tbuckley/cabot-search huggingface dataset:
Phase II/Pharmacodynamic Trial of Dose-Intensive, Weekly Parenteral Hydroxyurea and Fluorouracil Administered With Interferon Alfa-2a in Patients With Refractory Malignancies of the Gastrointestinal Tract
Authors: Scott Wadler, Snehal Damle, Hilda Haynes, Ron Kaleya, Richard Schechner, Robert Berkenblit, Robert D. Ladner, Anthony Murgo
Journal: Journal of Clinical Oncology (1999)

PURPOSE: Combined depletion of pyrimidine and purine DNA precursors has resulted in therapeutic synergism in vitro. The aims of the current study were to test this strategy in patients with refractory tumors and to assess its effects on selected nucleotide pools. PATIENTS AND METHODS: A single-institution phase II trial was initiated in patients with advanced carcinomas of the stomach and pancreas. Patients had measurable disease and had no prior chemotherapy except adjuvant fluorouracil (5FU) or gemcitabine. 5FU was administered by CADD + pump at 2.6 g/m 2 intravenously by 24-hour infusion on days 1, 8, 15, 22, 29, and 36. Parenteral hydroxyurea (HU) was administered at 4.3 g/m 2 as a 24-hour infusion concurrently with 5FU. Interferon alfa-2a (IFN-α2a) was administered at 9 million units subcutaneously on days 1, 3, and 5 each week. No drug was administered in weeks 7 and 8. Pharmacodynamic studies were performed to assess drug effects on levels of deoxyuridine triphosphate (dUTP) and thymidine triphosphate (TTP) pools in peripheral-blood mononuclear cells (PBMCs) before and 6 hours after treatment using a highly sensitive DNA polymerase assay. RESULTS: There were 53 patients enrolled onto the study (gastric carcinoma, 31; pancreatic carcinoma, 22). The median age was 61 years, with 22% of patients ≥ 70 years old. The predominant grade 3 to 4 toxicities were leukopenia (49%), granulocytopenia (55%), and thrombocytopenia (22%). Severe diarrhea occurred in 12%, mucositis in 0%, and vomiting in 10% of patients. Patients ≥ 70 years had no greater incidence of toxicities. Among the 30 assessable patients with gastric carcinoma, there were two (7%) complete responders and 11 (37%) partial responders (median duration, 7 months). Among the 21 assessable patients with pancreatic carcinoma, there was one responder. Median survival among all patients with gastric carcinoma was 10 months and 13 months for patients with pancreatic carcinoma. Twenty-three patients had samples studied for levels of dUTP and TTP. There was no change in the levels of TTP before and after treatment. Furthermore, dUTP was detected in only five of 28 samples after treatment with no increase in the dUTP/TTP ratio. CONCLUSION: Combination therapy with high-dose, weekly infusional HU and 5FU with IFN-α2a modulation was well-tolerated with activity in gastric cancer. Patients ≥ 70 years tolerated therapy as well as younger patients. This was the first study to correlate levels of TTP and dUTP after treatment with clinical outcome. In PBMCs used as a surrogate tissue, HU abrogated the 5FU-induced increase in dUTP levels without reversing the overall efficacy of the regimen.
Phase I dose escalation study of the anti-IGF-1R monoclonal antibody CP-751,871 in patients with refractory solid tumors
Authors: P. Haluska, H. Shaw, G. N. Batzel, L. R. Molife, A. A. Adjei, T. A. Yap, M. L. Roberts, A. Gualberto, J. S. de Bono
Journal: Journal of Clinical Oncology (2007)

