tbuckley/cabot-search huggingface dataset:
Evaluation of a cancer-specific comprehensive geriatric assessment (CGA) tool in older women with newly diagnosed primary breast cancer.
Authors: R. M. Parks, L. Hall, S. Tang, R. Lakshmanan, A. Hurria, L. Winterbottom, H. Kennedy, D. A. L. Morgan, D. Porock, K. Cox, K. Cheung
Journal: Journal of Clinical Oncology (2011)

e19518 Background: CGA is an analytical tool measuring physical and psychosocial function. Breast cancer is primarily a disease of the elderly. A pilot study was conducted evaluating a cancer-specific CGA tool in older women with primary operable breast cancer. Methods: Newly diagnosed women attending the Primary Breast Cancer Clinic for Older Women in Nottingham were invited to participate. CGA was completed within 6 weeks. The decision of primary treatment followed consultation with the clinical team and was not guided by CGA. 47 patients have thus far been recruited (mastectomy (Mx) n=20, breast conserving surgery (BCS) n=9, primary endocrine therapy (PET) n=17, primary radiotherapy n=1). Results: Patients were mostly widowed (52%); living with someone (54%); retired (96%); of white ethnicity (91%); had completed primary/secondary education (65%), with a mean age of 80 (range 68-92), Body Mass Index (BMI) of 27.4, and good scores for Activities of Daily Living (21/34), Karnofsky self-reported (6/8) and physician-rated (80/100) performance, mood measured by the Hospital Anxiety and Depression Scale (79/102), social activities (14/20) and support (49/60) measured by the Medical Outcomes Study Social Activity Limitations and Support measures. On average participants took 4 daily medications and scored 5 (out of 51) on the Physical Health Section measuring comorbidity. 25% had experienced a fall in the last 6 months and 2 had signs of cognitive impairment based on the Blessed Orientation-Memory-Concentration test. Average completion of the timed ‘up and go’ (TUG) was 16 seconds. Statistical significant association was found between PET (as opposed to surgery) and increasing age (p=0.001), greater comorbidity (p=0.022), more daily medications (p=0.002) and slower TUG (p=0.014). Logistic regression showed only age to be independently significant (p=0.016; odds ratio=12.69, 95% CI 1.60-100.69). Factors showing correlation to BCS rather than Mx were better mood (p=0.05) and higher BMI (p=0.033). Conclusions: There was an association between CGA factors and surgical treatment patterns in this cohort of older adults with breast cancer.
The Bruton's Tyrosine Kinase Inhibitor PCI-32765 Is Highly Active As Single-Agent Therapy in Previously-Treated Mantle Cell Lymphoma (MCL): Preliminary Results of a Phase II Trial
Authors: Luhua Wang, Peter Martin, Kristie A. Blum, Brad S. Kahl, Lauren S. Maeda, Ranjana Advani, Michael E. Williams, Simon Rule, Sara Rodriguez, Ching-Fai Pang, Eric Hedrick, Andre Goy
Journal: Blood (2011)
Abstract 3656: PARG inhibition: development of novel compounds and a biomarker strategy to determine cell line sensitivity in breast cancer
Authors: Ian D. Waddell, Dominic James, Kate Smith, Sarah Holt, Ben Acton, Emma Fairweather, Niall Hamilton, Nicola Hamilton, James Hitchen, Colin Huttom, Allan Jordan, Alison McGonagle, Helen Small, Alex Stowell, Bohdan Waszkowycz, Donald Ogilvie
Journal: Cancer Research (2015)

