tbuckley/cabot-search huggingface dataset:
Abstract IA-11: Discovery and preclinical activity of IPI-926, a Hedgehog pathway inhibitor
Authors: Julian Adams
Journal: Cancer Research (2009)

Abstract Malignant activation of the Hedgehog (Hh) pathway plays a key role in multiple types of human tumors, supporting the development of Hedgehog pathway antagonists as therapeutics for cancer. This pathway involves two cell-membrane proteins, Patched (Ptc) and Smoothened (Smo), and is regulated by the absence or presence of Hh ligand. Smo can promote growth of certain cancers via three modes of malignant activation of the Hh pathway: ligand-dependent signaling either to the tumor cell itself or from the tumor to its microenvironment, and ligand-independent signaling activated by genetic mutation. Smo has a critical role in the malignant activation of the Hh pathway because it initiates a signal transduction cascade that can result in cell differentiation, migration, and proliferation. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the Hh pathway. Efforts to improve the pharmaceutical properties and potency of cyclopamine led to the discovery of IPI-926, a novel semi-synthetic analogue that inhibits the Hh pathway by binding to Smo. IPI-926 demonstrates excellent oral bioavailability, a long plasma half-life and duration of action, and is highly distributed to tumor tissue. Daily oral administration of IPI-926 results in dose-dependent inhibition of tumor growth in multiple preclinical models of cancer. Following tumor debulking in a primary human xenograft SCLC model with a chemotherapy treatment regimen similar to that used clinically in patients with SCLC, once-daily oral administration of IPI-926 leads to a statistically significant delay in tumor regrowth. In certain cancers including pancreatic and ovarian cancer, the tumor cells produce Hh ligand that diffuses out to the surrounding stroma and binds Ptc, resulting in Smo-mediated Hh pathway activation. This paracrine mode of Hh activation leads to recruitment, growth, and maintenance of the stromal tissue in the tumor microenvironment that supports tumor growth. In a genetically engineered murine model of pancreatic cancer, IPI-926 treatment results in depletion of tumor-associated stroma and prolonged survival when given in combination with gemcitabine. Because Smo plays a critical role in malignant activation of the Hh pathway in both the tumor and the stromal microenvironment, Smo may be a target for the management of a broad range of cancers. IPI-926 is currently being investigated in a Phase 1 clinical trial. Citation Information: Cancer Res 2009;69(23 Suppl):IA-11.
THU0215 Establishing Cut-Off of Infliximab and Anti-Infliximab Antibody Levels Using a Commercial Elisa in Patients with Rheumatoid Arthritis
Authors: D. Hernández, I. D. la Torre, L. Martínez, J. Nieto, F. Llinares, J. Rosas, C. González, I. Monteagudo, J. López-Longo, M. Montoro, L. Carreño, L. Valor
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Inpatients with rheumatoid arthritis (RA) the reasons for failure or loss of response to infliximab (IFX) are controversial, so far both IFX serum levels and the presence of antibodies (Ab) anti-IFX have been associated with these events. In this study we evaluated the correlation of serum levels of IFX and anti-IFX Ab in relation to clinical response in patients with RA. <h3>Methods</h3> We assessed 59serum samples from patients diagnosed with RA treated with IFX (1<sup>st</sup> line), taken prior to infusion. Patients were classified as treatment response and DAS28 (Disease Activity Score 28 Joints) as sustained response or remission (DAS28 &lt;2.6,&gt; 6 months) or loss of response (no-remission, DAS28&gt; 3.2 with&gt; 1 swollen joint and / or elevated CRP / ESR). The concentrations of anti-IFX and IFX levels were measured using a commercial ELISA kit (Progenika ™) following the manufacturer's recommendations. The sample size was previously calculated to ensure a sensitivity (0.6) and specificity (0.8), with a confidence interval of 95%, and related to the measurement of clinical activity index DAS28. Statistical analysis to establish the appropriate values for the cutoff in relation to clinical remission was performed using median (percentiles 25-75), U test Mann-Whitney and ROC curves (Receiver Operating Characteristic). <h3>Results</h3> The medianIFX levels in no-remission RA patients (n = 35) was significantly lower (55 mg / ml, range: 0.0 to 163.5) compared with patients in remission (121 mg / ml; 40.7 to 262.8, p &lt;0.05). We identified the optimal cutoff with ROC analysis for IFX levels as &lt;0.73 mg / ml, which was associated with no-remission, with a sensitivity and specificity of 61% and 59%, respectively. Furthermore, the median titers of anti-IFX in patients in no-remission (0.0 AU / mL, 0.0 to 697.0) was not statistically different than in remission patients (0.0 AU / ml; 0,0-0, 0 UA, p&gt; 0.05). ROC analysis could not be calculated because of the low percentage of positivity for anti-IFX Ab in the selected patient group (n = 10/59, 16.9 %). <h3>Conclusions</h3> Thecutoff values for IFX serum, rather than anti-IFX Ab determination, may be useful in relation to determine clinical response measured by DAS28 in RA. However, there is a priority in standardizing laboratory techniques (variability inter / intra-assay and inter / intra-laboratory) to validate this information and its possible clinical application. <h3>Disclosure of Interest</h3> None Declared
Abstract 61: Integrated analysis of genetic and epigenetic alterations reveals CpG island methylator phenotype associated with clinical outcome of lung adenocarcinoma
Authors: Keiko Shinjo, Yutaka Kondo, Yasuyuki Okamoto, Toshihiko Yokoyama, Noriyasu Usami, Makiko Fujii, Hideki Murakami, Hirotaka Osada, Yoshitaka Sekido
Journal: Cancer Research (2011)

