tbuckley/cabot-search huggingface dataset:
Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix.
Authors: C F Verschraegen, T Levy, A P Kudelka, E Llerena, K Ende, R S Freedman, C L Edwards, M Hord, M Steger, A L Kaplan, D Kieback, A Fishman, J J Kavanagh
Journal: Journal of Clinical Oncology (1997)

PURPOSE A phase II study was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11), a water-soluble derivative of camptothecin, in patients with prior chemotherapy-treated squamous cell cancer of the cervix. PATIENTS AND METHODS Forty-two patients were included in the study. The median age was 44 years (range, 24 to 59 years). The median Zubrod performance status was 1. All patients were refractory to first-line chemotherapy and 88% had received prior radiotherapy. The initial dose of CPT-11 was 125 mg/m2 given as a weekly 90-minute intravenous infusion for 4 weeks, every 6 weeks. Subsequent doses were unchanged, reduced, or omitted according to toxicity grade. RESULTS Forty-two patients were assessable for response. The overall response rate was 21%. The median time to response was 6 weeks and the median duration of response was 12 weeks. The overall median duration of survival was 6.4 months. A statistically significant survival advantage (median of 12.6 v 5.1 months) was found in patients whose disease responded to the treatment (P &lt; .015). The major dose-limiting toxic effects (grade &gt; or = 3) were nausea and vomiting (45%), diarrhea (24%), and granulocytopenia (36%). Grade &gt; or = 3 anemia was encountered in 62% of patients and the incidence of thrombocytopenia was negligible. Less severe side effects were alopecia (48%), drug fever (43%), anorexia (33%), fatigue (33%), skin rash (21%), stomatitis (14%), and allergic reaction (9%). The gastrointestinal intolerance was dose-related. The incidence of bone marrow depression did not decrease with dose reduction, possibly because of a cumulative effect or hematologic intolerance by a subset of patients. CONCLUSIONS CPT-11 has significant activity in refractory cervical carcinoma. Gastrointestinal intolerance and hematologic toxicity must be monitored carefully. Further studies of alternative schedules may improve the tolerance and response rate.
How do children with asthma interact with parents about medications
Authors: Thomas Westergren, Sveinung Berntsen, Tonje Nilsen, Kristin Haraldstad, Ole Bjørn Kittang, Liv Fegran
Journal: European Respiratory Journal (2014)

Background  : There is evidence of substantial effect on lives of children with asthma related to suboptimal use of preventive medication (Rabe et al, JACI, 2004; 114 (1) , 40-47). Knowledge from children´s own perspective is; however, limited.    Aim  : To explore how interaction with parents influence use of prescribed medication in children with asthma.    Methods  : Six children with asthma (2 girls) aged 10-12 years participated in a six-week intervention pilot aiming to determine feasibility of a group based exercise program focusing on active play. Data were collected through 3 focus group interviews, observations of 5 exercise sessions, and during aerobic fitness testing focusing on children and parents management of asthma and medications. Interviews were transcribed verbatim and qualitative content analysis of interviews and observations were conducted.    Results  : Children described that they seldom were involved in their own medical check-ups, and had limited knowledge of physiological aspects of asthma. All children described negligence of medicines to different extent. The children experienced that parents nagged about taking medications and argued with severe consequences if they forgot to use their medications as supposed. However, parents also accepted independence and articulated that they wanted their children to manage their own medications.    Conclusions  : Limited involvement and limited knowledge of own body and disease combined with expanding independence, may influence use of medications in children with asthma. Health personnel should be aware of children´s independence, involvement and knowledge, and further exploration of interaction with peers, parents and health personnel in children with asthma are needed.
Abstract 1470: The Kinase Activity of Cyclin-Dependent Kinase-9 is Required for Phosphorylation of p300 and its Histone Acetyltransferase Activity during Cardiomyocyte Hypertrophy
Authors: Yoichi Sunagawa, Tatsuya Morimoto, Tomohide Takaya, Teruhisa Kawamura, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Toru Kita, Koji Hasegawa
Journal: Circulation (2008)