Abstract Background: DNA single strand breaks (SSBs) are the most common type of damage occurring in cells. Poly (ADP ribose) polymerase (PARP) binds to SSBs and auto-ribosylates itself using NAD+ as a substrate. PARG is the only enzyme known to efficiently catalyse the hydrolysis of O-glycosidic linkages of ADP-ribose polymers and exists (unlike PARP) as a single gene. We have developed novel inhibitors of PARG and here we describe our efforts to understand their sensitivity against a range of cell lines Methods: A robust and detailed screening cascade for small molecule inhibition of PARG has been developed. Active compounds are tested in cells for PAR chain persistence and for cytotoxicity using a 3-day HeLa assay. In addition, suitable compounds were then evaluated for their physico-chemical properties and their in vivo PK profiles determined. Compounds with the desired PK properties are subsequently profiled in tumour bearing mice to determine their pharmacodynamic effect before progressing to efficacy studies. Results: We have developed nM PARG inhibitors that are highly selective against ARH3 and PARP1and these derivatives show potent activity in cells. We have designed a breast cancer cell panel against which our compounds have been tested. Our initial bioinformatics analysis suggests that deficiency of a known tumour suppressor confers sensitivity to PARG inhibition. Conclusions: We have developed two drug-like series of PARG inhibitors that block the breakdown of PAR chains in cells after exogenous DNA damage by methylating agents. These tool compounds are potent, selective and have pharmacokinetic and pharmacodynamics properties that have allowed us to explore their anti-tumour potential. The discovery of a tumour suppressor profile indicating cell line sensitivity will aid the about identification of patient populations that will potentially benefit from PARGi therapies. Citation Format: Ian D. Waddell, Dominic James, Kate Smith, Sarah Holt, Ben Acton, Emma Fairweather, Niall Hamilton, Nicola Hamilton, James Hitchen, Colin Huttom, Allan Jordan, Alison McGonagle, Helen Small, Alex Stowell, Bohdan Waszkowycz, Donald Ogilvie. PARG inhibition: development of novel compounds and a biomarker strategy to determine cell line sensitivity in breast cancer. [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 3656. doi:10.1158/1538-7445.AM2015-3656
665. Therapeutic Efficacy of Third Generation Oncolytic HSV-1 (G47Δ) for Glioma Cells with Stem Cell Property
Authors: Hirotaka Ito, Yasushi Ino, Tomoki Todo
Journal: Molecular Therapy (2016)

Glioblastoma is the most malignant brain tumor with highly dismal prognosis. Recent studies suggest that glioblastoma cells form a subpopulation with stem cell properties, termed glioma initiating cells (GICs). GICs grow less rapidly but are resistant to standard therapies, and are deemed to be a major reason for the disease to be incurable. In this study, the efficacy of G47Δ, a third generation oncolytic herpes simplex virus type 1, was evaluated using GICs established from surgically removed clinical specimens. The GICs grew in vitro as CD133-positive, nestin-positive neurospheres in serum-free medium supplemented with growth factors, and the stemness was confirmed by sphere forming assay. As few as 5×103 GICs implanted in the brain of athymic mice were capable of forming intracerebral tumors that retained histopathological appearances consistent with glioblastoma. On magnetic resonance imaging, the GIC-derived intracerebral tumors appeared as iso intensity in T1 weighted images, high intensity in T2 weighted images, and non contrast-enhanced mass lesions. In in vitro cytotoxicity assays, G47Δ killed 60 to 80% of GICs by day 4 when cells were infected at MOI of 0.01. Infecting GIC spheres with G47Δ caused significant inhibition in secondary sphere formation when compared with mock. In mice harboring GIC-derived intracerebral tumors, a single G47Δ inoculation (8 × 104 pfu, 10 days after tumor implantation) significantly prolonged the survival when compared with mock. Immunohistochemical study of G47Δ injected tumors demonstrated widespread distribution of G47Δ within the tumor but selective to tumor cells. These results indicate that G47Δ efficiently kills GICs as well as non-GIC glioma cells. Taken into account that a phase 2 clinical study with G47Δ in glioblastoma patients is ongoing in Japan, G47Δ may soon become a new therapeutic option for glioma patients with a potential of curing glioblastoma.