3586 Background: The insulin-like growth factor 1 receptor (IGF-IR), a tyrosine kinase, and its ligands (IGF-I &amp; -2) are upregulated in many human tumors (e.g., breast, prostate, colon and non-small cell lung cancer) and enhance proliferative and prosurvival signaling. Inhibition of IGF-IR activation in tumor models suppresses tumor growth and increases tumor sensitivity to chemotherapy, supporting the development of agents targeting IGF-IR. CP-751,871 is a potent, highly specific, fully humanized, monoclonal antibody that inhibits IGF-IR autophosphorylation and induces receptor internalization. Methods: A Phase I dose escalation study was initiated to define the safety and tolerability, and to characterize the pharmacokinetic properties of CP-751,871 in patients with advanced solid tumors refractory to standard therapies. Results: Following informed consent and screening, a total of 24 patients with refractory solid tumors (e.g. colorectal, NSCLC, sarcoma and prostate cancer; 1–6 previous regimens) were enrolled. Patients received 3 to 20 mg/kg of CP-751,871 by IV infusion on Day 1 of 3-week cycles in four dose-escalation cohorts of 3 patients. No dose limiting toxicities were identified and the maximum feasible dose (MFD) cohort of 20 mg/kg was extended with 12 additional patients. No higher than grade 3 CTCAE v3.0 toxicities, attributed to study drug, have been so far reported. Grade 3 toxicities, all reported in patients dosed with 20 mg/kg of CP-751,871, are increased GGT (4%) and fatigue (4%). Grade 2 toxicities include: anorexia (7%), diarrhea (7%), increased GGT (4%), hyperglycemia (4%), fatigue (4%), increased urinary frequency (4%), nausea (4%), increased ALT (4%) and increased AST (4%). Pharmacokinetic analysis is currently ongoing. No objective responses were observed. At the MFD, patients received a median of 4 cycles (1–16). Three patients were stable for &gt; 6 months and one patient, currently at cycle 16, remains on study. An additional cohort of 12 adrenocortical cancer patients is under evaluation. Conclusions: These data indicate that CP-751,871 is safe and well tolerated. Due to its good safety profile, CP-751,871 may constitute a suitable targeted agent to use in combination with approved therapies in multiple tumor types. No significant financial relationships to disclose.
Examining the Ethics of Clinical Use of Unproven Interventions Outside of Clinical Trials During the Ebola Epidemic
Authors: Seema K. Shah, David Wendler, Marion Danis
Journal: The American Journal of Bioethics (2015)

The recent Ebola outbreak in West Africa began in the spring of 2014 and has since caused the deaths of over 6,000 people. Since there are no approved treatments or prevention modalities specifically targeted at Ebola Virus Disease (EVD), debate has focused on whether unproven interventions should be offered to Ebola patients outside of clinical trials. Those engaged in the debate have responded rapidly to a complex and evolving crisis, however, and this debate has not provided much opportunity for in-depth analysis. Additionally, the existing literature on access to unproven therapies has focused on contexts like HIV/AIDS and oncology, which are very different than the Ebola epidemic. In this paper, we examine the ethical issues surrounding access to unproven therapies in the context of the recent Ebola outbreak to yield new insights about this controversial and unsettled issue. We argue first that, in this context, the interests of patients in obtaining access to unproven therapies are not fully aligned with the interests of their providers and drug developers. Second, we focus on the resource constraints facing providers, funders, and patients and conclude that they often counsel against the use of unproven interventions against EVD.
Docetaxel followed by capecitabine as first-line chemotherapy in metastatic breast cancer patients: Preliminary results
Authors: R. Bernabe Caro, J. L. Bayo, J. Salvador, M. Lomas, M. Ruiz, J. M. Baena, D. Vicente, M. D. Pineda
Journal: Journal of Clinical Oncology (2005)

