tbuckley/cabot-search huggingface dataset:
Abstract B06: Studying cytarabine resistance through PDX models in acute myeloid leukemia
Authors: Thomas Farge
Journal: Clinical Cancer Research (2016)

Abstract The major therapeutic barrier in acute myeloid leukemia (AML) is chemotherapy resistance. AML cells resistant to conventional chemotherapy targeting DNA synthesis are thought to be enriched in quiescent leukemic stem cells (LSCs). In order to better understand chemotherapy resistance in AML, we analyzed the response to cytarabine (AraC) through patient-derived xenograft (PDX) models with 20 primary AML patient specimens from two clinical sites and in the context of a French “Innovative models initiative” (IMODI) program. After confirming AML engraftment, highly immunodeficient NOD/LtSz-scid IL2Rγc null (NSG) mice were treated with AraC administered IP for 5 days as a single agent at 60 mg/kg daily, which correlates with human dosing. In all mice treated with this regimen, there was a significant but variable cytoreductive effect (4- to 46-fold reduction of tumor cell burden; 2- to 13-fold induction of apoptosis) at 3 days post-treatment. This in vivo AraC response in PDX models has been compared to clinicobiological data of their matched patients (including overall survival, FAB classification, and age at diagnosis). Furthermore, residual leukemic cells (RLCs), surviving after in vivo AraC treatment, have been characterized for their cell surface phenotype, stem cell frequency, cell cycle and metabolic status. Gene expression of RLCs from three different PDX models showed an enrichment of genes involved in inflammatory, immune and stress/ROS responses. When tested in three independent cohorts of AML patients (Verhaak et al. 2009; TGCA. 2011; Metzeler et al. 2011), the down-regulated gene signature is associated with an unfavorable prognosis in patients treated with intensive chemotherapy. Altogether, these results suggest a novel model of AraC chemotherapy resistance uncovering the control of the oxidative and mitochondrial energy metabolism in vivo and the relevance of PDX models for clinical investigations and new preclinical drug assessment. Further studies of the role of immune and stromal microenvironment will be assessed in this model to extend our findings in a more relevant setting. Citation Format: Thomas Farge{Authors}. Studying cytarabine resistance through PDX models in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B06.
Iron Chelation in Regularly Transfused Patients with Aplastic Anemia: Efficacy and Safety Results from the Large Deferasirox EPIC Trial
Authors: Jong Wook Lee, Sung-Soo Yoon, Zhi Xiang Shen, Hui-Chi Hsu, Arnold Ganser, Dany Habr, Gabor Domokos, Abdel Hmissi, John B Porter
Journal: Blood (2008)
Feasibility of using home-based mobile sensors for remote patient monitoring in cancer care and prevention.
Authors: Susan K. Peterson, Karen Basen-Engquist, Wendy Demark-Wahnefried, Alexander V. Prokhorov, Eileen H. Shinn, Stephanie L. Martch, Emilia Farcas, Chaitan Baru, Ingolf H. Krueger, Adam S. Garden, Beth Michelle Beadle, Cathy Eng, Paul M. Cinciripini, Maher A. Karam-Hage, Gary Brandon Gunn, Clifton David Fuller, William H. Morrison, David Ira Rosenthal, Jack Phan, Kevin Patrick
Journal: Journal of Clinical Oncology (2014)

