authors: Jiyeon Ryu, Youngil Koh, Hyun Jung Lee, Hyun Sub Chung, Sung-Soo Yoon
Journal: Cancer Research (2015)

Abstract Introduction: Multiple myeloma (MM) is an incurable neoplastic plasma cell disorder and many studies about MM biologic complexity have been reported. Despite the advances of treatment for MM, still many patients of MM exhibit early relapses and the mechanism of MM relapse is not well understood Patient with early relapse after autologous bone marrow transplantation need to be biologically characterized to better understand and reach complete remission. Materials and Methods: To define altered gene expression and pathways, we performed microarray with bone marrow from 16 relapsed MM patients who underwent autologous bone marrow transplantation. Gene expression profile was compared (P &amp;lt; 0.01) in 16 MM patients divided into two groups on the basis of their progression-free survival (PFS) at the point of 12 months or only four patients with shortest and longest duration of PFS. Results: 77 genes over two fold up-regulated were identified and inputted in pathway enrichment analysis. To ascertain of the result, only four patients with shortest and longest duration of PFS were examined with same way of analysis that 163 genes over two fold up-regulated were inputted in KEGG pathway database. Interestingly, both of the analysis showed common up-regulated Integrin-α8 (ITGA8) and its associated pathway, ECM receptor interaction and focal adhesion, was identified (P &amp;lt; 0.05). Several integrin family members are well documented to involve in MM disease progression but ITGA8 in MM is largely unknown. Functionally, we have investigated ITGA8 in MM cell lines that ITAG8 mediates MM cell adhesion, migration and drug resistance through bone marrow microenvironment which is regarded as leading events of MM relapse. Furthermore, its expression in MM is correlated with poor survival outcomes after autologous bone marrow transplantation. Conclusion: Our study demonstrated that gene expression in MM patients showed distinctly different pattern between early relapse and late relapse. Additionally, our speculated specific gene up-regulated in early relapse in MM, ITGA8, is a potential prognostic marker and suggests attractive target for future research. Citation Format: Jiyeon Ryu, Youngil Koh, Hyun Jung Lee, Hyun Sub Chung, Sung-Soo Yoon. Integrin-alpha 8 as a potential therapeutic target in multiple myeloma early relapse. [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 2021. doi:10.1158/1538-7445.AM2015-2021
Effect of WBC<i> BRCA1</i> promoter methylation on ovarian cancer risk.
Authors: P. E. Lonning, M. Bjornslett, S. Knappskog, L. Vatten, P. Romundstad, U. Axcrona, D. G. Evans, A. Howell, A. Dørum, R. Chrisanthar
Journal: Journal of Clinical Oncology (2011)

5029 Background: Recently, some studies have reported BRCA1 WBC hypermethylation to be associated with increased risk of breast cancer. We assessed WBC BRCA1 promoter methylations in ovarian (OC) and breast cancer (BC) patients and healthy controls. In an OC subgroup harboring WBC BRCA1 methylation, we confirmed promoter methylation status in normal tissue. Methods: WBC DNA from 899 OC patients, 425 BC patients and 719 healthy controls were analyzed for BRCA1 promoter methylation by methylation specific PCR. In addition, we analyzed WBC DNA from 256 OC and 393 BC patients in blood samples drawn prior to diagnosis in a population-based study. We also analyzed 24 BC patients with a family history (BRCAPRO scores > 80%; Manchester score >40) without BRCA1/2 mutations. Paraffin-embedded normal tissue from 5 OC patients harboring WBC BRCA1 methylation was analyzed for BRCA1 methylation status. Finally, to determine potential risk factors in cis, we investigated BRCA1 haplotype status in a sub-cohort of 10 individuals with WBC methylated BRCA1and 13 controls. Results: We detected WBC BRCA1 promoter hypermethylation in 2.4% of healthy controls and 3.1% of BC patients (all BC individuals). No difference in BRCA1 methylation incidence was recorded between BC patients with blood samples drawn before (4.1%) or after (2.1%) diagnosis. In contrast, we detected WBC BRCA1 methylation in 10.3% of OC patients having blood samples drawn at diagnosis. Among OC patients with blood sampling 0-13 years (median 4.6 y) prior to diagnosis, BRCA1 promoter methylation was detected in 6.6%. BRCA1 promoter methylation was associated with a non-significant elevated risk of BC (HR 1.302; 95% CI 0.697-2.431) but a significantly increased risk of OC in the cohort of patients with blood samples drawn at time of (OR 4.765; CI 2.814-8.069) or prior to (OR 2.937; CI 1.476-5.845) diagnosis. We confirmed BRCA1 promoter methylation in normal tissue from all 5 individuals analyzed, excluding WBC promoter methylation being due to circulating DNA contamination. No association between BRCA1methylation and promoter haplotype was found. Conclusions: WBC BRCA1 promoter methylation is associated with increased risk of ovarian cancer.This finding has clinical as well as biological implications..