Abstract 669: BGB-283 effectively enhances MEK inhibitor induced tumor suppression in RAS mutant cancers
Authors: Xi Yuan, Zhiyu Tang, Rong Du, Shing-Hu Cheung, Jing Wei, Yuan Zhao, Yunguang Du, Rui Hao, Xiaoxia Hu, Wenfeng Gong, Yong Liu, Yajuan Gao, Min Wei, Changyou Zhou, Lai Wang, Lusong Luo
Journal: Cancer Research (2015)

Abstract Mutation in K-RAS, which drives constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway, is one of the most frequent genetic alterations in human cancers. Pharmacological targeting RAS mutants directly is extremely challenging and targeted inhibition of K-RAS downstream effector MEK has shown limited clinical activity in suppressing the progression of K-RAS mutant tumors. The reduced sensitivity of K-RAS-mutated cancer cells to MEK inhibitors (MEKi) is associated with feedback phosphorylation of MEK and rebound of phosphorylated ERK levels after prolonged treatment. A synthetic lethal screen provided the rational of targeting both RAF1 and MEK in K-RAS mutated cancers. In this study, we investigated whether combining BGB-283, a potent inhibitor to RAF dimers, and a series of MEKi could achieve better therapeutic effect of the latter. We confirmed that selumetinib (AZD6244) induced strong MEK phosphorylation in K-RAS mutated cancer cells. Either knockdown of B-RAF/C-RAF or addition of BGB-283 in the presence of selumetinib potently inhibited RAF-dependent MEK phosphorylation and led to sustained inhibition of ERK activity. Furthermore, BGB-283 and selumetinib showed synergistic effect in inhibiting proliferation of several non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) cell lines harboring RAS mutations. In vivo, combined dosing of BGB-283 and AZD6244 also exhibited enhanced antitumor activity in K-RAS mutant NSCLC and CRC xenograft models compared to monotherapies. Pharmacodynamic (PD) analysis revealed improved inhibition of ERK phosphorylation in dually treated tumors. Together, these findings suggested that combining RAF dimer inhibitor BGB-283 and MEKi could be a promising strategy in treating RAS mutated cancers. Citation Format: Xi Yuan, Zhiyu Tang, Rong Du, Shing-Hu Cheung, Jing Wei, Yuan Zhao, Yunguang Du, Rui Hao, Xiaoxia Hu, Wenfeng Gong, Yong Liu, Yajuan Gao, Min Wei, Changyou Zhou, Lai Wang, Lusong Luo. BGB-283 effectively enhances MEK inhibitor induced tumor suppression in RAS mutant cancers. [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 669. doi:10.1158/1538-7445.AM2015-669
637. Targeting of Myeloid Leukemia by IL-10-Engineered Human CD4+ Tr1 Cells
Authors: Grazia Locafaro, Grazia Andolfi, Fabio Russo, Barbara Camisa, Fabio Ciceri, Angelo Lombardo, Attilio Bondanza, Maria Grazia Roncarolo, Silvia Gregori
Journal: Molecular Therapy (2016)

T regulatory type 1 (Tr1) cells, characterized by the co-expression of CD49b and LAG-3 and the ability to secrete high amounts of IL-10, control immune responses by IL-10 and TGF-beta production and by killing of myeloid cells via a Granzyme B-dependent mechanism. Tr1 cells are induced in vitro in the presence of recombinant human IL-10 or tolerogenic dendritic cells secreting high amounts of IL-10 (DC-10). Proof-of-principle clinical trials suggest that Tr1 cells can modulate Graft-versus Host Disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, their ability to mediate anti-leukemic activity or their effects of Graft versus Leukemia is largely unknown. We previously showed that enforced IL-10 expression converts human CD4+ T cells into Tr1-like (CD4IL-10) cells that suppress effector T cells in vitro and prevent xenogeneic-GvHD in humanized models. We now demonstrate that these CD4IL-10 cells selectively kill myeloid cell lines and myeloid blasts in vitro in HLA-class I-dependent but antigen-independent manner. Moreover, cytotoxic activity of CD4IL-10 cells is Granzyme B-dependent, is specific for CD13+ cells, and requires CD54 and CD112 expression on target cell lines or primary leukemic blast. Adoptive transfer of CD4IL-10 cells in humanized models mediates direct anti-leukemic activity, and does not compromise the anti-leukemic effect of allogeneic T cells while inhibits xeno-GvHD. These findings provide a strong rationale for designing personalized immunotherapy approaches using CD4IL-10 cells after allo-HSCT to cure myeloid malignancies.
