tbuckley/cabot-search huggingface dataset:
Host conditioning and rejection monitoring in hepatocyte transplantation in humans
Authors: Kyle A. Soltys, Kentaro Setoyama, Edgar N. Tafaleng, Alejandro Soto Gutiérrez, Jason Fong, Ken Fukumitsu, Taichiro Nishikawa, Masaki Nagaya, Rachel Sada, Kimberly Haberman, Roberto Gramignoli, Kenneth Dorko, Veysel Tahan, Alexandra Dreyzin, Kevin Baskin, John J. Crowley, Mubina A. Quader, Melvin Deutsch, Chethan Ashokkumar, Benjamin L. Shneider, Robert H. Squires, Sarangarajan Ranganathan, Miguel Reyes-Mugica, Steven F. Dobrowolski, George Mazariegos, Rajavel Elango, Donna B. Stolz, Stephen C. Strom, Gerard Vockley, Jayanta Roy-Chowdhury, Marilia Cascalho, Chandan Guha, Rakesh Sindhi, Jeffrey L. Platt, Ira J. Fox
Journal: Journal of Hepatology (2016)
Current perceptions and practice patterns of oncologists in managing patients with gastric cancer.
Authors: J. C. Williamson
Journal: Journal of Clinical Oncology (2011)

60 Background: The management of gastric cancer is evolving with advances in the development of targeted therapies. This study was conducted to assess the current practice patterns in the management of patients with gastric cancer and identify gaps that may be addressed through educational initiatives. Methods: A survey composed of patient case vignettes designed to elicit practice pattern information on testing and treating patients with gastric cancer, and questions regarding attitudes towards gastric cancer management, was distributed electronically to medical oncologists currently practicing in the U.S. in March 2010; 126 were completed and included for analysis. Results: A lack of confidence was identified in appropriately staging, selecting appropriate treatment, or staying up-to-date with new therapies for gastric cancer with 44%-48% rating confidence as 7 or less on a 10 point confidence scale. Even more (66%) lack confidence in using molecular markers for treatment selection. Perceived levels of familiarity with these topics were rated similarly. In a case vignette of a patient with metastatic gastric cancer, most oncologists (84%) included HER2 testing to help inform treatment. However, a majority (54%) use HER2 testing for their patients with advanced gastric cancer infrequently (50% of the time or less). Also, almost half (44%) would not include H. pylori testing in an initial work-up for a patient whose biopsy confirmed gastric adenocarcinoma. In another case vignette, oncologists were more likely to select a surgery (61%) rather than a preoperative chemotherapy (39%) as supported by current evidence. Late detection is perceived as a significant barrier by 72% of oncologists in managing patients with gastric cancer. Conclusions: With the confidence and familiarity gaps of oncologists in managing patients with gastric cancer, the infrequent HER2 testing patterns, and lack of preoperative chemotherapy treatment, continued education in the latest evidence is needed. No significant financial relationships to disclose.
Abstract 5513: Employing a unique panel of breast cancer cellular lipids extracts in the development of a novel nanoliposome drug platform
Authors: Hanan M. Alharbi, Robert B. Campbell
Journal: Cancer Research (2015)