801 Background: Docetaxel (D) has been concomitantly administered with capecitabine (C) offering clinical benefit to women with metastatic breast cancer (MBC) (ORR: 42%). The aim of this trial was to evaluate the efficacy and tolerance of sequentially administered D plus C as first line treatment in MBC. Methods: Patients ≥ 18 years old with MBC, ECOG performance status (PS) ≤2, HER-2 neu negative, non-chemotherapy naive were included in this prospective, multicentre, non-randomized, phase II study. Three cycles of D (100 mg/m2 d 1) followed by three cycles of C (1250 mg/m2 PO bid d 1–14), were both administered every 3 weeks. Results: To date, 18 patients are evaluable for toxicity and 12 for response. Median age 55 years (36–76); PS 0/1: 59%/41%. All patients had previously received neo/adjuvant anthracyclines treatment, 5 of them concomitant with paclitaxel. The most frequent metastatic sites were: nodes 44%, lung 28% and liver 22%. 72% patients had ≥2 metastatic sites. To date, 18 and 12 patients have received D and C cycles, respectively. A total of 75 cycles have been administered: D 45 cycles (median 3, range 1–3)/ C 30 cycles (median 3, range 1–3). Dose reduction per patient: D 33%/ C 25%. Dose delay per patient: D 17%/ C 17%. Median relative dose intensity: D 0.91 (range: 0.75–1.00), C 0.93 (range: 0.26–1.0). D grade III/IV toxicities: mucositis 4/18 (22%), febrile neutropenia 3/18 (17%), asthenia 3/18 (17%), rash 2/18 (11%), infection 1/18 (6%), diarrhea 1/18 (6%), nausea 1/18 (6%). C grade III toxicities: hand foot syndrome 1/12 (8%), nausea 1/12 (8%), anorexia 1/12 (8%). Three patients have dropped up the study: 1 due to D toxicity and 2 for progressive disease after 2nd C cycle. Three out of 12 patients evaluable for overall response reached a complete clinical response and 4 a partial response with an ORR of 58%. Conclusions: These preliminary results show the efficacy of the sequential treatment of D and C that seems to be comparable to the concomitant administration of both drugs with a better toxicity profile. No significant financial relationships to disclose.
Concurrent balloon dilation of stenosed aortopulmonary Gore-Tex shunts and branch pulmonary arteries∗∗Editorials published in Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: P.Syamasundar Rao
Journal: Journal of the American College of Cardiology (2001)
Of That Waltz in My Heart⁎†⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.†From the London musical “The Dancing Years” (1939), Ivor Novello and Christopher Hassall.
Authors: Jagat Narula, Mani A. Vannan, Anthony N. DeMaria
Journal: Journal of the American College of Cardiology (2007)
Cooperation Achieves Results at UNC-CH
Authors: Mary Eubanks
Journal: Environmental Health Perspectives (2004)

Now that scientists have solved the code for the human genome and are moving forward to sequence the genomes of other organisms, a significant challenge lies in how to harness this vast amount of new information to benefit society.Recognizing that cross-communication and cooperation among different research labs is essential to realizing the potential of genomic science for toxicology,
A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma
Authors: Bhuvana S. Doddapaneni, Sergiy Kyryachenko, Sharmeen E. Chagani, Raid G. Alany, Deepa A. Rao, Arup K. Indra, Adam W.G. Alani
Journal: Journal of Controlled Release (2015)
Abstract 4179: Id3 generated cancer stem-like cells: A microvascular niche for the development of glioma
Authors: Jayanta Das, Quentin H. Felty
Journal: Cancer Research (2015)

Abstract Pro-angiogenic vascular stem cells and angiogenesis are key events in the process of glioma formation. Vascular lesions that arise from a focal budding of endothelial cells have been associated with a poor prognosis in glioblastoma multiforme. Hyper-proliferative endothelial lesions are common in patients with severe brain tumors, however, little is known about the relevance of vascular stem cells in the development of these lesions. We tested the hypothesis that the overexpression of the inhibitor of DNA binding and differentiation protein 3 (ID3) reprograms the molecular signature of endothelial cells to stem-like cells; and we hypothesize that these stem-like cells participate in the development of vascular lesion formation in glioma. We generated ID3 overexpressing cells using the human cerebral microvascular endothelial cell line, hCMEC/D3; and determined the effect of ID3 on molecular stem-like signature and vascular lesion formation. ID3 overexpressing cells resided more in the G0/G1 phase and showed a significantly higher level of stem cell markers CD34, CD133, Oct-4, and Sox-2 than wild-type cells. ID3 overexpressing cells also showed a significant increase in VEGFR3, an endothelial growth factor receptor that has been previously reported to correlate with tumor grade of malignant gliomas. In addition, ID3 overexpressing cells showed increased levels of Pyk2, a kinase that has been shown to control glioma cell migration. In the 3-D culture model, we observed that ID3 was essential for the growth of endothelial spheroids. Our findings demonstrate that ID3 generated vascular stem-like cells have the capacity to participate in vascular lesion formation and that vascular stem-like molecular signatures are regulated in part by ID3. Furthermore, the correlation of ID3 overexpression with an increase in VEGFR3 and Pyk2 suggests the importance of ID3 in malignant glioma endothelium. Assessing ID3 in malignant gliomas on a functional level may enable a better understanding for how the microvascular niche contributes to the development of glioma. A better understanding of how microvascular lesions depend on ID3 may open new avenues for the prevention and treatment of glioma. Citation Format: Jayanta Das, Quentin H. Felty. Id3 generated cancer stem-like cells: A microvascular niche for the development of glioma. [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 4179. doi:10.1158/1538-7445.AM2015-4179
Abstract 2515: A Selective IKur Blocker, BMS-394136 Selectively Prolongs Atrial APD and Refractoriness in Beagles and Rabbits
Authors: Dezhi Xing, Huabin Sun, Jialong Zhu, Heather Finlay, John Lloyd, Paul Levesque
Journal: Circulation (2009)