Etodolac Inhibits EBER Expression and Induces Bcl-2-Regulated Apoptosis in Burkitt’s Lymphoma Cells.
Authors: Miki Kobayashi, Satoki Nakamura, Kiyoshi Shibata, Naohi Sahara, Kazuyuki Shigeno, Kaori Shinjo, Kensuke Naito, Kazunori Ohnishi
Journal: Blood (2005)
In Vitro and In Vivo downregulation of Leukemogenesis by FMNL1 Inhibition In Namalwa Cell Line
Authors: Patricia Favaro, Fabiola Traina, Joao Machado-Neto, Mariana Lazarini, Matheus Rodrigues Lopes, Fernando Ferreira Costa, Sara T. Olalla Saad
Journal: Blood (2011)
The MicroRNA (miR) Profile in B-Cell Chronic Lymphocytic Leukemia (CLL) Reveals a Differential Expression of miR-21, miR-155 and miR-150 between Leukemic and Normal B Lymphocytes, and of miR-150, miR-29bc and miR-223 between IgVH Mutated and Unmutated Patients.
Authors: Sabina Chiaretti, Valerio Fulci, Marina Goldoni, Gianluca Azzalin, Simona Tavolaro, Monica Messina, Roberta Maggio, Nadia Peragine, Simona Santangelo Miss, Francesca R. Mauro, Anna Guarini, Giuseppe Macino, Robert Foa
Journal: Blood (2006)
Mechanisms of Resistance to Reprogramming of Cells Defective In the Fanconi Anemia DNA Repair Pathway
Authors: Lars Mueller, Michael D. Milsom, Kristina Brumme, Chad Harris, Kalindi Parmar, Kaya Zhu, London Wendy, Kelly Strait, Alan D. D'Andrea, George Q. Daley, David A. Williams
Journal: Blood (2010)
204. Treatment with Modified Erythropoietin Gene Therapy Is Neuroprotective in a Mouse Model of Induced Ocular Hypertension
Authors: Wesley S. Bond, YPaul L. Chang, Mara N. Davis, Rebecca M. Sappington, Tonia S. Rex
Journal: Molecular Therapy (2015)

Our goal is to investigate the neuroprotective efficacy of systemic rAAV gene delivery of erythropoiesis-attenuated erythropoietin-R76E (EPO-R76E) in a mouse model of experimental glaucoma. We investigated the efficacy of EPO-R76E gene therapy commenced before and after induction of ocular hypertension. C57BL/6 mice were injected intramuscularly with 109 vgc rAAV delivering eGFP or Epo-R76E behind a CMV promoter. To induce ocular hypertension, anterior chambers were injected with 15-μm diameter microbeads or saline, and elevation of intraocular pressure (IOP) was verified by tonometry. For pre-treatment, gene delivery was performed using rAAV2/8 serotype one month prior to IOP elevation. For delayed treatment, gene therapy was administered using rAAV2/1 serotype concurrently with IOP elevation. At 1 month post-IOP elevation, tissue was collected and retinal ganglion cell (RGC) axon function was assessed by optic nerve histology and fluorescent cholera toxin B anterograde transport. Hematocrit was also assessed at collection. Hematocrit was significantly elevated in mice pre-treated with rAAV2/8.CMV.Epo-R76E (59.6±9.1%) and in mice given rAAV2/1.CMV.Epo-R76E delayed (55.0±3.6%) compared to eGFP controls (42.7±3.2%). Mean IOP of 20.3±2.9 mmHg was observed in microbead-injected eyes 1 week post-induction compared to 15.4±2.1 mmHg in saline-injected controls. At 1 month post-induction, microbead-injected eGFP controls developed 20% reduction of RGC axons and 22% impairment of RGC anterograde transport compared to saline-injected controls. Microbead-injected mice pre-treated with rAAV2/8.CMV.Epo-R76E showed 4% reduction of RGC axons and 5% impairment in RGC anterograde transport. Microbead-injected mice given delayed treatment with rAAV2/1.CMV.Epo-R76E showed 18% reduction of RGC axons and 6% impairment of RGC anterograde transport. Gene delivery of modified EPO attenuates glaucomatous pathology of retinal ganglion cells in the induced model of ocular hypertension. Pre-treatment with EPO gene therapy provides more robust preservation of RGC axons than EPO gene therapy commenced at onset of hypertension. Delayed gene therapy preserves axon transport significantly, however, which may be due to delayed therapy preserving normal function of surviving RGC axons while failing to attenuate early axon loss.