PTH-104 Prevalence of genetic haemochromatosis gene mutations in patients with coeliac disease
Authors: S S Salunke, E Lightbody, A Morgan, A Nicol, J Kelly, A Cooke, A J Morris, E H Forrest, R Gillespie, J Winter, D R Gaya, A Cahill, A J Stanley
Journal: Gut (2010)

<h3>Introduction</h3> Genetic haemochromatosis (GH) and Coeliac disease (CD) are both common conditions in people of North European/or Celtic decent with a high prevalence in Scotland. <h3>Aim</h3> To assess the prevalence of GH gene mutations in patients with CD and compare with local controls, and examine whether the presence of GH mutations is associated with an older age of diagnosis of CD. <h3>Methods</h3> Following ethical approval, patients with CD attending Gastroenterology clinics at Glasgow Royal Infirmary and Stobhill Hospitals were recruited into the study. Each patient had blood taken for C282Y and H63D gene mutation analysis in addition to standard bloods at clinic. The samples were anonymised but split into those from patients &lt;45 years (group A) and those &gt;45 years (group B). The mutation results were analysed for carrier and mutation frequency. The results were compared to 340 local controls anonymously tested for GH mutations as part of larger genetic disease prevalence screening programme. <h3>Results</h3> 138 patients were recruited (A=59, B=79). The C282Y carrier frequency was 1 in 6.0 among CD patients compared to 1 in 8.1 among controls (NS). C282Y and H63D mutation frequencies were 8.1% and 14.5% in CD patients compared with 6.2% and 15.5% in controls (NS). There was no difference in mutations frequencies between CD patients diagnosed younger or older than 45 years old: 16.9% vs 16.5% for C282Y mutations, and 35.6% vs 24.1% for H63D. <h3>Conclusion</h3> The frequency of GH mutations in CD is similar to that in the local population. The presence of these mutations does not appear to delay the diagnosis of CD.
Alteration of blood clotting and lung damage by protamine are avoided using the heparin and polyphosphate inhibitor UHRA
Authors: Manu Thomas Kalathottukaren, Libin Abraham, Piyushkumar R. Kapopara, Benjamin F. L. Lai, Rajesh A. Shenoi, Federico I. Rosell, Edward M. Conway, Edward L. G. Pryzdial, James H. Morrissey, Charles A. Haynes, Jayachandran N. Kizhakkedathu
Journal: Blood (2016)
Deletion of IKZF1 in Pediatric Precursor-B ALL Is a Strong Prognostic Marker for Relapse.