9585 Background: Remote monitoring of patients outside of the clinic setting during critical periods of care is an emerging paradigm in oncology. CYCORE (CYberinfrastructure for COmparative effectiveness REsearch) is a software-based prototype for a user-friendly cyberinfrastructure that supports collection and analyses of data from multiple domains using home-based mobile sensors. We evaluated CYCORE's feasibility in three studies that represented diverse oncology settings and that assessed: (1) physical functioning in colorectal cancer (CRC) patients; (2) adherence to swallowing exercises in head and neck cancer (HNC) patients during radiation therapy; and (3) tobacco use in cancer survivors who completed an in-house tobacco treatment program (TTP). Methods: Eligible participants were ≥ age 18 years, English proficient, and had a history of cancer. Participants used home-based sensors for two non-consecutive 5-day periods. CRC patient sensors provided blood pressure, heart rate, accelerometry and global positioning system (GPS) data; HNC patient sensors captured video of swallowing exercises; and TTP patient sensors captured expired carbon monoxide and adherence videos. Patient-reported outcome measures were completed daily using smartphones. Feasibility outcomes included study completion rate, and perceived ease of use, self-efficacy and overall satisfaction with sensors. Results: For the CRC, HNC and TTP studies, respectively, we enrolled 50, 37, and 50 participants over 18, 8.5, and 20 month time periods, with 96%, 84%, 96% completion rates. Participant characteristics for the respective studies included: 50%, 27%, 72% female; 70%, 92%, 70% White; 68%, 97%, 46% married; and 80%, 68%, 58% with at least some college education. Between 91-100% of all participants rated their ease and self-efficacy for each sensor as highly favorable, 72-100% gave equivalent ratings for overall satisfaction, and 72-93% had low or no concerns about data privacy. Conclusions: Using home-based mobile sensors for remote monitoring was feasible and highly acceptable for patients. CYCORE serves as a new model for sensor- and home-based monitoring that can inform both research and clinical care.
ANKHD1 Interacts with the Proapoptotic Protein SIVA and Plays a Role in the Proliferation and Stathmin Activation of Acute Leukemia Cells.
Authors: Joao Machado-Neto, Mariana Lazarini, Patricia Favaro, Paula de Melo Campos, Renata Scopim-Ribeiro, Gilberto Carlos Franchi-Junior, Alexandre Eduardo Nowill, Irene Lorand-Metze, Fernando Ferreira Costa, Sara T. Olalla Saad, Fabiola Traina
Journal: Blood (2012)
Gene regulation of apoptosis and telomere length in COPD and lung cancer
Authors: Dimitry Bazyka, Iryna Ilyenko, Lyudmila Shvajko, Kostyantyn Bazyka, Oleg Belyaev
Journal: European Respiratory Journal (2011)

The aim of this study was to investigate the role of gene regulaton of apoptosis (TP53, TP53 I3, FASLG, BAX, CCND1) and telomere function (TRF1, TRF2) in peripheral blood lymphocytes in COPD and lung cancer.

Methods: Groups included 16 COPD patients (FEV1 41-64), 5 lung cancer and 12 controls. Relative telomere length and apoptosis in peripheral blood cells were analyzed by flow cytometry. Relative quantification (RQ) of gene expression was investigated by the RT-PCR using 7900 HT System and TaqMan technology.

Results: In COPD a decreased RQ was shown for FASLG, TP53 and TP53 I3 genes with overexpression of BAX (p<0,001) and CCND1 genes and increased presentation of BAX-protein and MAPK14 (p38) on CD16+56+ cells by flow cytometry.

A significant decrease was demonstrated TERF1 and especially TERF2 expression (Fig. 1). In lung cancer high Ki-67+ and HER2+ cell counts were combined with a decrease of BIRC5 and FASLG expression and MADD, MAPK14 and CDKN1B over-expression. The RTL was higher in lung cancer as comparing with COPD and control but no correlation was seen with TERT or TERF2 gene expression.

![Figure][1] 



Conclusion: In COPD the association is demonstrated between the cytotoxic cells activation, MAPK and CCND1 genes and decreased apoptosis. Some independence is shown between TERT and T-loop genes expression and the telomere length in lung cancer and COPD, supposing the influence of different regulation pathways.

 [1]: pending:yes
Association between HER2/neu overexpression and calcifications in breast cancer
Authors: C. J. Christy, M. Rishi, J. Schwartz, B. J. Grube, V. Bossuyt, L. Philpotts, M. P. DiGiovanna, F. Tavassoli, D. R. Lannin
Journal: Journal of Clinical Oncology (2009)

579 Background: HER-2/neu overexpression is an important parameter that influences prognosis and treatment for breast cancer. The purpose of this study is to explore the relationship between HER-2/neu overexpression and calcifications identified by either mammographic imaging or histologic examination. Methods: A retrospective review of the prospectively collected database was performed to evaluate the mammographic and histologic characteristics of all cases of invasive breast cancers diagnosed between 2003 and 2008. HER-2/neu positivity was defined as either overexpression by FISH analysis or 3+ staining on immunohistochemistry. Results: Of 502 invasive cancers, 165 (33%) had calcifications on mammography and 337 (67%) did not. HER-2/neu positivity was found in 63 (38%) of the calcification cases and 40 (12%) of the non-calcified cases (p &lt; 0.001). This association persisted across all age groups and races and was independent of tumor size, nodal status, or hormone receptor status. Calcifications seen histologically also correlated with HER-2/neu overexpression, but the relationship was more complex. Among 155 cases with histologic calcifications seen within a ductal intraepithelial neoplasia (DIN) component, there were 45 (29%) that were HER-2/neu positive, compared with 67/414 (16%) that did not have calcifications within DIN (p &lt; 0.001). If the calcifications were only within invasive tumor, the rate of HER-2/neu overexpression was less, 9/63 (14%). Univariate analysis demonstrated that tumor grade, necrosis, lymphovascular invasion and hormone receptor negativity were significantly associated with HER-2/neu overexpression (all p &lt; 0.01). Multivariate logistic regression showed only the following factors to be significantly associated with HER-2/neu overexpression: grade of invasive tumor, presence of necrosis, progesterone receptor negativity in either the invasive or the in situ component, and mammographic calcifications. Conclusions: Recognition of the strong association between HER-2/neu overexpression and mammographic calcifications may have clinical usefulness and could lead to a better understanding of the underlying tumor biology of this important tumor marker. [Table: see text]
Development of prognostic molecular markers in pediatric rhabdomyosarcoma based on gene expression and copy number variations.
Authors: Edoardo Missiaglia, Dan Williamson, Julia C. Chisholm, Pratyaksha Wirapati, Gaëlle Pierron, Khin Thway, Odile Oberlin, Kathy Pritchard-Jones, Olivier Delattre, Mauro Delorenzi, Janet Shipley
Journal: Journal of Clinical Oncology (2012)