Introduction: IKur is a repolarizing K+ current encoded by the KCNA5 gene and is expressed predominantly in atrium of rabbit, dog and human. IKur is a potential atrial-selective target for treatmen...
A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas
Authors: Alice Soragni, Deanna M. Janzen, Lisa M. Johnson, Anne G. Lindgren, Anh Thai-Quynh Nguyen, Ekaterina Tiourin, Angela B. Soriaga, Jing Lu, Lin Jiang, Kym F. Faull, Matteo Pellegrini, Sanaz Memarzadeh, David S. Eisenberg
Journal: Cancer Cell (2015)
‘LungGENS’: a web-based tool for mapping single-cell gene expression in the developing lung: Figure 1
Authors: Yina Du, Minzhe Guo, Jeffrey A Whitsett, Yan Xu
Journal: Thorax (2015)

We developed LungGENS (Lung Gene Expression iN Single-cell), a web-based bioinformatics resource for querying single-cell gene expression databases by entering a gene symbol or a list of genes or selecting a cell type of their interest. Gene query provides quantitative RNA expression of the gene of interest in each lung cell type. Cell type query returns associated selective gene signatures and genes encoding cell surface markers and transcription factors in interactive heatmap and tables. LungGENS will be broadly applicable in respiratory research, providing a cell-specific RNA expression resource at single-cell resolution. LungGENS is freely available for non-commercial use at https://research.cchmc.org/pbge/lunggens/default.html.
Abstract 2437: 18F -FDG Uptake in Arterial Plaques of Diabetic, Hyperlipidemic Swine
Authors: Eileen M Rattigan, Alexey Aleshin, Marija Sedlar, Ashish Gupta, Lilya Deshchenko, Joanne Tetens, Ann Marie Schmidt, Lynne L Johnson
Journal: Circulation (2006)

Background- Diabetes mellitus and hyperlipidemia are two well characterized risk factors for the development of accelerated atherosclerotic vascular disease. Identification of metabolically active ...
Corrigendum to “Efficacy and safety of tenofovir disoproxil fumarate (TDF) in pregnancy to prevent perinatal transmission of hepatitis B virus” [J Hepatol 2014;61:502–507]
Authors: Astrid-Jane Greenup, Pok Kern Tan, Vi Nguyen, Anne Glass, Scott Davison, Ushmi Chatterjee, Susan Holdaway, Dev Samarasinghe, Kathy Jackson, Stephen A. Locarnini, Miriam T. Levy
Journal: Journal of Hepatology (2015)
Application of SELEX in vivo identifies tumor specific RNA aptamers
Authors: Jing Mi, Yingmiao Liu, Zhiyong Mi, Zhongguang Yang, Bruce A. Sullenger, Paul C. Kuo, Bryan M. Clary
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2331 