Introduction: A zinc finger protein GATA4 is one of the factors involved in transcriptional regulation during myocardial cell hypertrophy and forms a complex with an intrinsic histone acetyltransferase (HAT), p300. HAT activity of p300 is required for acetylation and the transcriptional activity of GATA4 as well as for cardiomyocyte hypertrophy and the development of heart failure in vivo . By tandem affinity purification and mass spectrometric analyses, we identified cyclin-dependent kinase-9 (Cdk9), a component of positive transcription elongation factor b, as a novel GATA4-binding partner. Cdk9 also formed a complex with p300 as well as GATA4. However, the precise functional relationships among p300, GATA4, and Cdk9 remain unknown. Methods and Results: A series of GST pull-down assays revealed that the N-terminal of Cdk9 bound to the N-terminal zinc finger domain of GATA4 and C/H-3 domain of p300, respectively. By chromatin immunoprecipitation and DNA pull-down assay, we showed that GATA4 recruited Cdk9 onto GATA elements within the endothelin-1 promoter. Immuno-precipitation followed by Western blotting demonstrated that intact p300 induced not only the acetylation of GATA4, but also the interaction between GATA4 and Cdk9. Furthermore, p300 induced the hyperphosphorylation of RNA Pol II, suggesting that p300 is involved in the regulation of Cdk9 kinase activity. All of these effects were inhibited by the co-expression of a dominant-negative form (DN-) of p300. Conversely, Cdk9 induced not only the hyperphos-phorylation of RNA Pol II, but also the phosphorylation of p300. Notably, Cdk9 induced the acetylation and DNA binding of GATA4. However, DN-Cdk9, which loses its kinase activity by a single amino acid substitution, was unable to achieve these, suggesting the requirement of Cdk9 kinase activity for p300 HAT activity. Finally, a Cdk9 kinase inhibitor, DRB, inhibited phenylephrine-induced hypertrophic responses as well as the acetylation of GATA4 in cardiomyocytes. Conclusion: These findings demonstrate that Cdk9 is required for the phosphorylation of p300 and its HAT activity, and forms a functional complex with p300/GATA4 during cardiomyocyte hypertrophy.
Efficacy and Safety of Gemtuzumab Ozogamicin in Patients With CD33-Positive Acute Myeloid Leukemia in First Relapse
Authors: Eric L. Sievers, Richard A. Larson, Edward A. Stadtmauer, Elihu Estey, Bob Löwenberg, Hervé Dombret, Chatchada Karanes, Matthias Theobald, John M. Bennett, Matthew L. Sherman, Mark S. Berger, Catharine B. Eten, Michael R. Loken, Jacques J.M. van Dongen, Irwin D. Bernstein, Frederick R. Appelbaum
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent Mylotarg (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA), an antibody-targeted chemotherapy agent, in patients with CD33-positive acute myeloid leukemia (AML) in untreated first relapse. PATIENTS AND METHODS: The study population comprised 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m 2 , at 2-week intervals for two doses. Patients were evaluated for remission, survival, and treatment-emergent adverse events. RESULTS: Thirty percent of patients treated with Mylotarg obtained remission as characterized by 5% or less blasts in the marrow, recovery of neutrophils to at least 1,500/μL, and RBC and platelet transfusion independence. Although patients treated with Mylotarg had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of grade 3 or 4 mucositis (4%) and infections (28%) were relatively low. There was a low incidence of severe nausea and vomiting (11%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Many patients received Mylotarg on an outpatient basis (38% and 41% of patients for the first and second doses, respectively). Among the 142 patients, the median total duration of hospitalization was 24 days; 16% of patients required 7 days of hospitalization or less. CONCLUSION: Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.
LSC 2013 abstract - Increased risk for lung injury in PDGF-Rα deficient newborn mice
Authors: Anne Hilgendorff, Isabella Thiel, Noopur Jain, Markus Koschlig, Oliver Eickelberg, Andreas Schulze, Harald Ehrhardt, Tushar Desai
Journal: European Respiratory Journal (2013)

