tbuckley/cabot-search huggingface dataset:
Abstract 3989: Ovarian cancer protein biomarker identification from the tumor tissue microenvironment
Authors: Ebony R. Hoskins, Brian Hood, Tom Conrads, Robert P. Edwards
Journal: Cancer Research (2010)

Abstract Objective: In order to circumvent the challenges associated with serum-based biomarker discovery for ovarian cancer screening development, we utilized a novel sampling strategy to harvest shed and secreted proteins from tissue interstitial fluid (TIF) from the ovarian tumor tissue microenvironment. The motivating hypothesis is TIF, the proximal fluid that bathes ovarian cancer cells and stroma, is rich in cancer-specific proteins that are readily identifiable by mass spectrometry (MS)-based proteomics. Materials: Ovarian tumor tissue and ascites were collected within 30 minutes of removal from the patient, at the time of debulking surgery. Samples used in the analysis were from four chemotherapy naïve patients with pathology-proven papillary serous ovarian cancer. We implemented a standardized sampling strategy, involving incubation of tumor tissue in saline for 1 hour immediately following resection resulting in protein rich TIF. The TIF and ascites samples were analyzed by MS for protein sequence identification and relative quantitation. Results: Over 2700 total proteins were identified in TIF across all patient samples, while ascitic fluid contained over 2000 proteins across all patient samples. 13 proteins were identified in all TIF samples that were 3-fold or greater in quantity compared to ascitic fluid samples. For comparison, 14 proteins that were 3-fold greater in ascitic fluid compared to TIF, was also identified. Interestingly, these select proteins from two microenvironments had contrasting function and location. TIF samples contained largely intracellular proteins, which are secreted and/or shed while ascitic fluid sample contained extracellular proteins, similar to serum, thus confirming the utility of TIF representing the tumor microenvironment, see figure. The results demonstrate the ability to readily identify hundreds of proteins in TIF, which are at higher abundance compared to those, identified in ascitic fluid from the same patients. Conclusions: We developed a standard workflow for the discovery of candidate biomarkers from the ovarian cancer tissue microenvironment. The TIF proteome contains more lower abundant and cancer specific proteins compared to ascitic fluid. We are prospectively validating candidate biomarkers from this microenvironment in patient serum by western blot analysis and immunohistochemistry. Ultimately we will expand our standard protocol to a cohort of patients with likely early stage cancers in order to translate to a serum-based screening test. 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 3989.
Some Clinical Aspects of the Normal Electroencephalogram in Epilepsy
Authors: John A. Abbott, Robert S. Schwab
Journal: New England Journal of Medicine (1948)

WHAT does it mean if the electroencephalogram of an epileptic patient is normal between seizures? On the one hand, the physician may have been led to believe that an abnormal electroencephalogram is highly characteristic of epilepsy. On the other hand, if he regularly refers his epileptic patients for electroencephalographic study, he forms the impression that, for a goodly portion of them, the tracings, at least at the time of examination, which is almost always done between seizures, are described as normal. This may be true even for patients examined when not taking anticonvulsive medicine.Statistically, a review of the literature . . .
P5-05-01: Vitamin D Status in Newly Diagnosed Breast Cancer Patients Inversely Correlates with Tumor Size and Moderately Correlates with Outcome.
Authors: S Hatse, D Lambrechts, M Verstuyf, A Smeets, B Brouwers, T Vandorpe, O Brouckaert, G Peuteman, A Laenen, C Kriebitzsch, A-S Dieudonné, R Paridaens, P Neven, M-R Christiaens, R Bouillon, H Wildiers
Journal: Cancer Research (2011)

