tbuckley/cabot-search huggingface dataset:
A phase II, multicenter, placebo-controlled trial of apatinib in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after two previous treatment regimens.
Authors: Li Zhang, Meiqi SHI, Cheng Huang, Xiaoqing Liu, Jian ping Xiong, Gongyan Chen, Wei Liu, Wenchao Liu, Yiping Zhang, Kai LI, Hao Yu, Haoyuan Jiang
Journal: Journal of Clinical Oncology (2012)

7548 Background: Apatinib is an oral, small molecular tyrosine-kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR). Phase II study has showed that apatinib significantly improved the outcome of patients with advanced or metastatic gastric cancer (Li J, et al. ASCO 2011). The primary object of this study is to determine whether apatinib can improve progression free survival (PFS) compared with placebo in patients with advanced non-squamous NSCLC who failed two lines of treatment. Methods: This study recruited histologically diagnosed advanced non-squamous NSCLC patients who failed more than two lines of treatment including EGFR TKIs. Other eligible criteria included ECOG ≤1, adequate organ function and no prior exposure to VEGFR-TKI. The patients were randomized to receive apatinib at a dose of 750 mg or placebo (at allocation ratio of 2:1) orally once daily until the disease progression or unacceptable toxicity. Results: 135 patients (90 in apatinib arm, 45 in placebo arm) were included at 20 centers in China until Aug 2011. Median PFS was 4.7 months for apatinib group versus 1.9 months for placebo group, hazard ratio (HR) was 0.278 (95% CI 0.170, 0.455) (p&lt;0.0001). The response rate (RR) and disease control rate (DCR) were also significantly better in study arm (12.2% and 68.9%) than in placebo arm (0% and 24.4%)(P=0.0158 and P&lt;0.0001). The most frequently observed AEs were hypertension, proteinuria, and hand-foot syndrome (HFS). These AEs were generally mild or moderate in severity and were manageable. Conclusions: This randomized phase II trial shows that apatinib has substantial clinical activity without significant additional toxicity in patients with advanced non-squamous and non-small cell lung cancer. Continued investigation of apatinib is warranted in future clinical studies.
525. CD8+ T Cell Tolerance To Epitopes Downstream of Non-Sense Mutations
Authors: Scott Ashley, Deirdre McMenamin, Christine Draper, Suryanarayan Somanathan, James M. Wilson
Journal: Molecular Therapy (2015)

Recent success in gene therapy clinical trials have shown great promise towards developing efficacious treatments, however immune responses to the therapeutic protein resulting in transgene expression attenuation or loss still remains a concern. Expression can elicit a CD8+ T cell response against "non-self" regions of the protein as they were not presented during the process of central tolerance. Individuals with genes containing non-sense mutations could be at increased risk of developing a CD8+ T cell response following gene therapy as peptide sequences downstream of the mutation would not have previously been presented to the immune system. The effect of nonsense and missense mutations on the immune response to corrected gene expression was studied using the OTC gene, which is mutated in ornithine transcarbamylase deficiency. The immunodominant epitope SIINFEKL was fused to the C-terminus of OTC to evaluate the effect of mutations on the ability to elicit a transgene-specific immune response, as a surrogate for expression and presentation of SIINFEKL to CD8+ T cells. Using an ex-vivo stimulation assay, CD8+ T cells from OT-1 mice were mixed with fibroblasts transiently transfected with a panel of mutant or wild-type human hOTC-SIINFEKL constructs. T cell activation was determined by IFN-γ ELISPOT assay. Surprisingly, activation of T cells occurred to epitopes in the C-terminal region of genes containing non-sense mutations upstream of the SIINFEKL epitope. The most immunogenic nonsense mutant was selected for further studies in C57BL/6 mice. Packaging of this mutant hOTC-SIINFEKL transgene into highly immunogenic adenovirus 5 (Ad5) elicited an immune response in vivo to the downstream SIINFEKL epitope. To study if expression and presentation of epitopes downstream non-sense mutations to CD8+ T cells could result in tolerance induction all of the non-sense mutant constructs were used to generate AAV8 vectors. C57BL/6 mice were administered the non-immunogenic AAV8 vectors and then subsequently challenged the mice with Ad5 hOTC-SIINFEKL or Ad5 OVA. Mice pre-treated with AAV8 had a drastically reduced CD8+ T cell activation to the SIINFEKL epitope compared to no treatment as measured by flow cytometry and IFN-γ ELISPOT assay. These results suggest that patients with non-sense mutations could have immunological tolerance to the therapeutic protein decreasing the risk of a transgene specific immunologic response.
PTH-024 Obesity and colonoscopy: not so difficult after all? The experience of a bowel cancer screening unit
Authors: S R Hazeldine, J Heneker, J Williams, C J Vickery, P D Thomas, S Pugh
Journal: Gut (2010)