Rationale:  Although life-saving treatment for respiratory failure, mechanical ventilation with O2-rich gas (MV-O2) promotes chronic lung disease (CLD) in the neonate. Similarly, lungs of newborn mice undergoing MV exhibited histologic changes including altered extracellular matrix (ECM), angiogenesis, and alveolar septation together with reduced lung expression of PDGF-A and increased TGF-β signaling. Impaired lung development in PDGF-A deficient mice was associated with reduced migration of myofibroblasts (MFBs).   Objective and Methods:  To test whether impaired PDGF signaling alters the adverse effects of prolonged MV on lung development, wild-type (PDGF-Rα +/+ ; WT) and PDGF-Rα haploinsufficient (PDGF-Rα +/- )5-6 day old mice received MV-O2 at 180 breaths/min; controls breathed 40%O2. After 8h, lungs (n=10-12/group) were harvested for histologic and protein analysis including ECM proteins, vessel markers and growth factor signaling. Primary MFBs from newborn mouse lungs were subjected to mechanical stretch (Flexcell®) and TGF-β incubation.   Results:  MV caused a significant increase in airspace size and decreased alveolar number in PDGF-Rα +/- , but not in WTpups. These changes were paralleled by decreased lung VEGF-A protein and reduced vessel markers (CD-31, VE-Cadherin).  In vitro , stretched MFBs revealed reduced VEGF-A expression; supernatants from PDGF-Rα depleted cells led to increased apoptosis in HUVECs. TGF-β incubation of MFBs reduced PDGF- Rα expression stretch-independent.   Conclusion:  Giving insight on how PDGF signaling affects alveolar and vessel development, these results will help to formulate new treatment strategies in CLD.
BCR-ABL Induces the Expression of Skp2 through the PI3K Pathway to Promote p27Kip1 Degradation and Proliferation of Chronic Myelogenous Leukemia Cells
Authors: Enrique J. Andreu, Elisa Lledó, Enric Poch, Carmen Ivorra, M. Pilar Albero, José Angel Martínez-Climent, Cristina Montiel-Duarte, José Rifón, Javier Pérez-Calvo, Cristina Arbona, Felipe Prósper, Ignacio Pérez-Roger
Journal: Cancer Research (2005)

Abstract Chronic myelogenous leukemia (CML) is characterized by the expression of the BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show in both BCR-ABL cells (Mo7e-p210 and BaF/3-p210) and primary CML CD34+ cells that STI571 inhibition of BCR-ABL tyrosine kinase activity results in a G1 cell cycle arrest mediated by the PI3K pathway. This arrest is associated with a nuclear accumulation of p27Kip1 and down-regulation of cyclins D and E. As a result, there is a reduction of the cyclin E/Cdk2 kinase activity and of the retinoblastoma protein phosphorylation. By quantitative reverse transcription-PCR we show that BCR-ABL/PI3K regulates the expression of p27Kip1 at the level of transcription. We further show that BCR-ABL also regulates p27Kip1 protein levels by increasing its degradation by the proteasome. This degradation depends on the ubiquitinylation of p27Kip1 by Skp2-containing SFC complexes: silencing the expression of Skp2 with a small interfering RNA results in the accumulation of p27Kip1. We also demonstrate that BCR-ABL cells show transcriptional up-regulation of Skp2. Finally, expression of a p27Kip1 mutant unable of being recognized by Skp2 results in inhibition of proliferation of BCR-ABL cells, indicating that the degradation of p27Kip1 contributes to the pathogenesis of CML. In conclusion, these results suggest that BCR-ABL regulates cell cycle in CML cells at least in part by inducing proteasome-mediated degradation of the cell cycle inhibitor p27Kip1 and provide a rationale for the use of inhibitors of the proteasome in patients with BCR-ABL leukemias.
Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee.
Authors: R Heyn, R B Raney, D M Hays, M Tefft, E Gehan, B Webber, H M Maurer
Journal: Journal of Clinical Oncology (1992)

