tbuckley/cabot-search huggingface dataset:
The OPAL study: A phase II study to evaluate the efficacy, safety, and tolerability of tosedostat (CHR-2797) in elderly subjects with treatment refractory or relapsed acute myeloid leukemia.
Authors: J. E. Cortes, E. J. Feldman, K. W. Yee, M. J. Toal, A. Richardson, A. Charman, N. Flores
Journal: Journal of Clinical Oncology (2010)

TPS277 Background: Tosedostat (CHR-2797) is a novel oral aminopeptidase inhibitor. Aminopeptidases catalyze hydrolysis of terminal amino acids from (poly)peptides generated by proteasomal degradation. Inhibition of aminopeptidases leads to a deficiency of amino acids for protein synthesis. Malignant cells appear to be more dependent on protein cycling, so this pathway is a potential target for novel agents. In preclinical experiments, tosedostat exerts antineoplastic activity in solid tumor, leukemia and myeloma cell lines in vitro. A phase I-II study with tosedostat included 51 patients with acute myeloid leukemia (AML), and showed promising antileukemia effects and good tolerability. Thirty-five of these patients had relapsed or refractory AML. Complete response (CR) was defined as <5% blasts, partial response (PR) as 5-15% blasts. 11 of 35 had favorable responses (6 CRs, 5 PRs), an overall response of 31.4%. In follow-up, 5 of the 6 CRs were observed to result in 3 Complete Remissions, 1 CRp and 1 CRi. Longer median overall survival was noted for complete (334 days) and partial (361 days) responses compared to all patients (118 days) or nonresponders (97 days). This study formed the basis for the ongoing study. Methods: The OPAL study is a phase II study in 2 parts. Part A is a dose selection part in which 60 patients aged over 65 years with refractory or relapsed AML, whose first induction resulted in a complete remission for up to 12 months (Estey 1996), will be randomized to receive first salvage with tosedostat 120 mg daily for 6 months OR tosedostat 240 mg daily for 2 months followed by 120 mg for 4 months. A benefit-risk analysis will take place to determine the dose for Part B in which a further 130 patients will be treated with tosedostat. Responses will be assessed using IWG criteria (Cheson et al 2003). Results: Five patients were randomized by January 8, 2010. Updated enrollment numbers will be presented. Part B will commence in Q3/2010. Conclusions: Tosedostat is a promising agent for the treatment of refractory or relapsed elderly AML patients. The OPAL study will further evaluate the efficacy and safety of tosedostat in these patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chroma Therapeutics Ltd. Chroma Therapeutics Ltd. Chroma Therapeutics Ltd.
Epigenetic Signaling Is Required for HoxA9-Based Leukemic Transformation.
Authors: Aditya Chaubey, Chinavenmeni S. Velu, Shane Horman, Anil Jegga, Monica L. Guzman, Laurie Risner, Nancy J. Zeleznik-Le, Craig T. Jordan, Martin Carroll, Brian Gebelein, H. Leighton Grimes
Journal: Blood (2009)
171. Production of Therapeutically Relevant Levels of FVIII After Transduction of Lungs With F/HN-Pseudotyped Lentivirus
Authors: Kamila M. Pytel, Michael Paul-Smith, Jenny McIntosh, Mario Chan, Cuixiang Meng, Ian Pringle, Lee Davies, Makoto Inoue, Mamoru Hasegawa, Stephen C. Hyde, Deborah R. Gill, Amit C. Nathwani, Eric W.F.W. Alton, Uta Griesenbach
Journal: Molecular Therapy (2015)