<h3>Introduction</h3> Obesity is a risk factor for the development of colorectal cancer (CRC).1 Colonoscopy in obese patients has been suggested to be more technically difficult,23 but variation in indication and age of patients, and operator technical ability may be confounding factors. The Bowel Cancer Screening Programme (BCSP) has a single indication for colonoscopy in a narrow age band (60–70 years) and the colonoscopists are of a proven standard, therefore studying data from this group of patients may avoid confounding factors and give a truer assessment of technical difficulty. <h3>Methods</h3> We compared measures of technical difficulty (quality of preparation; caecal intubation rate and time; sedation/analgesia dose; and patient tolerance) and findings (polyp and cancer detection) in the Taunton Faecal Occult Blood positive (FOB+ve) BCSP colonoscopy patients in 2008/9 (N=359, males 209, females 150) in relation to their BMI. <h3>Results</h3> BMI was known in 348, and was 15.7–58.3 (median 28.0). One hundred and eleven patients (31.8%) had BMI &gt;30. Bowel preparation scores were not affected by BMI (Fisher9s Exact Test, p=0.62), nor were sedation and analgesia requirements (all comparisons obese vs non-obese, Fisher9s Exact Test or regression analysis). Comfort scores were similar (minimal or no discomfort 63% vs 68%, p=0.33). Overall caecal intubation rates were 96.3%, vs 97.4% (p=0.73). Caecal intubation time was not effected by BMI (r=0.022, p=0.68). Polyps were found in 210 (58.4%) patients and cancer in 43 (11.9%) in total. BMI did not affect the number of polyps found (p=0.33). There was no significant difference in the number of cancers identified in patients with a BMI&gt;30 (14 of 97) compared to the others (29 of 208) (p=1.0). <h3>Conclusion</h3> Obesity does not impair the technical performance of colonoscopy in this population. There is a high rate of obesity in the FOB +ve BCSP population, but the effect of obesity on findings cannot be assessed by this study, since the proportion of obese patients in the overall population from which this group is drawn was not available. Nether-the-less this study suggests that obesity should not be a factor in deciding whether colonoscopy is an appropriate investigation to exclude CRC.
Abstract P147: Antiangiogenic Effect of Doxorubicin on Human Cardiac Microvascular Endothelial Cells Does Not Result from Reduced Vascular Endothelial Growth Factor Production
Authors: Eugene A Konorev, Zuyue Sun
Journal: Circulation Research (2011)

Clinical use of the potent anticancer agent doxorubicin (DOX) is limited by a dose-dependent cardiomyopathy. Although cardiac muscle has been thought to be a primary target of the cardiotoxic effect of doxorubicin, our studies indicate that adult cardiomyocytes may be resistant to the direct effects of this agent. These studies have prompted us to identify alternative targets for doxorubicin in adult heart that may contribute to the development of cardiomyopathy. Additionally, recent literature report ( Lee et al. PNAS 2009;106:2353–2358 ) indicated that DOX inhibited tumor angiogenesis due to the reduced production of vascular endothelial growth factor (VEGF) by tumor cells. We set out therefore to test the hypothesis that DOX inhibits angiogenesis by human cardiac microvascular endothelial cells (HCMVEC) via inhibition of VEGF production. We detected reduced proliferation/viability of HCMVEC cultures treated with DOX. DOX increased caspase-3-like activity and development of apoptosis in HCMVEC, and inhibited the formation of vascular tubule formation in a co-culture of HCMVEC with human cardiac fibroblasts (HCF) with an IC 50 of 8 nM. HCF cultures released 7-fold greater amounts of VEGF into the culture media as compared with HCMVEC under the normoxic conditions while 1% hypoxia and 100 μM CoCl 2 further increased the production of VEGF by HCF. DOX moderately inhibited hypoxia- and CoCl 2 -induced VEGF release by these cells at concentrations above 500 nM whereas inhibition of vascular tubule formation by DOX in a co-culture system occurred at much lower concentrations and was not associated with the reduced production of VEGF. We conclude that DOX is a very potent antiangiogenic agent in the human cardiac microvascular endothelial cell system. However, this effect of DOX is not caused by the reduced production of VEGF. Inhibition of vascular network formation in the heart is likely to contribute to the development of doxorubicin cardiomyopathy in treated patients.
Abstract 2135: Survivin is a novel target of the Hedgehog/GLI signaling pathway in human tumor cell lines
Authors: Kateřina Vlčková, Lubica Ondrušová, Jiri Réda, Jiri Vachtenheim, Petra Záková
Journal: Cancer Research (2015)