Abstract Background: Lung cancer is the leading cause of cancer-related death worldwide. While targeted therapy, such as tyrosine kinase inhibitors (TKIs), has been used against the non small cell lung cancers (NSCLCs) patients with epidermal growth factor receptor (EGFR) mutation, not all the patients received benefit from TKIs. Epigenetic alterations have been recognized as one of the important mechanism of NSCLCs. The aim of this study is to clarify the significance of DNA methylation, especially the clinical impacts of CpG island methylator phenotype (CIMP), in NSCLCs. Methods: Using methylated CpG island amplification-microarray (MCAM), a genome-wide DNA methylation analysis, 41 lung adenocarcinomas (AdCas) were analyzed. DNA methylation of newly identified genes from MCAM analysis was further examined in another cohort of 86 AdCas with bisulfate pyrosequencing method. Results: Unsupervised hierarchical cluster analysis revealed that DNA methylation was extensively accumulated in one subgroup (n=4, 9.8%), which may represent CIMP tumors (651 genes vs. 354 genes, P=0.0004). DNA methylation status of newly identified 7 CIMP markers revealed that 8 (9.3%), 12 (14%), and 66 (76.7%) were classified into CIMP-high, CIMP-low, and CIMP-negative tumors, respectively. CIMP-high tumors showed no EGFR mutations and frequent exposure to smoking. In addition, these tumors had worse prognosis than the other tumors (P=0.035), suggesting that CIMP-high tumors have characteristic clinical features, which may represent an alternative mechanism to the EGFR mutation. Treatments of NSCLC cell lines showed that CIMP positive AdCa cell lines are sensitive to DNA demethylating agent regardless of EGFR status. Conclusions: Our data suggest that CIMP in AdCas appears to be a unique subgroup, which has distinguished clinical traits from the other AdCas. Applying DNA demethylating agent to CIMP-high tumors might be a new strategy for the treatment of NSCLCs without EGFR mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 61. doi:10.1158/1538-7445.AM2011-61
Differences in Incidence Rates of Cancers of the Respiratory Tract by Anatomic Subsite and Histologic Type: An Etiologic Implication
Authors: C. P. Yang, R. P. Gallagher, N. S. Weiss, P. R. Band, D. B. Thomas, D. A. Russell
Journal: JNCI Journal of the National Cancer Institute (1989)