Background: Recent reports have demonstrated that strategies capable of targeting molecular alterations specific to tumors and/or the vasculature that support them are capable of effecting antitumor responses in the clinical setting. The authors describe a novel and powerful technique utilizing an in vivo application of SELEX (Systematic Evolution of Ligands by Exponential Enrichment) to create RNA aptamers capable of specifically recognizing tumor tissue. The protein targets of these aptamers can be identified through well-delineated processes. In addition these aptamers can be utilized directly or indirectly (as escorts of toxic moieties) as therapeutic reagents. Methods: Balb C mice bearing 10-day-old intrahepatic tumors (CT26) were inoculated systemically with a random, nuclease-resistant RNA oligonucleotide library whose variable sequences were 40 nucleotides in length. After a 20-minute circulation period, mice were sacrificed and the intrahepatic tumors removed. Total RNA was then extracted, and RT-PCR performed with aptamer specific primers. Following amplification and transcription, the enriched population of aptamers was then inoculated into tumor bearing mice. This cycle was repeated a total of 14 times. A limited number of aptamer clones were then sequenced. Binding specificity of the aptamers generated, to tumor and normal organs were ascertained through fluorescent labeling, P32 affinity binding, and gel-shift assays. Results: From 20 clones isolated after round 14, two main aptamer families with shared sequences were identified. One aptamer from each family (apt14-8 and apt14-16) were tested from tumor tissue-specific binding as follows: (1) Utilizing a hexyl-ATP fluorescent labeling strategy, apt14-8 and apt14-16 specifically labeled hepatic CT26 tumors prepared on cryostat sections in comparison to a control aptamer population (from round 2). Apt14-8 and apt14-16 failed to label normal liver, brain, kidney, lung, and spleen. (2) 32P-labeled apt14-16 and apt14-8 demonstrated an increased affinity (over 3-fold) in binding the total tumor membrane protein fraction when compared to control aptamer. (3) 32P-labeled Apt 14-8 and apt 14-16 demonstrated shifts on an electrophoretic mobility shift assay in those lanes where tumor membrane protein was instilled, but not in those lanes where normal liver membrane protein was present. Competition with an excess of unlabeled apt 14-8 or apt14-16 respectively eliminated the shift, whereas competition with unlabeled control aptamer did not. Conclusion: Through an in vivo application of SELEX, RNA aptamers can be created that specifically recognize tumor tissue. Given the complexity of the random RNA libraries (over 1016) this technique is a promising approach to developing targeted therapeutics.
Alternate Approaches for Pediatric Type 1 Diabetes Drug Development and Potential Regulatory Approval: A Perspective
Authors: J. Rick Turner, Kelly L. Close, G. Alexander Fleming, Diane K. Wherrett, Linda A. DiMeglio
Journal: Diabetes Care (2015)

The incidence and prevalence of pediatric type 1 diabetes are increasing globally, including in the U.S. While the increasing number of cases of pediatric diabetes makes expeditious availability of new medical products and therapies for diabetes care essential, there have been many barriers encountered in bringing some drugs and devices to pediatric patients who may benefit. Newer insulins have been studied and approved for use in children. However, hurdles exist in the inclusion of children in studies of therapies aimed at preventing β-cell loss in those with new-onset diabetes and those at risk for type 1 diabetes. This Perspective focuses on potential solutions to the challenges experienced in bringing new drugs for pediatric type 1 diabetes to marketing approval. Given their central importance as the users of medical products, patient perspectives are included along with scientific and regulatory considerations.
The stone workers exposure to crystalline silica in the construction industry
Authors: Youlim Lee, Boowook Kim, Hyun seok Kwak, So young Park, Byung-Soon Choi
Journal: European Respiratory Journal (2014)

Purpose:  The stone workers can be exposed to crystalline silica, causative agent of lung cancer and silicosis. But the exposure levels of crystalline silica were not investigated in the stone workers of construction industry yet.  Methods:  Stone workers are the worker who attaches the stone in the wall. The 23 samples of respirable dust were collected by a cyclone (GK2.69, BGI Corp, USA) in the four construction sites, and then the crystalline silica contents in the samples were analyzed according to the NIOSH method 7500.  Results:  The geometric mean (GM) of crystalline silica contents was 0.043 mg/m 3  in the 14 personal samples. Fifty percent and 71% of the personal samples exceeded the Korean occupational exposure limit(0.05 mg/m 3 ) and the ACGIH-TLV(0.025 mg/m 3 ), respectively. Especially, the highest content in the samples, 0.133 mg/m 3 , was above twice as high as the Korean occupational exposure limit.  The GM of crystalline silica contents was 0.013 mg/m 3  in the 9 area samples. None of the area samples exceeded the Korean occupational exposure limit and the ACGIH-TLV.  Conclusions:  It was found that the stone workers in the construction industry was exposed to crystalline silica above the current occupational exposure limits and high risk group of occupational lung cancer.
The Role of Multidrug Resistance Proteins and Drug Sensitivity in Relation to Poor Prognosis Identified by ZAP-70 Expression and IgVH Mutation Status in B-CLL.
Authors: S. Narat, N. I. Folarin, R. J. Baker, V. Duke, B. C. Yogashangary, D. T. Jones, S. M. Hart, R. G. Wickremasinghe, A. Victor Hoffbrand, A. B. Mehta, L. Foroni, K. Ganeshaguru
Journal: Blood (2004)
Expression of the multidrug resistance-associated P-glycoprotein (P- 170) in 59 cases of de novo acute lymphoblastic leukemia: prognostic implications [see comments]
Authors: JE Goasguen, JM Dossot, O Fardel, F Le Mee, E Le Gall, R Leblay, PY LePrise, J Chaperon, R Fauchet
Journal: Blood (1993)