Abstract Aims: To study the impact of Vitamin D (VitD) status and genetic variability in key VitD regulatory genes on patient and breast tumor characteristics, and on breast cancer related outcome. Methods: We examined serum 25-hydroxyvitamin D3 (25OHD) levels in a cohort of 1800 early breast cancer patients treated in Leuven between 2003 and 2010. Serum was collected at diagnosis for all patients; germline DNA from peripheral blood was also available for the majority of them. Serum 25OHD was measured by radioimmunoassay, and single nucleotide polymorphisms (SNP's) were assessed by Sequenom. Statistical analysis was done by multivariable regression models including age, BMI and season and by a Cox proportional hazard model for analysis of disease-specific survival and disease-free interval. Results: Lower 25OHD serum levels were significantly correlated with larger tumor size (0,4 ng/ml decrease in 25OHD per 1 cm increment in tumor size, p=0.0063) but not with lymph node invasion, estrogen receptor and HER2 status, or tumor grade. Serum 25ODH level was significantly affected by genotypes of rs10741657 and rs1993116 (25-hydroxylase; CYP2R1) and of rs222040, rs7041 and rs4588 (D-binding protein; DBP), yet its observed association with tumor size did not differ between distinct genotypes. Although not statistically significant, patients with higher 25OHD levels tended to have slightly improved survival. Also, a significant increase in relapse risk became apparent after 3 years for patients with 25OHD&amp;lt;30 ng/mL. Conclusion: Vitamin D Level in breast cancer patients inversely correlates with tumor size and moderately correlates with outcome. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-05-01.
Toxicity and survival by sex in patients with advanced non-small cell lung carcinoma (NSCLC) on modern Southwest Oncology Group (SWOG) trials
Authors: K. S. Albain, J. Unger, C. C. Gotay, A. M. Davies, M. Edelman, R. S. Herbst, K. Kelly, S. Williamson, A. J. Wozniak, D. R. Gandara
Journal: Journal of Clinical Oncology (2007)

7549 Background: The older lung cancer clinical trial literature suggests that women have better survival than men, possibly due to sex-related changes in drug metabolism based on estrogen levels. A detailed analysis of this issue has not been conducted in the modern chemotherapy era. Thus, the SWOG Lung Committee analyzed outcomes in recent trials, with the hypotheses that either sex-specific toxicity profiles and/or age (as a surrogate for estrogen level) may explain outcome differences. Methods: A data base of eligible patients with complete toxicity data enrolled on 6 consecutive SWOG phase II or III advanced stage NSCLC trials was formed. Treatment was platin-based, plus either gemcitabine, vinorelbine, or a taxane. Toxicities were categorized by type, number and grade with alpha=0.01 (multiple comparisons). Kaplan-Meier survival estimates and Cox multivariate models were computed (alpha=0.05), plus exploratory age by sex interaction analyses. Results: There were1,324 patients (36% women). No difference by sex was found in either maximum toxicity grade, number of toxicities, or specific toxicity types, except for marginally more severe or worse metabolic (12% vs 9%, p=0.02) and life- threatening or worse neurologic (2% vs 1%, p=0.04) toxicities in women. Median, 1- and 2-year survivals were significantly better for women (11 mos, 46%, 19%) vs men (8 mos, 35%, 13%). After adjustment for prognostic factors, women had 14% reduced risk of death (HR 0.86; 95% CI: 0.75, 0.98; p=0.02). The exploratory age by sex cutpoint analysis found women age 60 or older had better survival (11 vs 8 mos, p=0.006), whereas survival was similar by sex for those under age 60. No other age cutpoint was significant. Conclusions: Women with advanced NSCLC survive longer than men after adjustment for other prognostic factors in the modern chemotherapy era. There was no difference in toxicity profile by sex to explain this finding. The survival benefit for women appeared limited to patients age 60 and older, suggesting that estrogen levels may interact with the efficacy of current chemotherapy prescriptions or other as yet undefined factors. This finding, if validated, could be potentially exploited in designing new therapies. No significant financial relationships to disclose.
Abstract 2580: Single-chain antibody based immunotoxins targeting Her2/neu: design optimization and impact of affinity on antitumor effects
Authors: Yu Cao, James D. Marks, Walter N. Hittelman, Gregory P. Adams, Heidi H. Simmons, Lawrence H. Cheung, Michael G. Rosenblum
Journal: Cancer Research (2010)