Authors: Roland P. Kuiper, Esmee Waanders, Vincent H.J. Van der Velden, Simon V van Reijmersdal, Blanca Scheijen, Jayne Hehir-Kwa, Suzanne T.M. Keijzers-Vloet, Edwin Sonneveld, Jacques JM van Dongen, Frank N. van Leeuwen, Ad Geurts van Kessel, Peter M. Hoogerbrugge
Journal: Blood (2009)
Bortezomib-Thalidomide-Dexamethasone Compared with Thalidomide-Dexamethasone as Induction and Consolidation Therapy Before and After Double Autologous Transplantation In Newly Diagnosed Multiple Myeloma: Results From a Randomized Phase 3 Study
Authors: Michele Cavo, Giulia Perrone, Silvia Buttignol, Elisabetta Calabrese, Monica Galli, Sara Bringhen, Tonino Spadano, Luca Baldini, Tommaso Caravita, Chiara Nozzoli, Annamaria Brioli, Luciano Masini, Anna Furlan, Lucia Pantani, Daniele Derudas, Stelvio Ballanti, Francesco Pisani, Valerio De Stefano, Gioacchino Catania, Luca Castagna, Felicetto Ferrara, Vincenzo Callea, Pellegrino Musto, Elena Zamagni, Michele Baccarani
Journal: Blood (2010)
Abstract 16723: Variation in Atrial Fibrillation Incidence After Atrial Flutter Ablation According to Follow-up Characteristics: Meta-analysis Study
Authors: Maria Isabel Pino, Oscar L Llanos, Abdul Hakeem, Karam Ayoub, Amjad Abualsuod, Ramez Nairooz, Naga V Pothineni, Waddah Maskoun
Journal: Circulation (2015)

Background: Atrial Flutter (AFL) is usually initiated with short bursts of Atrial Fibrillation (AF). New-onset atrial fibrillation (AF) after catheter ablation for typical atrial flutter (AFL) has been described in prior studies with significant variation in AF incidence rate. We hypothesized that the variation in the incidence rate depends on the characteristics of the post-ablation follow-up: type and duration of follow up. Methods: We performed a meta-analysis by searching online databases for articles from January 1996 to April 2015, and abstracts in the last 2 years which described patients with new AF after successful typical AFL ablation (Complete bidirectional block). We evaluated AF incidence rate based on duration of follow-up in patients who were followed by ECG, clinic visit and Holter monitoring for &lt; 7 days per year. We also evaluated AF rates in studies with &lt; 2 years follow-up based on type of follow-up by categorizing them in 3 groups: Group 1 included ECG, clinical follow-up and symptom-driven evaluation, Group 2 additionally included scheduled 24-hour Holter monitoring for &lt; 7 days per year regardless of symptoms, group 3 included scheduled &gt; 7 days Holter monitoring per year or patients with implant loop recorder. Results: A total of 49 studies were included (5452 patients, typical AFL ablation success rate: 95% and no prior AF). Total incidence of new-onset AF was 29% for a weighted mean follow-up of 30 months. Incidence of AF correlated with duration of follow-up as illustrated in the bubble regression plot (figure 1). The incidence of AF was 12.4% in group 1 (755 patients), 19.3% in group 2 (357 patients), 45% in group 3 (178 patients). Mean follow-up duration was 15.2, 18, and 16.4 months respectively. Conclusions: The incidence rate of AF after AFL ablation in patients with no prior history of AF, significantly increases with time. Closer monitoring detects a higher rate of AF during short duration follow-up.
Distinct Functions of Erythropoietin and Stem Cell Factor Are Linked to Activation of p70S6/mTOR Kinase Signaling Pathway in Primary Erythroid Progenitors.
Authors: Amittha Wickrema, Uddin Shahab, Jeong Ah-Kang, Ying Zhou, Koen van Besien, Jodie Ulaszek
Journal: Blood (2004)
Clinical and Cost Outcomes of Double Umbilical Cord Blood Versus Bone Marrow and Peripheral Blood Unrelated Hematopoietic Stem Cell Transplants.