We have previously shown that the lung can be used as "factory" for production of secreted proteins, which are released into the circulation, using Sendai virus-mediated gene transfer. However, gene expression was transient and repeated administration of the vector was not feasible due to induction of immune responses. We have developed a lentiviral vector which is specifically pseudotyped with the Sendai virus envelope proteins F and HN (rSIV.F/HN) to allow efficient transduction of the airways. The unique features of rSIV.F/HN, namely stable expression for >20 months after a single dose and efficient transduction after repeated administration, make the vector an attractive candidate for a large range of disease indications. Here, we first transduced mouse lung with rSIV.F/HN carrying the secreted reporter gene Gaussia luciferase (GLux) or a control virus by nasal instillation (1e6 transduction units (TU)/mouse, n=5-6/group). Persistent levels of GLux expression were detectable in lung (3 logs above control) and broncho-alveolar lavage fluid (BALF, 4 logs above control) for at least 12 months. Importantly, even this modest dose of virus lead to significant (p<0.01) levels of GLux in serum (274±72 RLU/ul, control: 41±6 RLU/ul) which persisted for at least 12 months further supporting the hypothesis that the lung is a suitable, non-invasive factory for production of secreted proteins. Gene therapy strategies for haemophilia have focussed on intravenous or intramuscular delivery of the gene transfer agent. Here, we treated the murine lung with rSIV.F/HN carrying the FVIII cDNA (1.6e8-3.4e8 TU/mouse, n=3-4/group) or placebo and assessed whether therapeutically relevant levels of FVIII can be produced. Significant (p<0.05) and dose-related levels of FVIII were detectable in lungs and BALF 10 and 28 days post-transduction. Dose-related levels of FVIII were also detectable in plasma, which reached a therapeutically relevant level of 3.0% of normal 1 month after gene transfer. These data support the concept that rSIV.F/HN-mediated transduction of lungs can produce therapeutically relevant and persistent levels of recombinant protein in blood.
OP21CHARACTERISING THE TRANSITION ZONE FROM TUMOUR TO NORMAL BRAIN IN GLIOBLASTOMAS USING MULTIMODAL MRI
Authors: Sarah A. Leir, Timothy J. Larkin, Natalie R. Boonzaier, Victoria Lupson, Laila A. Mohsen, Adam Young, Stephen J. Price
Journal: Neuro-Oncology (2015)

INTRODUCTION: Identification of the invasive margin is a key limitation to treating Glioblastomas. Conventional T1-weighted and T2-weighted imaging methods are still used to assess the extent of tumour for resection. However, it is shown in histological specimens that malignant cells extend for several centimetres beyond the contrast enhancing regions. The transition between tumour edge, peritumoural oedema and normal brain remains ambiguous. Multi-modal MR (diffusion tensor, spectroscopy and perfusion) is a promising new imaging technique to study tumour invasion. An improvement in the understanding of the tumour margin would allow individualized tailoring of treatment. METHOD: 80 patients with glioblastomas were imaged pre-operatively at 3T with anatomical sequences, diffusion-tensor, dynamic susceptibility contrast and spectroscopy. Data was co-registered to the same imaging space. Regions of interest (ROIs) were selected in a circumferential consecutive pattern from the edge of the T1-weighted enhancing region to normal appearing brain. The parameters were calculated per voxel and expressed as a ratio to normal brain. RESULTS: The isotropic component of diffusion-tensor remained raised at a 30mm distance beyond the edge of the enhancing region (1.18 ± 0.02, p < 0.000 at 30mm). Perfusion was persistently elevated within each consecutive expanding circumference (1.56 ± 0.06 at 30mm). Choline remained raised in comparison to the contralateral hemisphere at 20mm (1.14 ± 0.04) beyond the edge of the T1-enhancing region. CONCLUSION: MRI biomarkers of tumour cell presence extend up to 3 cm beyond the conventionally determined tumour margin. Incorporating multimodal MRI data into treatment planning will allow more precise surgical resection and planning of radiotherapy.
206. Follicle-Stimulating Hormone Receptor as a Target in the Redirected T-Cell Therapy for Cancer
Authors: Katarzyna Urbanska, Caitlin Stashwick, Daniel J. Powell
Journal: Molecular Therapy (2015)