9510 Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and comprises two major histological subtypes: alveolar and embryonal. The majority of alveolar tumors harbor PAX/FOXO1 fusion genes. Current patient risk stratification, unlike other pediatric embryonal tumors, does not utilize any molecular data. Therefore, we aimed to improve the risk stratification of RMS patients through the use of molecular biological data. Methods: Two independent data sets of gene expression profiling for 124 and 101 RMS were used to derive prognostic gene signatures by meta-analysis. Genomic array CGH data for 109 RMS was also evaluated to develop a prognostic marker based on copy number variations (CNVs). The performance and usefulness of these derived metagenes and CNVs as well as a previously published metagene signature were evaluated using rigorous leave-one-out cross-validation analyses. Results: The new prognostic gene expression signature, MG15, and one previously published (MG34) (Davicioni. JCO. 2010) performed well with reproducible and significant effects (HR 3.2 [1.7-5.9] p &lt; 0.001 and HR 2.5 [1.5-4.3] p &lt; 0.001, respectively). However, they did not significantly add new prognostic information over the fusion gene status (PAX3/FOXO1, PAX7/FOXO1 and Negative). Similarly, a prognostic CNV marker, although showing HR 2.9 [1.5-5.6] p &lt; 0.01, was also not improving models with fusion gene status. Within fusion negative RMS, the analysis identified prognostic markers based on either gene expression or CNVs and showed significant association with patients outcome (HR 6.3 [1.5-26.3] p ≤ 0.016 and HR 11.2 [2.5-50.7] p &lt; 0.010, respectively). Moreover, these were able to identify distinct risk groups within the COG (Children's Oncology Group) risk categories, which is currently used to guide treatment. Conclusions: Molecular signatures derived using all RMS effectively stratify patients by their risk, but most of their prognostic information is contained in the PAX/FOXO1 fusion gene status which is simpler to assay. New markers developed within the fusion negative population seem improving current RMS risk classifier and should be tested in follow-up studies.
Glucosidase inhibitors induce HCV glycoproteins misfolding, impair viral assembly and release, and reduce the infectivity of residually secreted HCV particles
Authors: C Chapel, C Garcia, B Bartosch, P Roingeard, N Zitzmann, Cosset F-L., J Dubuisson, R Dwek, C Trepo, F Zoulim, D Durantel
Journal: Hepatology (2006)
Pretransplant Characteristics Could Predict Full Donor Chimerism on Day +90 and Day +180 and Outcomes in Reduced Intensity Alemtuzumab Conditioning Allogeneic Transplantation Can Be Influenced by Chimeric Status
Authors: Emmanouil Nikolousis, Charles F. Craddock, Shankaranarayana Paneesha, Sudhir Tauro, Prem Mahendra, Mark Cook, Fiona Clark, Richard Lovell, Sridhar Chaganti, Donald Milligan, Dominique Mcmullan, Mike Griffiths, Stephen P Robinson
Journal: Blood (2008)
CTLA-4 Polymorphisms and Haplotype Correlate with Survival and aGVHD after Allogeneic Stem Cell Transplantation from Related HLA-Haplotype-Mismatched Donor
Authors: Xiao-Ying Qin, Yu Wang, Guo-Xuan Li, Yazhen Qin, Lan-Ping Xu, Fengrong Wang, Huan Chen, Wei Han, Jing-Zhi Wang, Xiao-Hui Zhang, Ying-Jun Chang, Kaiyan Liu, Zheng-Fan Jiang, Xiao-jun Huang
Journal: Blood (2015)
Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis
Authors: Francesco Niola, Xudong Zhao, Devendra Singh, Ryan Sullivan, Angelica Castano, Antonio Verrico, Pietro Zoppoli, Dinorah Friedmann-Morvinski, Erik Sulman, Lindy Barrett, Yuan Zhuang, Inder Verma, Robert Benezra, Ken Aldape, Antonio Iavarone, Anna Lasorella
Journal: Journal of Clinical Investigation (2014)
Abstract A29: Evaluating the dynamics of epigenetic changes conferring targeted cancer drugs resistance in tumor xenograft propagation model
Authors: REN-IN YOU, CHUN-SHAN CHEN, CHUN-YI CHEN, Simarmata Agustina
Journal: Clinical Cancer Research (2016)