Abstract Survivin, a pivotal antiapoptotic protein is expressed in tumors whereas its expression in normal tissues is extremely low. It is believed that transcription of the survivin gene is driven mainly by the transcription factor Sp1. We have identified 11 potential consensus sites for GLI trancription factors in the survivin promoter, albeit non of them has been a full consensus. Interestingly, the distal part of the promoter (-1765 to -941, ending at +39) containing 4 GLI sites showed about 2-fold higher activity than the proximal promoter (-941 to +39). The survivin promoter-reporter has been found to be upregulated mainly by plasmids encoding GLI2 and deltaN-GLI2, a more active GLI2 truncated mutant. Its activity was even higher than the Sp1 activity. The promoter-reporter plasmid is also inhibited by the GLI1/2 inhibitor GANT61. Moreover, by analyzing 40 human tumor cell lines of various origin, we have found that the endogenous survivin protein level substantially decreases after the incubation with GANT61 in most cell lines. Real-time PCR for the survivin mRNA in GANT61-sensitive cell lines showed a decrease by up to about 50 per cent. These data suggest that survivin may be a novel important target regulated by the Hedgehog/GLI signaling pathway, which has been reported previously to be deregulated in the majority of tumor types. The work was supported by the grant NT/14005 from IGA, Ministry of Health, Czech Republic. Citation Format: Kateřina Vlčková, Lubica Ondrušová, Jiri Réda, Jiri Vachtenheim, Petra Záková. Survivin is a novel target of the Hedgehog/GLI signaling pathway in human tumor cell lines. [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 2135. doi:10.1158/1538-7445.AM2015-2135
Abstract 3176: Linking suppressive activity and ER-Stress in Myeloid Derived Suppressor Cells
Authors: Thomas C. Condamine, Vinit Kumar, Dmitry I. Gabrilovich
Journal: Cancer Research (2015)