Abstract Recombinant immunotoxins, consisting of single-chain antibodies (scFv) genetically fused to polypeptide toxins represent potentially effective candidates for cancer therapeutics. Antibody affinity, internalization rates and intracellular fate of molecular constructs play critical roles in the eventual cytotoxic activities of these constructs although these events related to the design characteristics of fusion constructs have not been comprehensively explored. We evaluated the relationship between affinity of various anti-Her2 scFv fused to recombinant gelonin (rGel) and its effect on cytotoxic activity. A series of rGel-based immunotoxins were created from the human anti-Her2/neu scFv C6.5 and various affinity mutants (designated ML3.9, MH3B1 and B1D3-in increasing affinity order). The affinities of the scFv ranged from 10−8 to 10−11 M and the rGel fusion toxins retained the affinities of the scFv from which they were derived. Against BT474M1 human breast tumor cells, the immunotoxins demonstrated IC50 values of 18.9, 10.9, 3.9 and 1.2nM for the C6.5, ML3.9, MH3B1 and B1D3 based immunotoxins respectively. Targeting indices were highest for the B1D3/rGel construct with the highest affinity. The internalization rate of the fusion constructs into target cells directly correlated with the cytotoxic effects. Competition studies showed that addition of soluble Her2/neu extracellular domain (ECD) as the competitive factor significantly reduced the cytotoxic effects of the highest-affinity fusion construct (B1D3/rGel) while the lower-affinity constructs showed lesser impact of Her2/neu ECD addition on the cytotoxic effect. Animal model efficacy studies against several Her2/neu overexpressing tumors are ongoing but appear to suggest that the construct containing the highest affinity antibody was comparatively less effective in vivo than constructs containing antibodies of intermediate affinity. These studies suggest that human MH3B1/rGel fusion construct with an apparent affinity of 10−10 M displayed an overall optimal cell-killing activity to several Her2/neu positive cancer cells especially in the presence of free Her2/neu ECD. These findings demonstrate the necessity to consider antibody affinity in design considerations for targeted therapeutics. In addition, the potential impact of soluble target or truncated receptor molecules in the environment need to be considered when evaluating the efficacy of targeted therapeutics. Research Conducted, in part, by the Clayton Foundation for Research. 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 2580.
Molecular Pathways: Breaking the Epithelial Cancer Barrier for Chimeric Antigen Receptor and T-cell Receptor Gene Therapy
Authors: Christian S. Hinrichs
Journal: Clinical Cancer Research (2016)

Abstract Adoptive transfer of T cells genetically engineered to express a tumor-targeting chimeric antigen receptor (CAR) or T-cell receptor (TCR) can mediate cancer regression in some patients. CARs are synthetic single-chain proteins that use antibody domains to target cell surface antigens. TCRs are natural heterodimeric proteins that can target intracellular antigens through recognition of peptides bound to human leukocyte antigens. CARs have shown promise in B-cell malignancies and TCRs in melanoma, but neither approach has achieved clear success in an epithelial cancer. Treatment of epithelial cancers may be particularly challenging because of a paucity of target antigens expressed by carcinomas and not by important healthy tissues. In addition, epithelial cancers may be protected by inhibitory ligands and soluble factors in the tumor microenvironment. One strategy to overcome these negative regulators is to modulate expression of T-cell genes to enhance intrinsic T-cell function. Programmable nucleases, which can suppress inhibitory genes, and inducible gene expression systems, which can enhance stimulatory genes, are entering clinical testing. Other work is delineating whether control of genes for immune checkpoint receptors (e.g., PDCD1, CTLA4) and cytokine and TCR signaling regulators (e.g., CBLB, CISH, IL12, IL15) can increase the antitumor activity of therapeutic T cells. Clin Cancer Res; 22(7); 1559–64. ©2016 AACR.
Abstract 2451: A novel humanized anti-CD40 RabMAb exhibits potent efficacy in preclinical models
Authors: Yongke Zhang, Jihong Dai, Yaohuang Ke, Wenjun Li, Qiu Yu, Mingzhen Li, Lifeng Feng, Zhiqiang An, Guo-Liang Yu, Weimin Zhu
Journal: Cancer Research (2010)