Data from nine population-based cancer registries participating in the Surveillance, Epidemiology, and End Results Program (1973-1982) were analyzed to determine whether the incidence of different histologic types of respiratory tract cancers varies by anatomic location. The variation in cancer incidence among respiratory tract subsites was remarkable for squamous cell carcinoma, but the variation was less prominent for adenocarcinoma. The rates of squamous cell carcinoma and adenocarcinoma along the airways correspond closely with the deposition pattern of large and small smoke particles, respectively. Also, the rates of adenocarcinoma parallel the distribution of surface glandular cells of the respiratory tract. Our results support the hypothesis that anatomy and physiology, in conjunction with size of particles in inhaled cigarette smoke, play an important role in the genesis of specific histologic types of respiratory tract cancers.
Cardiac Arrhythmias in Chronic Cor Pulmonale
Authors: Leo J. Corazza, Bernard H. Pastor
Journal: New England Journal of Medicine (1958)

CARDIAC arrhythmias are generally considered rare in chronic cor pulmonale. Harvey, Ferrer and Cournand1 believe that their occurrence strongly suggests the coexistence of another type of heart disease. In a recent comprehensive review by Hecht2 cardiac irregularities, particularly atrial fibrillation, are said to be "quite infrequent" in any type of cor pulmonale. A similar opinion is expressed in some textbooks,3 , 4 and others do not mention arrhythmias at all.5 Bellet and Bernstein6 state that atrial fibrillation is a common arrhythmia in chronic cor pulmonale, but do not refer to other disturbances of rhythm.At the Philadelphia Veterans Administration Hospital frequent, persistent . . .
Abstract 758: Cancer vaccine immunotherapy employing Saccharomyces cerevisiae (yeast) as a vector can modulate the balance between CD4+ T cells and regulatory T cells (Tregs) and enhance the specific antitumor immune response
Authors: Matteo Vergati, Vittore Cereda, Chiara Intrivici, Ngar-Yee Huen, Maria Giovanna Di Bari, Caroline Jochems, James L. Gulley, David Apelian, Jeffrey Schlom, Kwong Y. Tsang
Journal: Cancer Research (2011)

Abstract Regulatory T cells (Tregs) have been broadly related to modulation of the antitumor immune response. We have previously shown that whole, heat-killed, recombinant Saccharomyces cerevisiae yeast genetically modified to express carcinoembryonic antigen (yeast-CEA) can efficiently activate human dendritic cells (DCs) and stimulate CEA-specific CD8+ T cells. In the present study, we further investigated how the balance between CD4+ T cells and Tregs induced by yeast-treated DCs might affect the generation of a CEA-specific immune response. Autologous CD4+ T cells were co-cultured with human DCs matured by yeast vs. CD40L. Activated CD4+CD25+ effector T cells (Teffs) and CD4+CD25+CD127- Tregs isolated from the two co-cultures were analyzed. A higher Teff/Treg ratio, greater levels of Th1-related cytokines, lower expression of FoxP3 in Tregs, decreased FoxP3 demethylation levels in the Treg-specific demethylated region, and decreased Treg suppressive function were found in the cells isolated from the yeast co-culture compared to those from the CD40L co-culture. DCs isolated from the yeast co-culture showed a significant decrease in surface expression of programmed death ligand 2 (PD-L2) vs. the CD40L co-culture (55.7% vs. 31.2%). No differences were observed in programmed death ligand 1 (PD-L1) levels. Teffs isolated from the yeast co-culture had higher levels of PD-L1 (22.9% vs. 13.7%), but significantly lower levels of programmed death 1 (PD-1, 2.4% vs. 11.6%), compared to the co-culture using CD40L-matured DCs. Tregs isolated from the yeast co-culture showed a significant increase in surface expression of PD-L1 (25.5% vs. 3.6%) and no difference in levels of PD-1 (0.7% vs. 1.4%) compared to the CD40L co-culture. These pro-inflammatory changes may partially explain both the increased CEA-specific CD4+ T-cell proliferation using yeast- vs. CD40L-treated DCs pulsed with CEA protein, and the higher percentage of CEA-specific CD4+ T cells generated when yeast-matured DCs vs. CD40L-treated DCs were used as antigen-presenting cells in the presence of CEA protein. This is the first study to report on the role of yeast-treated human DCs in modulating the balance between Teffs and Tregs and thus enhancing the antitumor immune response. Altogether, these preliminary findings provide a rationale for further evaluation of yeast constructs in cancer vaccine immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 758. doi:10.1158/1538-7445.AM2011-758
Optimal Selection of Radiotherapy as Part of a Multimodal Approach for Hepatocellular Carcinoma
Authors: Hong In Yoon, Jinsil Seong
Journal: Liver Cancer (2016)