Abstract Breast cancer is a major cause of cancer death in women worldwide. Breast cancer is a heterogeneous disease characterized by variant pathological features, disparate responses to therapeutics, and substantial differences in patient's long-term survival. The use of drug delivery systems such as liposomes can favorably alter the pharmacokinetic and biodistribution profile of commonly used drugs used to treat breast cancer disease. An important feature of a drug delivery system is its ability to recognize and selectively target tumor cells with relatively high affinity when compared to healthy tissues. For this reason, the goal of this study was to develop a novel nanoliposome system that would target tumor cells to a significantly greater extent when compared to more conventional liposome systems. In this study, natural lipids extracted directly from breast cancer cells were used to prepare cellular lipid-extracted nanoliposomes (CLENs). The rationale is that an array of different lipids with a unique composition profile would represent a more relevant source of lipid material when compared to more traditional methods of liposome preparation. We therefore investigated whether the inclusion of extracted lipids derived from breast cancer cells would improve the selective uptake of liposomes by breast cancer cells, and related formulation features. To achieve these goals, three breast cancer cell lines were used (4T1, BT-20, and SK-BR-3), a normal breast fibroblast (CRL-2089), and an ovarian cancer cell line (SK-OV-3- used as a negative control). The size of CLENs fell within the size range of 120- 203 nm and possessed a negatively-charged liposome surface charge potential (ranging between -10.97 and -20.97 mV). The nanoliposomes were also non-toxic to cells within the concentration range evaluated (up to 1μmol). Furthermore, without exception, the cellular uptake of CLENs was greatest when the extracted material used to prepare CLENs was the same as the target cell from which the lipids were extracted. In addition, when the breast cancer cell lines (4T1, SK-BR-3 and BT-20) were used to prepare CLENs, SK-OV-3 and CRL-2089 cell lines took up CLENs to a lesser extent, suggesting a more selective and differential cellular uptake. In conclusion, the novel nanoliposome platform represents a promising drug delivery alternative to more conventional nano drug delivery systems. Additional formulation studies are currently underway. Citation Format: Hanan M. Alharbi, Robert B. Campbell. Employing a unique panel of breast cancer cellular lipids extracts in the development of a novel nanoliposome drug platform. [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 5513. doi:10.1158/1538-7445.AM2015-5513
First Line Antiviral Therapy Significantly Improves Survival of Patients with Acute, Chronic and Smoldering ATL: a Worldwide Meta-Analysis.
Authors: Ali Bazarbachi, Yves Plumelle, Juan Carlos Ramos, Patricia Tortevoye, Zaher Otrock, Graham Taylor, Antoine Gessain, William J Harrington, Gérard Panelatti, Olivier Hermine
Journal: Blood (2009)
Age-Related Risk of Non-Relapse Mortality Associated with Acute Graft-Versus-Host Disease.
Authors: Takahiro Fukuda, Yukiko Iisaka, Fusako Ohara, Atsushi Fujieda, Satoshi Yamasaki, Sung-Won Kim, Shin-ichiro Mori, Ryuji Tanosaki, Yuji Heike, Atsushi Makimoto, Kensei Tobinai, Yoichi Takaue
Journal: Blood (2006)
Abstract 815: DTX1 is an epigenetically regulated tumor suppressor gene discovered by integrative analysis of epigenetic and transcriptional alterations in HNSCC
Authors: Daria A. Gaykalova, Veronika Zizkova, Ilse Tiscareno, Yingying Wei, Rajita Vatapalli, Patrick T. Hennessey, Julie Ahn, Ludmila V. Danilova, Zubair Khan, Justin A. Bishop, Wayne M. Koch, William H. Westra, Michael F. Ochs, Joseph A. Califano
Journal: Cancer Research (2015)

Abstract Half a million new cases of Head and Neck Squamous Cell Carcinoma (HNSCC) are diagnosed annually worldwide. Given the advanced stage at diagnosis, 5 year survival after initial diagnosis is only 50% for HNSCC patients despite the current therapeutic strategies. Recently, high throughput technologies have accelerated the genome-wide characterization of HNSCC, but given the high sensitivity of this methodology, these data require careful evaluation. To improve the detection of cancer-related changes in HNSCC we applied outlier statistics to high throughput DNA methylation and gene expression data, and identified 76 top-scoring candidate proto-oncogenes and tumor suppressor genes with significantly changed expression in tumors compared to normal tissues. We identified epigenetically regulated candidates with potential role in HNSCC by selecting genes with strong negative correlation between gene expression and DNA methylation of their promoters. Differential expression and methylation of selected candidates were confirmed with assays on an independent HNSCC cohort and on public domain high throughput data on TCGA-HNSCC cohort (The Cancer Genome Atlas). We further performed functional evaluation of a lead candidate - DTX1 and demonstrated that DTX1 is a negative regulator of cell migration. We confirmed that epigenetic-dependent downregulation of DTX1 enhanced invasiveness of head and neck cancer cells. Outlier analysis integrated with high throughput expression and methylation can be used to identify an epigenetically- regulated tumor suppressor genes, including DTX1. Citation Format: Daria A. Gaykalova, Veronika Zizkova, Ilse Tiscareno, Yingying Wei, Rajita Vatapalli, Patrick T. Hennessey, Julie Ahn, Ludmila V. Danilova, Zubair Khan, Justin A. Bishop, Wayne M. Koch, William H. Westra, Michael F. Ochs, Joseph A. Califano. DTX1 is an epigenetically regulated tumor suppressor gene discovered by integrative analysis of epigenetic and transcriptional alterations in HNSCC. [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 815. doi:10.1158/1538-7445.AM2015-815
Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non–Small Cell Lung Cancer
Authors: Valsamo Anagnostou, Kellie N. Smith, Patrick M. Forde, Noushin Niknafs, Rohit Bhattacharya, James White, Theresa Zhang, Vilmos Adleff, Jillian Phallen, Neha Wali, Carolyn Hruban, Violeta B. Guthrie, Kristen Rodgers, Jarushka Naidoo, Hyunseok Kang, William Sharfman, Christos Georgiades, Franco Verde, Peter Illei, Qing Kay Li, Edward Gabrielson, Malcolm V. Brock, Cynthia A. Zahnow, Stephen B. Baylin, Robert B. Scharpf, Julie R. Brahmer, Rachel Karchin, Drew M. Pardoll, Victor E. Velculescu
Journal: Cancer Discovery (2016)