Abstract In recent years, immunotherapies have shown great promise for the treatment of cancer patients. However, the presence of a very potent immunosuppressive microenvironment in the tumor site remains one of the major obstacles in fully harnessing the potential of immunotherapeutic strategies. Myeloid Derived Suppressor cells (MDSC) represent one of the main suppressive populations inside the tumor. These cells can be divided in two sub-populations: PMN-MDSC and Monocytic-MDSC. They suppress immune response using various well-known mechanisms and accumulate to a large extent in tumor-bearing hosts. Despite the increasing body of literature on MDSC, which mechanisms drives their suppressive capacity remains unclear. Our group recently reported that the ER-Stress response is activated in MDSC isolated from tumor bearing mice and cancer patients. In this study, we investigated the possibility that the ER-stress response could be responsible for the immune suppressive capacities of MDSC. To test this hypothesis, we induce ER-Stress using well-known chemical inducer into non suppressive myeloid cells (PMN and monocyte) and assess their ability to suppress T cells function. Our results show that, following ER-Stress induction, normal myeloid cells were able to suppress T cells response (in murine and human system). To better understand how the ER-Stress response can induce suppressive capacities, we performed microarray analysis following treatment with ER-Stress inducer. Interestingly, we found that arginase-1, one the major enzyme implicated in MDSC suppressive capacities, was induced by more than 5 fold. Altogether, our results suggest that activation of the ER-Stress response in MDSC could be responsible for the up-regulation of arginase-1 and the suppressive phenotype of MDSC. These results suggest that targeting the ER-Stress response in cancer patients could inhibit the suppressive activity of MDSC and improve the efficacy of current immunotherapies. Citation Format: Thomas C. Condamine, Vinit Kumar, Dmitry I. Gabrilovich. Linking suppressive activity and ER-Stress in Myeloid Derived Suppressor 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 3176. doi:10.1158/1538-7445.AM2015-3176
Complex Interstitial Deletions of 11q and Copy-Neutral Loss of Heterozygosity of 11q Are Detected by Whole Genome Copy Number Variation Analysis of Early-Intermediate Stage, High Risk Chronic Lymphocytic Leukemia Patients.
Authors: Steven A. Schichman, Annjanette Stone, Maria Winters, Weleetka Carter, Lori Frederick, Jeanette Eckel-Passow, Timothy G. Call, Tait D. Shanafelt, Neil E. Kay, Clive S. Zent, David S. Viswanatha
Journal: Blood (2009)
Progression of Lung Disease in Preschool Patients with Cystic Fibrosis
Authors: Sanja Stanojevic, Stephanie D. Davis, George Retsch-Bogart, Hailey Webster, Miriam Davis, Robin C. Johnson, Renee Jensen, Maria Ester Pizarro, Mica Kane, Charles C. Clem, Leah Schornick, Padmaja Subbarao, Felix A. Ratjen
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Implementation of intervention strategies to prevent lung damage in early cystic fibrosis (CF) requires objective outcome measures that capture and track lung disease.Objectives: To define the utility of the Lung Clearance Index (LCI), measured by multiple breath washout, as a means to track disease progression in preschool children with CF.Methods: Children with CF between the ages of 2.5 and 6 years with a confirmed diagnosis of CF and age-matched healthy control subjects were enrolled at three North American CF centers. Multiple breath washout tests were performed at baseline, 1, 3, 6, and 12 months to mimic time points chosen in clinical care and interventional trials; spirometry was also conducted. A generalized linear mixed-effects model was used to distinguish LCI changes associated with normal growth and development (i.e., healthy children) from the progression of CF lung disease.Measurements and Main Results: Data were collected on 156 participants with 800 LCI measurements. Although both LCI and spirometry discriminated health from disease, only the LCI identified significant deterioration of lung function in CF over time. The LCI worsened during cough episodes and pulmonary exacerbations, whereas similar symptoms in healthy children were not associated with increased LCI values.Conclusions: LCI is a useful marker to track early disease progression and may serve as a tool to guide therapies in young patients with CF.
Characterization of an Abiraterone Ultraresponsive Phenotype in Castration-Resistant Prostate Cancer Patient-Derived Xenografts
Authors: Hung-Ming Lam, Ryan McMullin, Holly M. Nguyen, Ilsa Coleman, Michael Gormley, Roman Gulati, Lisha G. Brown, Sarah K. Holt, Weimin Li, Deborah S. Ricci, Karin Verstraeten, Shibu Thomas, Elahe A. Mostaghel, Peter S. Nelson, Robert L. Vessella, Eva Corey
Journal: Clinical Cancer Research (2016)