A multimodal approach to treatment is a basic oncologic principle with proven survival benefits for most cancer types. However, existing guidelines recommend single modalities for treating each stage of hepatocellular carcinoma (HCC). Nonetheless, multimodal approaches can be considered for HCC, depending on the characteristics of the disease in individual cases. Radiotherapy (RT), an effective local modality, is a critical element of most multimodal approaches. Improved RTtechnology and increased understanding of the tolerance of the liver to radiation have contributed to the popularity of RT for treating liver tumors in clinical practice. Consequently, numerous reports have described the effects of RT on liver cancer, despite a lack of stringent evidence for its benefits. RT can be delivered using various technologies and approaches, which may be the source of some confusion. For example, high-dose ablative RT can be curative on its own, or high-dose ablative or conventional RT can complement other treatments such as radiofrequency ablation and transarterial chemoembolization. Combinations of systemic agents and RT can also be applied. This review discusses the optimal selection of RT as part of a multimodal approach for HCC.
Abstract 952: Protein kinase C theta (PKCθ) and c-Jun regulate proliferation through cyclin D1 in KIT-independent gastrointestinal stromal tumors
Authors: Wen-Bin Ou, Christopher D.M. Fletcher, George D. Demetri, Jonathan A. Fletcher
Journal: Cancer Research (2011)

Abstract Oncogenic KIT or PDGFRA receptor tyrosine kinase (RTK) mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GISTs), and the KIT/PDGFRA kinase inhibitor, imatinib, is standard of care for patients with metastatic GIST. However, most patients eventually develop clinical resistance to imatinib and other KIT/PDGFRA kinase inhibitors due to acquisition of secondary mutations in the KIT kinase domain, genomic amplification of KIT, or activation of alternate oncoproteins. Approximately 10% of KIT-dependent GIST metastases lose KIT expression at time of clinical progression during imatinib therapy. We performed whole transcriptome sequencing in KIT-expressing GIST vs. KIT-negative GIST, and thereby identified strong cyclin D1 expression only in KIT-negative GISTs. KIT-negative GISTs showed complete loss of the GIST biomarker, PKCθ, and restoration of PKCθ expression in these cells resulted in loss of Cyclin D1 expression. Lentivirus-mediated CCND1 (Cyclin D1) short hairpin RNA (shRNA) knockdown resulted in profound anti-proliferative and pro-apoptotic effects in KIT-negative GIST cell lines, and was associated with activation (dephosphorylation) of the tumor suppressor Rb and upregulation of the p27 CDK inhibitor. c-Jun expression levels paralleled the Cyclin D1 expression in the GIST lines, and c-Jun shRNA knockdown resulted in downregulation of cyclin D1 in the KIT-negative GIST lines, and was accompanied by profound anti-proliferative effects, including p27 upregulation, and pro-apoptotic effects as evidenced by PARP cleavage. By contrast, cyclin D1 and c-Jun silencing showed little anti-proliferative and pro-apoptotic effects in KIT-positive, KIT-dependent GIST lines. These findings show that cyclin D1 and c-Jun overexpression serve a crucial oncogenic role in KIT-independent GISTs, including those enabling clinical resistance to imatinib or sunitinib targeted kinase inhibitor therapies. Our findings also show that PKCθ downregulation and c-Jun upregulation coordinately enable cyclin D1 overexpression in KIT-independent GISTs. These novel findings highlight the relevance of c-Jun/cyclin D1 as novel therapeutic targets in GISTs that have lost KIT oncoprotein expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 952. doi:10.1158/1538-7445.AM2011-952
EARLY OUTCOMES WITH THE EVOLUT R REPOSITIONABLE SELF-EXPANDING TRANSCATHETER AORTIC VALVE IN THE UNITED STATES
Authors: Mathew Williams, James Slater, Muhamed Saric, Chad Hughes, Kevin Harrison, Susheel Kodali, Robert Kipperman, John Brown, G. Michael Deeb, Stanley Chetcuti, Jeffrey Popma
Journal: Journal of the American College of Cardiology (2016)
Abstract 2753: Change in tumor size by RECIST correlates linearly with progression-free and overall survival in phase I studies
Authors: Rajul K. Jain, J. Jack Lee, David Hong, Jing Gong, Aung Naing, Jennifer Wheler, Razelle Kurzrock
Journal: Cancer Research (2010)