Abstract Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non–small cell lung cancer after initial response to immune checkpoint blockade with anti–PD-1 or anti–PD-1/anti–CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens. Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264–76. ©2017 AACR. See related commentary by Yang, p. 250. This article is highlighted in the In This Issue feature, p. 235
652. Antibody Epitopes in Mice Immune to Lethal Influenza Virus
Authors: Eric A. Weaver
Journal: Molecular Therapy (2015)

Vaccination is a key factor in the control and prevention of influenza virus (flu). Every year the Center for Disease Control and the World Health Organization make an educated guess as to which flu strain will be circulating in the next season. The predicted strains are often mismatched to the actual emerging strain. This happens to be the case with the 2014-2015 flu vaccine, where researchers have discovered that the emerging strain has "drifted" and is antigenically distinct from the flu vaccine formulation. In this study we seek to identify the immunological epitopes that are responsible for protection against the flu. Groups of mice were infected with sublethal doses of flu virus. The mice showed typical signs of illness, but recovered from the flu infection. The mice were then challenged with a lethal dose of flu virus. The mice were completely protected and showed no signs of disease. The serum from these naturally immunized mice was screened for linear B-cell epitopes using a peptide microarray consisting of 15-mer peptides overlapping by 14 amino acids. The microarray represented 3 divergent H3 flu strains, A/Aichi/2/68, A/Mississippi/1/85 and A/Texas/1/77. We found 26 antibody binding epitopes induced by the 3 flu strains. Many of the epitopes were shared between the 3 flu strains, however all strains induced antibodies that were strain-specific to unique epitopes. This study describes the protective "immunosignatures" against three divergent flu strains. Data from this study can be used to evaluate the potential efficacy of new flu vaccines or aid in the production of better cross-protective vaccine antigens.
A phase II study of S-1 in patients with metastatic pancreatic cancer
Authors: J. Furuse, T. Okusaka, A. Funakoshi, N. Boku, K. Yamao, S. Ohkawa, H. Saito
Journal: Journal of Clinical Oncology (2005)

4104 Background: The purpose of this study was to determine the efficacy and toxicity of S-1 in patients with metastatic pancreatic cancer. S-1, an oral anticancer agent, contains tegafur (FT: a prodrug of 5-fluorouracil), 5-chloro-2,4-dihydroxypyridine (CDHP: a dehydropyrimidine dehydrogenase inhibitor), and potassium oxonate (Oxo: an orotate phosphoribosyl transferase inhibitor) at a molar ratio of FT:CDHP:Oxo = 1:0.4:1. Methods: Patients with histologically or cytologically confirmed, bidimensionally measurable metastatic pancreatic adenocarcinoma not amenable to surgery or radiotherapy were eligible for the study. Other eligibility criteria included a Karnofsky performance status of 80 to 100%; an age of 20 to 74 years; adequate hematological, renal and liver functions; no prior chemotherapy; and written informed consent. S-1 was administered orally (40 mg/m2) b.i.d. for 28 consecutive days, repeated every 6 weeks. Patients continued to receive additional courses of S-1 until disease progression or the appearance of unacceptable toxicity. Results: Forty-one patients from seven institutions were enrolled between January 2003 and April 2004. One patient deteriorated before receiving treatment and was excluded from further analysis. Out of the 40 eligible patients, 15 patients had partial responses, for an objective response rate of 37.5% (95% c.i.: 22.7 - 54.2%); 11 patients had no change, 13 had progressive diseases, and the final patient was not evaluated. The median survival time was 8.8 months (95% c.i.: 7.5 - 10.8 months). A clinical benefit response was achieved in four of the ten evaluable patients. The main grade 3 - 4 toxicities were neutropenia (12.5%), anorexia (12.5%), diarrhea (7.5%) and nausea (7.5%). Other grade 3 - 4 toxicities, like vomiting, disseminated intravascular coagulation, colitis, hypotension, jaundice and liver dysfunctions, were less frequent. Conclusions: S-1 is active and well tolerated as a single agent chemotherapy in patients with metastatic pancreatic cancer. A prospective randomized trials evaluating S-1 monotherapy is warranted. No significant financial relationships to disclose.
Encapsulation and controlled release of chemotherapeutic drugs by novel γ-cyclodextrin derived carriers.
Authors: F. D. Arditti, D. Xu, D. Liu, D. Gourevich, Y. Medan, J. Gnaim, S. Cochran, A. Meltzer
Journal: Journal of Clinical Oncology (2011)