Purpose: To identify the molecular signature associated with abiraterone acetate (AA) response and mechanisms underlying AA resistance in castration-resistant prostate cancer patient-derived xenografts (PDXs).Experimental Design: SCID mice bearing LuCaP 136CR, 77CR, 96CR, and 35CR PDXs were treated with AA. Tumor volume and prostate-specific antigen were monitored, and tumors were harvested 7 days after treatment or at end of study for gene expression and immunohistochemical studies.Results: Three phenotypic groups were observed based on AA response. An ultraresponsive phenotype was identified in LuCaP 136CR with significant inhibition of tumor progression and increased survival, intermediate responders LuCaP 77CR and LuCaP 96CR with a modest tumor inhibition and survival benefit, and LuCaP 35CR with minimal tumor inhibition and no survival benefit upon AA treatment. We identified a molecular signature of secreted proteins associated with the AA ultraresponsive phenotype. Upon resistance, AA ultraresponder LuCaP 136CR displayed reduced androgen receptor (AR) signaling and sustainably low nuclear glucocorticoid receptor (nGR) localization, accompanied by steroid metabolism alteration and epithelial-mesenchymal transition phenotype enrichment with increased expression of NF-κB-regulated genes; intermediate and minimal responders maintained sustained AR signaling and increased tumoral nGR localization.Conclusions: We identified a molecular signature of secreted proteins associated with AA ultraresponsiveness and sustained AR/GR signaling upon AA resistance in intermediate or minimal responders. These data will inform development of noninvasive biomarkers predicting AA response and suggest that further inhibition along the AR/GR signaling axis may be effective only in AA-resistant patients who are intermediate or minimal responders. These findings require verification in prospective clinical trials. Clin Cancer Res; 23(9); 2301-12. ©2016 AACR.
Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis
Authors: Tingting Jiang, Weiwei Shi, Vikram B. Wali, Lőrinc S. Pongor, Charles Li, Rosanna Lau, Balázs Győrffy, Richard P. Lifton, William F. Symmans, Lajos Pusztai, Christos Hatzis
Journal: PLoS Medicine (2016)

Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02) and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05). Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D) TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021), and they had significantly higher mutation burden (p < 0.001) and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009). As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort.The comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in TNBC and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC.
A Novel DLL1-Anti-CD19 Chimeric Protein Effectively Targets Notch Activation to B-Cell Acute Lymphoblastic Leukemia and Induces Cell Death
Authors: Rebecca E Wiersma, Sankaranarayanan Kannan, Srinivas S. Somanchi, Lizhi Zeng, Patrick A. Zweidler-McKay
Journal: Blood (2015)
S131 What proportion of the uk population would be eligible for ct screening for lung cancer according to various proposed inclusion criteria?
Authors: K Gracie, M Kennedy, J Robson, M Callister
Journal: Thorax (2016)

<h3>Introduction</h3> Low dose CT screening reduced lung cancer mortality by 20% in the National Lung Screening Trial (NLST) using eligibility criteria of age 55–74 yrs, ≥30 pack year smoking history, and quit time &lt; 15 years. The US Preventative Services Task Force (USPSTF) has proposed using the NLST criteria extending the upper age limit to 80 years. Alternative proposed eligibility criteria use thresholds from composite risk prediction scores such as a 1.51% lung cancer risk over 6 years using the PLCO<sub>M2012</sub> model (derived from the Prostate Lung Colorectal and Ovarian Study) and a 5% lung cancer risk over 5 years using the Liverpool Lung Project (LLP) model (used in the UK Lung Screening trial). We sought to compare the proportions of patients in the UK who would be eligible for screening according to these criteria. <h3>Methods</h3> We commissioned an anonymous telephone survey in Yorkshire (Hull, Leeds and Wakefield) to collect parameters to calculate lung cancer risk (PLCO<sub>M2012</sub> and LLPv.2) and likelihood of participation in a future programme. Index of multiple deprivation (IMD) was recorded based on postcode and used to ensure a representative cohort. No patient identifiable information was entered into the research database. <h3>Results</h3> 2,424 persons 55–80 years agreed to participate in the telephone survey, of which 1,335 were ever-smokers. The proportion of patients (95% CI) eligible according to various criteria were as follows: NLST 11.9% (10.6%–13.2%), USPSTF 13.3% (12.0%–14.7%), PLCO<sub>M2012</sub> ≥1.51% 20.7% (19.1%–22.3%) and LLP ≥5% 15.8% (14.4%−17.3%). The proportions eligible by USPSTF, PLCO and LLP criteria by IMD and age cohort are shown in Figure 1. When asked how likely they would be to attend an NHS lung cancer screening programme, 62.6% indicated ‘very likely’. This proportion was similar between those eligible for screening by any criteria and those not (62.5% and 62.7% respectively) and current and ex-smokers (61.4% and 63.0% respectively). <h3>Discussion</h3> The proportions of the population eligible for screening differ considerably between various eligibility criteria, and according to deprivation and age. The criteria selected to determine screen-eligibility in a future national screening programme will have a significant impact on the cost and cost-effectiveness of such a programme.