Abstract Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancers. Although selective targeted therapy by kinase inhibitors have been emerged as important therapeutic agents in the treatment of a variety of human malignancies. Cancer cells become resistant to targeted cancer drugs are a major obstacle to successful cancer treatment. A major mechanism of resistance is the presence of a small sub-population of cancer cells have genetic changes, aberrant epigenetic modifications and activation of alternative signaling pathways by modifying the expression of several downstream effectors contribute to the acquisition of cancer target drug resistance. To dissect the alternate pathways exist to confer targeted cancer drugs resistance, the kinase inhibitors resistant cancer cells were established by continuous culture in increasing doses. Furthermore, the resistant cancer cells were inoculated into SCID mice and then tumors were excised and serially transplanted into additional mice for propagation. By in vivo serial dilution tumor-propagating assay, the established resistant cancer cell lines and xenografts were characterized using cell growth kinetics, targeted drug sensitivity and tumorigenicity. The gene overexpression and shRNA knockdown approaches were employed to investigate the mechanism of bypassing target gene effects from propagating cells in vitro. Confirmation of target drug sensitivity of drug resistant transfectants may allow for the identification of new therapeutic targets or prognostic biomarkers of cancer drugs response. The resistance-related genes having measurable effects in vitro and in vivo demonstrate that the established model in this study is appropriate for validation of genes that responsible for targeted drug resistance. Citation Format: REN-IN YOU, CHUN-SHAN CHEN, CHUN-YI CHEN, Simarmata Agustina. Evaluating the dynamics of epigenetic changes conferring targeted cancer drugs resistance in tumor xenograft propagation model. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A29.
Clinical outcomes following neoadjuvant nab-paclitaxel and cisplatin chemotherapy for locally advanced esophageal squamous cell carcinoma.
Authors: Fan Yun, Jiang You Hua, Zhou Xin Min, Chen Qi Xun, Huang Zhi Yu, Gong Lei, Yang Hai Yuan, Liu jin Shi, Chen Peng Chen, Zhao Qiang, Weimin Mao
Journal: Journal of Clinical Oncology (2015)

4055 Background: The combination of nab-paclitaxel and cisplatin as preoperative treatment for esophageal squamous cell carcinoma (ESCC) has not been investigated. We carried out a phase II feasibility and efficiency study of preoperative chemotherapy with nab-paclitaxel and cisplatin for locally advanced ESCC. Methods: Between January 2011 and October 2012, 35 patients, from stage IIA to IIIC, performance status 0-1, with 31 male and 4 females, were included in the study. All pts received nab-paclitaxel (100 mg/m2, d1, d8, d22 and d29) and cisplatin (75 mg/m2, d1 and d22) as neoadjuvant chemotherapy, followed by esophagectomy. Two cycles of adjuvant chemotherapy with same regimen was given in 4-6 weeks after the resection. Results: Thity-five enrolled patients including 31 males and 4 females, the clinical stage forIIA,IIB, IIIA, IIIB, IIIC were 3(8.6%), 5(14.3%), 10 (28.6%), 8 (22.9%) and 9 (25.7%) patients respectively. After two cycles of neochemotheray. 30/35 patients went to surgery (85.7%) and all had R0 resection (100%). Pathological complete response (pCR) was achieved in 4 patients (13.3%). Down-staging was observed in 19 of 30 patients (63.3%). 24/30 (80.0%) patients received adjuvant chemotherapy, including 7 patients (23.3%) received adjuvant chemoradiotherapy. Only 1 (3.3%) patient appeared surgical complication with anastomotic leaks. With median follow up of 27.1 months, the 16/30 patients (50.44%) still alive, and a median disease-free survival (DFS) of 22.5 months (95 % CI 14.2 - 29.8). The Median overall survival (OS) and DFS of Down-staging patients were significantly longer than non-down-staging patients (Hazard Ratio 0.30, 95% CI: 0.074 - 0.75 and Hazard Ratio 0.27, 95% CI: 0.071-0.59, respectively) (P = 0.0158 and P = 0.0037, respectively), and all of pCR patients were still DFS survival at the latest follow up. Conclusions: weekly nab-paclitaxel and cisplatin is effective as a neoadjuvant chemotherapy for local advanced ESCC, and its adverse effects are tolerable. Down-staging, especially the pCR patients have favorable outcome than non-down-staging patients. Clinical trial information: NCT01258192.
Parent-reported cognition and its clinical applications in pediatric oncology.
Authors: Jin-Shei Lai, Kevin R. Krull, Frank Zelko, Lynne I. Wagner, David Cella, Stewart Goldman
Journal: Journal of Clinical Oncology (2012)