Prospective, observational registry of branded imatinib (IM) and nilotinib (NIL) exposure in pregnant women: Voluntary post-authorization safety study.
Authors: Matthews Juma, Solveig Ericson, Dawn Fun Eng, Sandip Acharya, Darshan Wariabharaj, Tina Owugah, Bettine Avenia, Oleg Zernovak
Journal: Journal of Clinical Oncology (2012)

TPS6638 Background: Family planning decisions for cancer patients of childbearing age are impacted by their diagnosis. IM and NIL are category D drugs (demonstrated risk to the fetus based on mechanism of action and findings in animals; however, the benefits of therapy may outweigh the potential risk to the fetus); women should be advised not to become pregnant when taking these drugs. Limited data exist concerning safety of these drugs during pregnancy and consequences of interrupting treatment. The registry does not recommend patients receiving IM or NIL become pregnant, but serves only to document exposures that occur, and collect information on pregnancy outcome, maternal course of disease, and infant follow-up. Methods: The registry intends to enroll 150 women (≥18 years) treated with branded IM and NIL within 6 mo before or during pregnancy (generic IM and NIL reports are excluded). Schedule of visits and treatment is according to local standard of care. Women are divided into 2 exposure cohorts: 1) pregnancy/fetal: received tyrosine kinase inhibitors (TKIs) within 14 d of conception or at any time during pregnancy; 2) interrupted TKI: received TKIs within 6 mo before conception but interrupted TKIs in preparation for/due to pregnancy. To identify signals of teratogenicity, the registry uses a general population baseline rate of birth defects, and the prevalence of defects in cohorts 1 and 2 may be compared. Cases are quantitatively analyzed for the emergence of unique defects or patterns of defects. Primary objective: monitor TKI-exposed pregnancies to estimate the prevalence of birth defects (calculated by dividing number of birth defects by total number of exposed live births from cohort 1). Secondary objectives are to: 1) determine the impact of treatment interruption on maternal disease status; 2) assess and estimate the prevalence of serious adverse pregnancy outcomes; and 3) assess and estimate the prevalence of developmental delays and functional deficits among infants during the first year of life. Maternal disease status is analyzed, comparing disease status at registration, pregnancy outcome, and 1 y after birth, stratified by length of TKI interruption.