Adoptive transfer of T-cells engineered to express chimeric immune receptors is an effective strategy to treat hematological cancers, however, such therapy for solid cancers such as ovarian cancer remains challenging because a safe and effective immunotherapeutic target has not yet been identified. Here, we constructed and evaluated a novel redirected T-cell-based immunotherapy targeting human follicle-stimulating hormone receptor (FSHR), a highly conserved molecule in vertebrate animals with expression limited to gonadal tissues, ovarian cancer and cancer-associated vasculature. Receptor ligand-based anti-FSHR immune receptors were constructed that contained small binding fragments from the ligand for FSHR, follicle stimulating hormone (FSH), fused to T-cell transmembrane and T-cell signaling domains. Human T-cells transduced to express anti-FSHR immune receptors were specifically immunoreactive against FSHR-expressing human and mouse ovarian cancer cell lines in a MHC-non-restricted manner, and produced more than one Th1 type of proinflammatory cytokine. This observation is of special interest, as it provides the opportunity to address potential, but unpredicted, toxicity issues associated with targeting of FSHR in preclinical in vivo studies. Moreover, anti-FSHR-IR T-cells specifically upregulated surface expression of the activation marker CD69 in the presence of FSHR positive targets, but not FSHR-deficient the 293T cell line. Additionally, specific activation of anti-FSHR-IR T-cells by FSHR expressed on tumor cell surface led to efficient tumor cell killing in vitro. Furthermore, to assess the anti-tumor effect of anti-FSHR T-cells, we established human OvCa xenografts in NSG mice by subcutaneous flank injection of CaOV3 cancer cell line followed by two intravenous redirected T-cell administrations. As shown by caliper measurements, FSHR-redirected T-cells elicited anti-tumor potential with suppressed outgrowth of established tumor. Tumor growth was statistically reduced in comparison to control, GFP engineered T-cell treated group or PBS treated animals. These data suggest that systemic delivery of anti-FSHR T-cells to mice bearing FSHR-expressing tumors may result in tumor trafficking, activation, and lysis at location of tumor. In summary, we have successfully exploited for the first time a novel therapeutic antigen, the FSHR protein, expressed on tumor cell surface, to deliver T-cell based immune-therapy of cancer. Given its highly restricted expression in cancer, cancer-associated vessels and gonadal tissues, the rationale for FSHR targeting is strong and supports further exploration of FSHR-targeted immune therapy approaches for cancer patients.
An Ongoing Multinational Observational Study in Multiple Myeloma (PREAMBLE): Preliminary Report on Patient Survival
Authors: Gordon Cook, David Cella, Brian Durie, Hartmut Goldschmidt, David Kuter, Philippe Moreau, Ravi Vij, Catherine Davis, Abderrahim Oukessou, Teresa Zyczynski, Sergey Popov, Antonio Palumbo
Journal: Blood (2015)
Abstract 5017: The discovery of novel therapeutics that restore antigen processing pathways in immune-edited metastatic cancers
Authors: Lilian Nohara, Reinhard Gabathuler, Paul Ahn, Ping Cheng, David Williams, Raymond Andersen, Wilfred A. Jefferies
Journal: Cancer Research (2015)

Abstract Cancer immune-editing resulting in immune escape where Major Histocompatibility Complex I (MHC I) molecules and the endogenous Antigen Processing Pathway (APP) leading to MHC I expression are down regulated, are prevalent in metastatic forms of cancer. In the absence of MHC I, these tumors subvert host immune surveillance mechanisms and are thus resistant to many of the immunotherapies approaches that evoke adaptive immunity to eradicate tumors in humans. Previously, we showed that by restoring TAP-1 expression in metastatic disease it is possible to restore the APP and the CTL recognition of tumor specific antigen loaded MHC-I molecules in carcinomas. We continued to investigate this mechanism of TAP deficiencies leading to APP defects and were the first to discover that this phenotype is not regulated by defects or mutations in the TAP-1 gene, but it is epigenetically regulated and can be restored by treatment with Histone Deacetylase Inhibitors (HDACi). Here, we describe a novel mechanism of action of compounds in promoting immune responses against tumors. We have developed a high-throughput screening assay to identify compounds that induce antigen presentation in metastatic prostate and lung carcinomas. We have used this system to screen a pharmacological library made from deep-sea sponge extracts, as it has been found that marine invertebrates are a diverse source of pharmaceutical leads and also of chemical diversity. Our results exploiting this system indicate several extracts isolated from amongst 500 sea sponges result in an increase a significant increase in surface MHC I expression, while at the same time exhibiting low cytotoxicity. The chemical structures of several of the active components of these extracts have been determined and one particularly promising candidate has been synthesized and produced in sufficient quantities to commence animal testing. Initial studies indicate the compound is well tolerated and there is no toxicity in animals at the doses that were studied. Results will be presented regarding the activity of the compound against subcutaneously implanted metastatic tumors. The work described herein will provide new therapeutic candidates for harnessing the power of the immune system to recognize and destroy metastatic cancers. Citation Format: Lilian Nohara, Reinhard Gabathuler, Paul Ahn, Ping Cheng, David Williams, Raymond Andersen, Wilfred A. Jefferies. The discovery of novel therapeutics that restore antigen processing pathways in immune-edited metastatic 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 5017. doi:10.1158/1538-7445.AM2015-5017
E3508: A phase II randomized trial of carboplatin (C), paclitaxel (P), and bevacizumab (B) with or without IMC-A12 (cixutumumab) in patients with advanced nonsquamous, non-small cell lung cancer (NSCLC).
Authors: A. Argiris, J. Lee, J. H. Schiller
Journal: Journal of Clinical Oncology (2011)