Abstract Monoclonal antibodies directed against B cell antigens have shown clinical benefits to hematologic malignancies. CD40 is a member of the TNFR superfamily and is a target for potential treatment of B cell lineage hematological malignancies as well as certain carcinomas. To date, majority of the therapeutic monoclonal antibodies are of murine origin. To evaluate the therapeutic potential of rabbit monoclonal antibodies (RabMAb®), we generated functional RabMAbs against CD40 using Epitomics' RabMAb® platform. Here we report the characterization of EPI0050, a novel humanized anti-CD40 rabbit monoclonal antibody. EPI0050 specifically recognizes the CD40 ligand binding domain and selectively blocks the ligand binding to CD40. EPI0050 itself exhibits modest agonist effects as shown in the up-regulation of CD80, CD83 and CD86 in differentiated dendritic cells and direct inhibition of CD40 positive malignant B cells. EPI0050 bound CD40 strongly without much internalization, which conferred to a potent ADCC effect in vitro. In an established preclinical Ramos lymphoma model, EPI0050 significantly inhibited tumor growth with a long-term stabilization of the tumor post dosing as compared with Rituximab and another anti-CD40 antibody. EPI0050 was also able to regress established rebound tumors post Rituximab treatment. More animal models and MOA are being explored for EPI0050. Both in vitro and in vivo results support the preclinical and clinical development of EPI0050 as a bio-better tumor therapy. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 2451.
Immunologic Components of Hypersensitivity Reactions to Cromolyn Sodium
Authors: Albert L. Sheffer, Ross E. Rocklin, Edward J. Goetzl
Journal: New England Journal of Medicine (1975)

Manifestations of cellular and humoral hypersensitivity to cromolyn sodium were sought in six asthmatic patients suspected of having acute (three cases) or subacute (three cases) adverse reactions to cromolyn inhalation. Lymphocytes from all patients produced migration inhibition factor (MIF), and those from four patients incorporated increased amounts of 3H-thymidine in response to cromolyn in vitro. Lymphocytes from four of nine cromolyn-tolerant asthmatics demonstrated increased 3H-thymidine incorporation but none showed MIF production, whereas lymphocytes from normal subjects failed to react to cromolyn in either assay. Two of three patients with subacute reactions had increased serum binding of 3H-cromoglycate which was attributable to the IgG fraction. Thus although patients tolerating cromolyn therapy may demonstrate lymphocyte transformation in vitro, only those with clinically apparent adverse reactions produce lymphocyte MIF or possess serum-binding activity for the drug. (N Engl J Med 293:1220–1224, 1975)
Adolescent and Young Adult Oncology
Authors: Peter F. Coccia, Jessica Altman, Smita Bhatia, Scott C. Borinstein, Joseph Flynn, Suzanne George, Robert Goldsby, Robert Hayashi, Mary S. Huang, Rebecca H. Johnson, Lynda Kwon Beaupin, Michael P. Link, Kevin C. Oeffinger, Kathleen M. Orr, Alberto S. Pappo, Damon Reed, Holly L. Spraker, Deborah A. Thomas, Margaret von Mehren, Daniel S. Wechsler, Kimberly F. Whelan, Bradley J. Zebrack, Hema Sundar, Dorothy A. Shead
Journal: Journal of the National Comprehensive Cancer Network (2012)

Cancer is the leading cause of death among the adolescent and young adult (AYA) population, excluding homicide, suicide, or unintentional injury. AYA patients should be managed by a multidisciplinary team of health care professionals who are well-versed in the specific developmental issues relevant to this patient population. The recommendations for age-appropriate care outlined in these NCCN Guidelines include psychosocial assessment, a discussion of infertility risks associated with treatment and options for fertility preservation, genetic and familial risk assessment for all patients after diagnosis, screening and monitoring of late effects in AYA cancer survivors after successful completion of therapy, and palliative care and end-of-life considerations for patients for whom curative therapy fails.
Rupturing Aneurysm of the Posterior Inferior Cerebellar Artery
Authors: Z Stockinger
Journal: New England Journal of Medicine (1998)

Figure 1. Intracranial aneurysms often have catastrophic effects but are rarely seen at the moment of rupture. A 35-year-old woman with no previous neurologic history presented with severe headache and photophobia, with no localizing neurologic findings. Computed tomography of the brain without contrast medium revealed diffuse subarachnoid bleeding. Cerebral angiography was performed. Injection of the left vertebral artery revealed an aneurysm at the junction of this artery and the posterior inferior cerebellar artery (Panel A). Unfortunately, the aneurysm ruptured during arteriography (Panels B and C). The patient's condition deteriorated rapidly and could not be stabilized, and she died a few . . .
Abstract B34: Inhibition of lung cancer cell invasion by siRNAs delivered by cell-specific aptamers
Authors: Wei-Ya Wang, Wei-Yun Lai, Tzu-Hung Hsiao, Konan Peck
Journal: Clinical Cancer Research (2010)