e13062 Background: Cyclodextrins (CDs) have the ability to carry drugs in their cavities. CD derivatives conjugated with a targeting moiety are expected to be drug carriers capable of targeting cancer cells with high specificity. In order to obtain effective drug carrier complexes, efficient methods for increasing the drug inclusion ability of the CD cavities are required. Methods: Nano-Carriers were prepared by chemical modification of γ-Cyclodextrin (γ-CD) and characterized using spectroscopic and chromatographic methods. We evaluated the effects of Doxorubicin (DOX) on cancer cell viability and drug uptake, under different in-vitro conditions: drug concentration, exposure time, exposure temperature, carrier types, drug/carrier ratio, and cell types. Human KB (ovarian carcinoma) or MCF-7 (breast carcinoma) cells were seeded into 96 well plates and treated with hyperthermia (41oC-55oC) for 2-10 minutes. Cell viability was determined by the MTT assay. To determine the intracellular drug uptake, tumor cells were seeded into 24 well plates and following incubation with DOX at different experimental conditions, we determined the DOX content of the exposed cells by HPLC and fluorimeter. Results: Chemical modifications of the native γCD's structure led to a more efficient encapsulation of DOX. γ-CD nano-carriers showed higher encapsulation ability than a-CD and b-CD based carriers. The cytotoxicity of DOX was significantly reduced by molecular encapsulation with our nano-carriers as indicated by the reduced intracellular DOX and the increased cell viability. The novel carriers induced a reduction of up to 97% in the uptake of DOX into KB and MCF-7 cells at 37oC. The degree of encapsulation and drug deactivation was dependent on drug concentration and carrier/drug molar ratio. Hyperthermia (41-45oC) clearly increased the intracellular drug uptake and therefore the potency of the encapsulated drug as compared to the effect at 37oC. Conclusions: This study indicates that γ-CD based nano-carriers may be a promising delivery system for specific targeting of chemotherapeutic drugs by their controlled release on the tumor site. This work is supported by an EU FP7 Industrial Academia Partnership Pathway IAPP.
463. Safety and Biodistribution Study of rAAV2tYF-CB-hRS1 in RS1-deficient Mice
Authors: Guo-jie Ye, Thomas Conlon, Kirsten Erger, Peter Sonnentag, Alok K. Sharma, Niraj Tripathi Tripathi, Kellie Howard, David R. Knop, Jeffrey D. Chulay
Journal: Molecular Therapy (2015)