Authors: Guillermo López-González, Charles F. LeMaistre, Carlos Bachier, Brad Smith, Ka Wah Chan, Michael Grimley, Wilma Cain, Elina Delgado, Shawn Kaleel, Paul Shaughnessy
Journal: Blood (2008)
Relative Survival and Incidence Based Mortality of Diffuse Large B-Cell Lymphoma (DLBCL) in Rituximab Era: Population Based Study From Modena Cancer Registry (MCR)
Authors: Luigi Marcheselli, Raffaella Marcheselli, Alessia Bari, Claudia Cirilli, Eliana Valentina Liardo, Samantha Pozzi, Massimo Federico, Stefano Sacchi
Journal: Blood (2011)
Predictors of Mortality in Children and Adolescents with Sickle Cell Disease: The PUSH Study
Authors: Mehdi Nouraie, Sohail R. Rana, Oswaldo L Castro, Lori Luchtman-Jones, Craig Sable, Niti Dham, Caterina Minniti, Gregory J. Kato, Mark T Gladwin, Gregory Ensing, Manuel Arteta, Andrew Campbell, Victor R. Gordeuk
Journal: Blood (2011)
Elemene, a novel anticancer drug, triggers cell death and enhances cisplatin sensitivity via induction of apoptosis and cell cycle arrest in human non-small cell lung cancer cells
Authors: Gangduo Wang, Xiping Li, Furong Huang, Cynthia Cunningham, James Coad, Eddie Reed, Qingdi Li
Journal: Cancer Research (2004)

2981   Lung cancer is the leading cause of cancer death among the men and women in the United States. Therefore, there is a need to develop compounds that can effectively treat this disease. Elemene, an extract from the ginger plant, is a new antitumor drug, which was approved for the treatment of cervical cancer and carcinoma of the lung, liver, and brain in China, and is now in application for clinical studies in the United States. However, the mechanism underlying the effect of Elemene in lung cancer remains unknown. This study investigated the ability of Elemene to induce cell cycle arrest, to trigger apoptosis, and to sensitize cancer cells to cisplatin in non-small cell lung cancer (NSCLC) cells. We showed that Elemene has an effect on cell-killing in the human NSCLC cell lines H460 and A549, as determined by the MTT assay. Elemene was also found to increase cisplatin cytotoxicity and enhance cisplatin sensitivity in these cells. Moreover, we demonstrated, by using FACS analysis, Cell Death Detection ELISA Kit, and the TUNEL assay, that Elemene or cisplatin independently induced cell cycle arrest and apoptosis in a time- and dose-dependent manner in these systems and that a synergistic effect in this regard was seen when cells were treated with both agents. Further study showed that Elemene decreased the phosphorylation of cdk1 and cdk2, but increased the activity of caspases, including caspase-9, caspase-3, caspase-7, caspase-8, and caspase-10. Finally, we demonstrated that Elemene reduced the expression of cyclin A and cyclin B1, but increased the level of p27 protein in NSCLC cells, indicating that Elemene modulates the activity of the regulatory proteins in cell cycle and apoptosis in these cells. These findings suggest that Elemene may trigger cell death and reverse drug resistance to cisplatin in human NSCLC via the regulation of cell cycle control and apoptotic signals. This study was supported by NIH/NCRR grant P20 RR16440.
Beyond RCHOP: A Blueprint for Diffuse Large B Cell Lymphoma Research
Authors: Grzegorz S Nowakowski, Kristie A Blum, Brad S Kahl, Jonathan W Friedberg, Lawrence Baizer, Richard F Little, David G Maloney, Laurie H Sehn, Michael E Williams, Wyndham H Wilson, John P Leonard, Sonali M Smith
Journal: JNCI Journal of the National Cancer Institute (2016)

Diffuse large B cell lymphoma (DLBCL) comprises multiple molecular and biological subtypes, resulting in a broad range of clinical outcomes. With standard chemoimmunotherapy, there remains an unacceptably high treatment failure rate in certain DLBCL subsets: activated B cell (ABC) DLBCL, double-hit lymphoma defined by the dual translocation of MYC and BCL2, dual protein-expressing lymphomas defined by the overexpression of MYC and BCL2, and older patients and those with central nervous system involvement. The main research challenges for DLBCL are to accurately identify molecular subsets and to determine if specific chemotherapy platforms and targeted agents offer differential benefit. The ultimate goal should be to maximize initial cure rates to improve long-term survival while minimizing toxicity. In particular, a frontline trial should focus on biologically defined risk groups not likely to be cured with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP). An additional challenge is to develop effective and personalized strategies in the relapsed setting, for which there is no current standard other than autologous stem cell transplantation, which benefits a progressively smaller proportion of patients. Relapsed/refractory DLBCL is the ideal setting for testing novel agents and new biomarker tools and will require a national call for biopsies to optimize discovery in this setting. Accordingly, the development of tools with both prognostic and predictive utility and the individualized application of new therapies should be the main priorities. This report identifies clinical research priorities for critical areas of unmet need in this disease.