Abstract Cell-specific delivery of therapeutic agents and targeted therapy are highly pursued topics in medical researches for treating cancers and other diseases. We aim to develop technologies enabling delivery of siRNA to cancer cells to retard or inhibit metastasis of the cancer cells with minimal adverse effects to normal cells. As long as the cancer cells do not invade and are confined, they can be eradicated by means such as surgical resection or radiation therapy. Oligonucleotides of different sequences can fold into different conformations to bind to their targets with high specificity and affinity. These structured oligonucleotides are known as aptamers. We have identified new surface markers which prevalently expressed on lung cancer cells. By identifying functional aptamers against the surface marker proteins, we show that once the marker protein is activated by the aptamer, the surface marker protein/aptamer complex internalizes into the lung cancer cells. Therefore, it is feasible to employ the functional aptamer as a carrier to deliver siRNA into cancer cells to silence the expression of genes associated with metastasis. The aptamer-siRNA chimera is formed by chemical synthesis and bioconjguation methods. The chimera consists of an aptamer, which delivers therapeutic siRNA specifically to cancer cells but not normal cells to knock down the target genes that are pivotal in signaling pathways associated with the events of metastasis cascade. The effective knockdown of the metastasis associated genes by the nucleic acid chimera is verified by employing a series of invasion assays such as wound healing, Matrigel, filopodia formation, and others. The in vitro experimental results show that the aptamer-siRNA chimera is able to deliver therapeutics to specific target cells and silence the expression of the target genes in the cells. The in vitro experimental results are further verified by in vivo xenograft mouse model with immunohistochemistry examination, tumor size measurement, and circulating tumor cell detection by use of Alu sequence as the marker. By using lung cancer as a model, the data indicate that it is durable to employ the aptamer-siRNA chimera for cell- and target-specific therapy of cancer metastasis. Citation Information: Clin Cancer Res 2010;16(14 Suppl):B34.
Abstract 3544: Role of tumor-infiltrating gammadelta T lymphocytes in breast cancer
Authors: Chunling Ma, Qunyuan Zhang, Jian Ye, Yanping Zhang, Eric Wevers, Theresa Schwartz, Pamela Hunborg, Mark A. Vavares, Daniel F. Hoft, Eddy C. Hsueh, Guangyong Peng
Journal: Cancer Research (2012)

Abstract Breast cancer is the second leading cause of cancer-related deaths in women worldwide. Increasing evidence suggests that immunotherapy is a promising strategy for treating breast cancer, and understanding of the roles of different subtypes of tumor-infiltrating lymphocytes (TILs) in the tumor immunosuppressive microenvironment may be essential to cancer treatment and elimination. We recently discovered that enriched gammadelta1 T cell populations in the breast cancer TILs can suppress naïve and effector T cell responses and block the maturation and activities of dendritic cells (DC). In order to investigate the functional role of tumor-infiltrating gammadelta T cells in the immune pathogenesis of breast cancer, we further performed immunohistochemical staining to analyze gammadelta T cells, as well as CD4+, CD8+, IL-17-producing and FoxP3+ T cells in 50 freshly frozen tumor tissues from different stages of identified primary breast cancer and paired normal breast tissues. We found that the numbers of gammadelta T cells among tumor tissues were significantly increased compared with those in normal breast tissues in breast cancer patients. High numbers of gammadelta T cells were present in the patients with high tumor grades and lymph node metastases. Importantly, the patients with a high proportion of gammadelta T cells showed poorer survival rates in comparison to those with a low proportion of gammadelta T cells in breast cancer. These results indicate that gammadelta T cells constitute a dominant population existing in the breast tumor suppressive microenvironment that is negatively associated with clinical outcome, which may be an important cancer immunotherapeutic target for breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3544. doi:1538-7445.AM2012-3544