9532 Background: Parent-reported cognitive function (PCF) of their child's cognitive abilities is often used to trigger referral for comprehensive neuropsychological evaluation. The purpose of this study was to evaluate the clinical utility of PCF to predict impairment as measured by neuropsychological assessment and to identify factors associated with PCF. Methods: 565 patients (53% brain tumor, BT; 47% other types of cancer, non-BT) aged 7-21 (mean=14 yrs; 56% males) and their parents were recruited. 34% received radiation therapy, 72% chemotherapy and 71% surgery. Mean years since diagnosis= 5.7 yrs. PCF was measured using a 43-item pediatric perceived cognitive function item bank (pedsPCF). Parents completed the pedsPCF and a single item to rate their child's quality of life (QOL). Patients completed NINDS-NeuroQOL Depression, PedsQL Fatigue scales and neuropsychological tests (NPT) of psychomotor function, attention, learning and working memory using the CogState. K-Means clustering was used to group patients based on scores of depression, fatigue and pedsPCF. Results: PedsPCF significantly differentiated BT from non-BT, t=5.65, p&lt;.01. Correlations between pedsPCF and NPT ranged from 0-0.66 (BT, &lt; 1 yr diagnosis, psychomotor), depending on BT (vs non-BT), yrs since diagnosis and treatment, and NPT. Three clusters were identified with its own unique characteristics. Specifically, pedsPCF was significantly correlated w/ depression &amp; fatigue for cluster 1; correlated w/ NPT scores for non-BT for cluster 2; and correlated w/ NPT for BT for cluster 3. Cluster membership of patients were significantly differentiated by Karnofsky rating, surgery (yes/no), QOL, parent education, child age, and child gender, but not types of treatment, and grade repetition (yes/no). Conclusions: This is one of the first studies to report an association between perceived cognitive function, using parent ratings, and neuropsychological performance. PedsPCF demonstrated clinical utility in differentiating between children with a brain tumor from children with other cancer types. PedsPCF has the potential to serve as a screening tool to facilitate efficient referral for comprehensive neurocognitive assessment.
Short Survival and High Rates of Transformation Prevail in Chronic Myelomonocytic Leukemia Despite Hypomethylating Agent Therapy.
Authors: Emily J. Vannorsdall, Vu H. Duong, Xinyi Ng, Dan P. Zandberg, Michael L. Tidwell, Amy J. Davidoff, Maria R. Baer
Journal: Blood (2012)
Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2
Authors: Xiaoyan Yang, Seong-Hoon Park, Hsiang-Chun Chang, Jason S. Shapiro, Athanassios Vassilopoulos, Konrad T. Sawicki, Chunlei Chen, Meng Shang, Paul W. Burridge, Conrad L. Epting, Lisa D. Wilsbacher, Supak Jenkitkasemwong, Mitchell Knutson, David Gius, Hossein Ardehali
Journal: Journal of Clinical Investigation (2017)

SIRT2 is a cytoplasmic sirtuin that plays a role in various cellular processes, including tumorigenesis, metabolism, and inflammation. Since these processes require iron, we hypothesized that SIRT2 directly regulates cellular iron homeostasis. Here, we have demonstrated that SIRT2 depletion results in a decrease in cellular iron levels both in vitro and in vivo. Mechanistically, we determined that SIRT2 maintains cellular iron levels by binding to and deacetylating nuclear factor erythroid-derived 2-related factor 2 (NRF2) on lysines 506 and 508, leading to a reduction in total and nuclear NRF2 levels. The reduction in nuclear NRF2 leads to reduced ferroportin 1 (FPN1) expression, which in turn results in decreased cellular iron export. Finally, we observed that Sirt2 deletion reduced cell viability in response to iron deficiency. Moreover, livers from Sirt2-/- mice had decreased iron levels, while this effect was reversed in Sirt2-/- Nrf2-/- double-KO mice. Taken together, our results uncover a link between sirtuin proteins and direct control over cellular iron homeostasis via regulation of NRF2 deacetylation and stability.