Abstract INTRODUCTION: The Response Evaluation Criteria in Solid Tumors (RECIST) sets cutoff values for complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The efficacy of novel anticancer therapies is traditionally described as the percentage of patients with responses in each of these 4 categories. However, the boundary values defining these categories are arbitrarily set. We therefore study the relationship between change in tumor size by RECIST and both progression-free and overall survival (PFS and OS), and evaluate if boundaries exist or if alternatively the relationship is a continuous parameter. METHODS: We analyzed 468 participants on 24 phase I trials at MD Anderson from 10-1-04 to 6-30-08. Best response (best change by RECIST while on study) is correlated with PFS and OS by Somers' rank correlation. Kaplan-Meier survival curves of patients binned by response are also calculated (Table). Finally, a Cox model with no covariates is fit to the survival data, and analysis of best response versus the model residual is conducted. RESULTS: Rank order testing demonstrated a correlation between best response and survival (Dxy = −0.56 for PFS and −0.34 for OS). Kaplan-Meier analysis also demonstrated a strong correlation (p &amp;lt; 1×10−6, Table). Residual analysis of the Cox model (Methods) demonstrated a near linear relationship between changes in tumor size from −100% to +25% and survival; patients with a change of +25% or greater did uniformly poorly. Landmark analyses at multiple time points demonstrated identical trends regardless of the landmark. CONCLUSION: Given the linear relationship between best response to treatment and both PFS and OS, evaluating specific patient responses, for example through mechanisms such as waterfall plots, may be more valuable than aggregate CR, PR, SD, and PD rates. Additionally, the cutoffs for CR, PR, SD, and PD as defined by RECIST may not have special significance regarding survival in this population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2753.
Management of Tuberculosis in the United States
Authors: Peter M. Small, Paula I. Fujiwara
Journal: New England Journal of Medicine (2001)

In the 1980s, after decades of steadily declining rates of tuberculosis, ambitious plans were made to eliminate the disease in the United States. Despite these plans, the control of tuberculosis was neglected, resulting in a resurgence of the disease.1 This resurgence has reminded us that the overall goal of public health programs must be not merely the provision of health care for marginalized persons, but a systematic commitment to protect the health of the general public in a time of increasing globalization. Regrettably, these lessons have come at considerable costs, in terms of both individual health and health care budgets. . . .
Childhood Idiopathic Pulmonary Hemosiderosis
Authors: Charles Keller, Claire Langston
Journal: New England Journal of Medicine (2000)

Figure 1. A three-year-old girl with a declining growth rate and recurrent iron-deficiency anemia presented with a five-day history of nonproductive cough, fever, and anorexia. In association with an upper respiratory tract infection two weeks earlier, she had had hemoptysis involving 3-cm globs of bright red blood. Examination revealed a temperature of 39°C (102.2°F), a heart rate of 150 per minute, a respiratory rate of 60 per minute, and an oxygen saturation of 88 percent while she was breathing room air. Her breathing was labored, and breath sounds were decreased but coarse bilaterally. Chest radiographs revealed bilateral patchy alveolar infiltrates. . . .