AGTC is developing a recombinant adeno-associated virus (rAAV) vector expressing retinoschisin (RS1) for treatment of humans with X-linked retinoschisis (XLRS). Here we report results of a toxicology and biodistribution study of this vector administered by intravitreal injection in RS1-deficient mice. Three groups of male RS1-deficient mice (n=20 per group) received an intravitreal injection in one eye of vehicle or rAAV2tYF-CB-hRS1 at one of two dose levels (1 × 10^9 or 4 × 10^9 vg/eye). Half of the animals were sacrificed 30 days after vector administration and the remaining animals were sacrificed 90 days after vector administration. At each sacrifice time point half of the animals were used for evaluation of safety and half were used for evaluation of biodistribution. In the group scheduled for sacrifice on Day 90, an ophthalmic examination was conducted during week 4 and during the week prior to sacrifice. Blood for hematology (hemoglobin, hematocrit, red cell count, platelet count and white cell count with differential) and clinical chemistry (alanine aminotransferase, blood urea nitrogen, albumin and globulin) was collected at sacrifice. Blood for DNA PCR was collected 7 days after injection and at sacrifice. Serum for measurement of antibodies to AAV and RS1 was collected at the 90 day sacrifice. At necropsy, samples of eyes, brain, liver, spleen, heart, lung, kidney, parotid gland and testes were collected for histopathology and DNA PCR. The intravitreal injection procedure was well tolerated in all groups. Minimally to mildly higher white blood cell and absolute lymphocyte and monocyte counts on Day 90 in two animals in the low dose vector group were suggestive of mild inflammation. There were no other intergroup differences in hematology or clinical chemistry analyses and no test article-related gross necropsy observations. Microscopic pathology results demonstrated minimal to slight mononuclear cell infiltrates in the injected eyes in both vector-treated groups. At the Day 90 sacrifice there was a decrease in the severity of splitting/disorganization of the inner nuclear layer of the retina in high-dose vector-treated animals. Immunohistochemistry studies showed minimal to moderate RS1 labelling of the retina in the treated eye in both vector-treated groups. Intravitreal administration of rAAV2tYF-CB-hRS1 in RS1-deficient mice was well tolerated with minimal to slight ocular inflammatory cells detected by histopathology. RS1 expression demonstrated by immunohistochemistry was associated with decreased severity of splitting/disorganization of the inner nuclear layer of the retina at the higher dose level. These results support the use of rAAV2tYF-CB-hRS1 in clinical studies in patients with XLRS.
212. Of States and Fates: Predicting T-Cell Immunity By the Numbers
Authors: Colleen M. O'Connor, Sonny O. Ang, Jianrong Dong, Sourindra N. Maiti, Luay Nakhleh, Laurence J.N. Cooper
Journal: Molecular Therapy (2015)

The immune system is a complex network of checks and balances in constant flux. Quantitative characterization of the system dynamics, sampled via constituent components such as T cells, combined with mathematical modeling enabled us to obtain "statistical pattern recognition" of immune states and transitions over time. Here we show a statistical framework to characterize immune states for adoptive immunotherapy using serial infusions of activated polyclonal T cells into companion canines diagnosed with B-cell non-Hodgkin Lymphoma (NHL) post CHOP chemotherapy regimen as a model for human disease. We applied multiplexed gene profiling techniques to assess changes in gene expression data from 10 companion canine patient clinical samples and gene regulatory networks (GRN) information to build an "immune landscape" that predicts immune states, state transitions, and plasticity for immunomodulation ("reprogrammability") over the course of immunotherapy regimens. The potency of immune modulation and immune surveillance, two critical parameters of efficacy through inferred state transitions, were evaluated by measuring distortions and shifts in the immune landscape of canine patients undergoing treatment through system dynamics, Adjusted Rand Index, Pearson Correlation, and ANOVA analyses. Adjust Rand Index validated hierarchical clustering analyses. Pearson correlations isolated genes that were up- or down-regulated with regard to single genes of interest. ANOVA analyses indicated gene expression difference between temporal samples. Applying such analyses to adoptive T-cell immunotherapy, allowed us to examine clinical/tumor remissions through the lens of immune state transitions, affording real-time improvements to therapeutic regimens. In developing a formal framework to capture the effects of molecular signatures and GRN over time to describe distinct immune states, we enhanced the clinical cancer immunologist's analytical arsenal (with a measuring tool/sensor) and helped bridge the gap between bench and bedside.
The Plk-1 Inhibitor BI 2536 Counteracts the Growth of Neoplastic Mast Cells and Synergizes with the KIT D816V-Targeting Drug Midostaurin (PKC412) in Producing Growth-Inhibition.
Authors: Veronika Ferenc, Karoline V. Gleixner, Alexander Gruze, Michael Kneidinger, Christian Baumgartner, Matthias Mayerhofer, Winfried F. Pickl, Christian Sillaber, Peter Valent
Journal: Blood (2007)