TPS221 Background: Insulin-like growth factor type receptor 1 (IGF1R) signaling has been implicated in many carcinomas, including lung cancer. Cixutumumab (CX) is a fully human IgG1 monoclonal antibody to the IGF1R that has been shown to inhibit the growth of lung cancer cell lines and xenograft models. CX produces several biologic anticancer effects including downregulation of IGF1R, inhibition of downstream MAPK and AKT, induction of apoptosis, and cell cycle arrest. Preclinical studies support the use of a combination of IGF1R inhibitors and cytotoxic chemotherapy, including platinum and paclitaxel. CX is well tolerated as single agent in patients with advanced solid tumors. CPB is the reference Eastern Cooperative Oncology Group (ECOG) regimen based on a previous phase III trial (E4599) in patients with B-eligible, non-squamous advanced NSCLC. CX can potentially reverse resistance and enhance the efficacy of platinum-based chemotherapy for NSCLC. Methods: We designed a multicenter phase II randomized trial of CPB with or without CX in patients with advanced NSCLC. Eligibility criteria are similar to E4599. Patients are equally randomized to receive either P 200 mg/m² IV over 3 hours, day 1, followed by C AUC = 6.0, IV over 30 min, day 1, B 15 mg/kg IV over 30-60 min, every 21 days to a maximum of 6 cycles followed by B maintenance until progression (arm A) or same CPB plus CX 6 mg/kg IV over 1 hour, days 1, 8, and 15 during CPB and B maintenance (arm B). The primary endpoint is the PFS. The study hypothesis is that CPB plus CX will increase the median PFS from 6 months (based on E4599) to 9 months that corresponds to a 33% reduction in the PFS failure hazard rate. The sample size is 90 patients per arm (180 total). Toxicities of this novel regimen, such as grade ≥3 bleeding, febrile neutropenia and infection with grade 3-4 neutropenia, will be evaluated at the first stage of the study (after accrual of 18 patients/arm). Blood samples at baseline and after therapy (cycle 1/day 2 and cycle 2/day 1) and baseline tumor tissue are collected for future correlative studies. This trial (E3508; NCT00955305) is ongoing in the ECOG and has accrued 32 patients.
Highly Significant Impact of HLA-DRB3 and HLA-DRB4 Matching on Different Unrelated Allo-HSCT Outcomes: New Perspectives in the Unrelated Donor Selection
Authors: Marie Y. Detrait, Valerie Dubois, Mohamad Sobh, Stephane Morisset, Franck E. Nicolini, Helene Labussiere, Fiorenza Barraco, Giovanna Cannas, Sophie Ducastelle, Jihane Fattoum, Xavier Thomas, Youcef Chelghoum, Nathalie Tedone, Sylvie Rey, Mauricette Michallet
Journal: Blood (2011)
Abstract 684: Intensive Statin Therapy Decreases Lipid-Rich Coronary Plaques as Detected by 64-Slice Computed Tomographic Angiography
Authors: Toshiro Kitagawa, Hideya Yamamoto, Norihiko Ohhashi, Eiji Kunita, Hiroto Utsunomiya, Takafumi Ishida, Futoshi Tadehara, Hiroki Teragawa, Yukiko Nakano, Tomoki Shokawa, Yasuki Kihara
Journal: Circulation (2008)

Computed tomography (CT) densities within coronary plaques measured by multislice CT have been shown to reflect plaque components. We evaluated an effect of statin therapies on characteristics of non-calcified coronary atherosclerotic lesions (NCALs) defined by CT density. We studied 92 consecutive stable patients (67 men, age 67 ± 9 years) with at least one NCAL detected by 64-slice CT angiography (CTA). We excluded patients with previous coronary revascularization procedures. Each NCAL (size &gt;1-mm 2 , density &lt;120HU) was evaluated with the minimum CT density (ROI = 1-mm 2 ). NCALs with &lt;40HU were considered as lipid-rich based on our previous report. We examined drug uses (intensive statins [IS; atorvastatin or rosuvastatin], non-intensive statins [NS; pravastatin or simvastatin], ACE inhibitors or ARB, and aspirin) continuing for &gt;6-months before CTA in each patient. There were no significant differences in the patient’s characteristics and drug uses except for statin among the three groups classified by statin use (IS: n = 21, NS: n = 23, and no statin: n = 48). Serum LDL-cholesterol level (90 ± 18 vs. 115 ± 30 vs. 122 ± 34 mg/dl, p = 0.0005) and LDL/HDL-cholesterol ratio (1.6 ± 0.5 vs. 2.3 ± 0.7 vs. 2.5 ± 1.1, p = 0.002) were lower in the IS group than the others. A total of 191 NCALs (lipid-rich; 91 lesions) were detected by CTA. The number of all NCALs per patient was similar among the three groups (2.0 ± 0.9 vs. 2.1 ± 1.2 vs. 2.1 ± 1.0), while that of lipid-rich NCALs per patient was lower in the IS group than the others (0.5 ± 0.6 vs. 1.2 ± 0.9 vs. 1.1 ± 0.9, p = 0.01). On multivariate analysis regarding age, gender, coronary risk factors, and drug uses, the IS use was only significant predictor for decreasing lipid-rich NCALs (coefficient value −0.46, 95% CI −0.78– −0.14, p = 0.006). Otherwise, among the three groups classified by the number of lipid-rich NCALs per patient (absence: n = 26, one: n = 46, and ≥2: n = 20), the difference of LDL/HDL-cholesterol ratio was most significant (1.9 ± 0.6 vs. 2.1 ± 0.9 vs. 2.9 ± 1.1, p = 0.0004). Our CT findings support the concept that intensive statin therapy stabilizes lipid-rich coronary plaques. LDL/HDL-cholesterol ratio is most strongly related to lipid-rich NCALs on CTA.
Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women
Authors: Joshua N. Sampson, Roni T. Falk, Catherine Schairer, Steven C. Moore, Barbara J. Fuhrman, Cher M. Dallal, Douglas C. Bauer, Joanne F. Dorgan, Xiao-Ou Shu, Wei Zheng, Louise A. Brinton, Mitchell H. Gail, Regina G. Ziegler, Xia Xu, Robert N. Hoover, Gretchen L. Gierach
Journal: Cancer Research (2016)

Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation:16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies.
Comparison of the Dyspnoea-12 and Multidimensional Dyspnoea Profile in people with COPD
Authors: Marie T. Williams, David John, Peter Frith
Journal: European Respiratory Journal (2016)

We directly compared convergent, discriminant and concurrent validity of the Dyspnoea-12 (D-12) and Multidimensional Dyspnoea Profile (MDP) in people with chronic obstructive pulmonary disease. Breathlessness measures (D-12, MDP, visual analogue scales and descriptors) were completed for two focal periods (daily life and end of walk test). Instrument structure (D-12 and MDP item grouping) was assessed with factor analysis. Differences between airflow severity stage and focal periods (ANOVA, t-test and Chi-squared test), associations between D-12 and MDP (r, r 2 for static pulmonary function, 6-min walk test and self-reported measures of impairment) and individual consistency for comparable items of the D-12 and MDP (McNemar's test) were assessed. In 84 participants (mean± sd age 70±9 years, 47 males, forced expiratory volume in 1 s 48±17% predicted), item groupings were confirmed for both focal periods. Developer-recommended single and subdomain scores were highly correlated, and demonstrated similar convergent, discriminant and concurrent validity. Individual consistency differed between the D-12 and MDP according to item/item groups. At the level of developer-recommended single and subdomain scores, the D-12 and MDP share similar psychometric properties, but these instruments serve different purposes, do not assess the same sensations or emotions and are not interchangeable.
FDG-PET as a Marker of tumor proliferation Compared to Gene-Expression Proliferation Scores, MIB1%, and LDH In Untreated Mantle Cell Lymphoma (MCL)
Authors: Mark Roschewski, Marc Weniger, Karen Kurdziel, Stefania Pittaluga, Xin Tian, Megan Tweito, Kieron Dunleavy, Wyndham H Wilson, Adrian Wiestner
Journal: Blood (2010)
Analysis of Clonal Hierarchy Shows That Other Ancestral Events May Precede Evolution of Del(5q) in Myeloid Neoplasms
Authors: Naoko Hosono, Hideki Makishima, Bartlomiej P Przychodzen, Thomas LaFramboise, Chantana Polprasert, Michael J. Clemente, Jacqueline Boultwood, Mikkael A. Sekeres, Jaroslaw P. Maciejewski
Journal: Blood (2014)
Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial
Authors: Firas H El-Khatib, Courtney Balliro, Mallory A Hillard, Kendra L Magyar, Laya Ekhlaspour, Manasi Sinha, Debbie Mondesir, Aryan Esmaeili, Celia Hartigan, Michael J Thompson, Samir Malkani, J Paul Lock, David M Harlan, Paula Clinton, Eliana Frank, Darrell M Wilson, Daniel DeSalvo, Lisa Norlander, Trang Ly, Bruce A Buckingham, Jamie Diner, Milana Dezube, Laura A Young, April Goley, M Sue Kirkman, John B Buse, Hui Zheng, Rajendranath R Selagamsetty, Edward R Damiano, Steven J Russell
Journal: The Lancet (2016)