154. Applying Insights from Pri-miRNA Processing to shRNA Design
Authors: Xavier Bofill-De Ros, Lisheng Dai, Shuo Gu
Journal: Molecular Therapy (2016)

Short hairpin RNA (shRNA) technology permits efficient and stable gene regulation, providing a useful tool for gene therapy. shRNAs can be embedded in miRNA scaffolds that allow their expression from Pol II promoters, which is more amendable to control transcription. Under this platform, shRNAs are processed through the canonical miRNA maturation pathway, which includes stepwise cleavages by Drosha-DGCR8 complex (Microprocessor) and Dicer. Despite many successes, design of Pol II driven shRNA is far from optimal. Most Pol II driven shRNAs are based on primary transcript sequence of hsa-miR-30a. Recent studies have shown that different pri-miRNAs have distinct Drosha cleavage efficiencies leading to various levels of its mature form. Here, we seek to systematically explore how different pri-miRNA scaffolds can be adapted and optimized to provide the best shRNA expression and function. By taking advantage of DGCR8 KO cells and luciferase-based reporters, we were able to directly monitor Microprocessor cleavage efficiency of primary transcripts in vivo. We have analyzed the Microprocessor cleavage of 20 different primary miRNA transcripts that are the most abundant and widely expressed. Moreover, we have explored how the preservation of stem structure and endogenous surrounding sequences and motifs contribute to shRNA maturation. This study aims to pave the way for a universal miRNA-based shRNA expression platform.
Peritransplant Use of Ultraviolet-B (UVB) Phototherapy Is Detrimental to Outcome of Allogeneic Stem Cell Transplantation.
Authors: Meltem Yuksel, Elma Baron, Brenda W. Cooper, Hillard M. Lazarus, Stanton L. Gerson, Mary J. Laughlin, Kevin D. Cooper, Anita Gilliam, Omer N. Koc
Journal: Blood (2004)
Arsenic trioxide followed by autologous stem cell transplant for patients with relapsed APL.
Authors: D. D. Shepard, H. E. Kohrt, T. L. Rosenblat, J. G. Jurcic, J. H. Park, A. Goldman, J. S. Dalal, P. G. Maslak, A. A. Jakubowski, V. Klimek, E. Berman, S. Nand, S. E. Coutre, M. S. Tallman, H. P. Erba
Journal: Journal of Clinical Oncology (2011)

6619 Background: Arsenic trioxide (ATO) can induce remission in 80-90% of patients (pts) with relapsed APL. For pts achieving a 2nd remission autologous stem cell transplant (ASCT) improves 5-year disease-free survival (DFS) to 70-80%. However, few series have assessed outcomes after ASCT following ATO reinduction. We performed a retrospective analysis of ATO followed by ASCT for pts with relapsed APL. Methods: Pts who underwent ASCT in 2nd or greater remission were identified at the University of Michigan, Stanford University, Memorial Sloan-Kettering Cancer Center, and Loyola University. Pts who were in remission following an ATO based regimen were selected for study. No pts had ATO as part of initial therapy. Results: 21 pts were identified who had received ASCT from 8/1999-5/2009. Median age at diagnosis was 31 (1-54). 4 pts had WBC > 10x109/L (0.6-129) at diagnosis and 13 had platelet counts < 40 k/mm3. All first line induction regimens contained all-trans retinoic acid. 18 (85%) received maintenance therapy following consolidation in CR1. Median duration of CR1 was 17.6 mos (3.07-108). 2 CNS and 1 skin relapse occurred; other relapses were molecular/ hematologic. Median age at transplant was 33 yrs (2-58). Reinduction regimens included single agent ATO (15 pts), ATO plus intrathecal therapy (2 pts), and ATO plus cytotoxic chemotherapy (4 pts). 20 patients achieved a complete molecular remission following a median of 2 ATO cycles (1-5). Treatment related toxicity of ATO included APL differentiation syndrome (3 pts), prolonged QTc (3 pts), grade (gr) 3 infection (2 pts), and gr 2/3 transaminitis (2 pts). Gr 3 mucositis (4 pts) was the only gr 3/4 toxicity related to ASCT. Median interval between CR2 to ASCT was 90 days (11-299). 1 pt was excluded from DFS analysis due to graft failure followed by allogeneic transplant. 5 pts (25%) relapsed with median time to relapse of 384 days (126-513). The median DFS for the entire cohort was 4 years (0.34-10.8). Conclusions: For pts with relapsed APL, ATO and ASCT are effective therapies for reinduction and consolidation of remission. The combination is well tolerated and produces durable responses. The role of maintenance strategies following ASCT should be explored to further improve outcome.