PURPOSE We report on long-term health-related problems determined from extended follow-up of 86 children and adolescents who were treated for paratesticular rhabdomyosarcoma on the Intergroup Rhabdomyosarcoma Studies I and II (IRS I-II). PATIENTS AND METHODS Patients were treated between 1972 and 1984, and ages at diagnosis ranged from 10 months to 19 years. The majority of these patients had initial retroperitoneal lymph node dissection (RLND) or sampling performed. RESULTS Problems related to surgical procedures included bowel obstruction in nine patients, loss of normal ejaculatory function in eight, development of a hydrocele in five, and lymphedema of the leg in five. Sequelae related to radiotherapy were difficult to assess with the exception of three patients whose remaining testes were in the field of radiotherapy. In general, kidney and bladder function were normal in patients who received radiotherapy to the paraaortic lymph nodes and/or bladder. Four patients who had abdominal radiotherapy had chronic diarrhea. Two patients had urethral strictures and urethritis. Four patients had bone or soft tissue hypoplasia in the field of radiotherapy. Chemotherapy-related late effects were primarily hemorrhagic cystitis or gonadal dysfunction after cyclophosphamide. A third of the patients who received cyclophosphamide developed hemorrhagic cystitis, and half of these had extended periods of gross hematuria after therapy was discontinued. The testicular size was small in children whose testes were irradiated and in some who received cyclophosphamide. Tanner staging was normal in 45 patients for whom it was recorded. Elevated follicle-stimulating hormone (FSH) values or known azoospermia occurred in more than half the patients for whom data were available. CONCLUSIONS A variety of sequelae related to therapy were determined in this patient population. These findings suggest that some aspects of therapy warrant reevaluation and that improved plans for follow-up care need to be provided.
Sensitivity of Normal and Neoplastic Cells to the Damaging Action of Carcinogenic Substances: A Review
Authors: Juri M. Vasiliev, Vita I. Guelstein
Journal: JNCI Journal of the National Cancer Institute (1963)

Sensitivity of Normal and Neoplastic Cells to the Damaging Action of Carcinogenic Substances: A Review Get access Juri M. Vasiliev, Juri M. Vasiliev Laboratory of Mechanisms of Carcinogenesis, Department of Carcinogenic Agents, Institute of Experimental and Clinical Oncology, Academy of Medical Sciences, Moscow, USSR Search for other works by this author on: Oxford Academic PubMed Google Scholar Vita I. Guelstein Vita I. Guelstein Laboratory of Mechanisms of Carcinogenesis, Department of Carcinogenic Agents, Institute of Experimental and Clinical Oncology, Academy of Medical Sciences, Moscow, USSR Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 31, Issue 5, November 1963, Pages 1123–1151, https://doi.org/10.1093/jnci/31.5.1123 Published: 01 November 1963 Article history Received: 03 April 1963 Published: 01 November 1963
Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma.
Authors: D M Shin, B S Glisson, F R Khuri, L Ginsberg, V Papadimitrakopoulou, J J Lee, K Lawhorn, A M Gillenwater, K K Ang, G L Clayman, D L Callender, W K Hong, S M Lippman
Journal: Journal of Clinical Oncology (1998)

PURPOSE To assess the activity and toxicity profile of combined taxol (paclitaxel), ifosfamide, and platinum (cisplatin) (TIP) in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck. PATIENTS AND METHODS Recurrent or metastatic head and neck SCC patients received paclitaxel 175 mg/m2 in a 3-hour infusion on day 1; ifosfamide 1,000 mg/m2 in a 2-hour infusion on days 1 through 3; mesna 600 mg/m2 on days 1 through 3; and cisplatin 60 mg/m2 on day 1, repeated every 3 to 4 weeks. All were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic hematopoietic growth factors were not permitted. RESULTS Fifty-two patients were assessable for response and toxicity; 53 for survival (local-regional recurrence alone in 57% and distant metastasis with or without local-regional recurrence in 43%). Overall response rate was 58% (30 of 52) of patients; complete response rate was 17% (nine of 52) of patients, with six complete responses that continued for a median 15.7+ months. Median follow-up of all patients was 17.7 months. Median survival was 8.8 months (95% confidence interval [CI] 8.1 to 17.5 months). Toxicity was relatively well tolerated and caused no deaths. The most frequent moderate-to-severe toxicity (90% of patients) was transient grades 3 to 4 neutropenia; neutropenic fever occurred in 27%. Grade 3 peripheral neuropathy occurred in three patients, none had grade 4. Grade 3 mucositis occurred in only one patient, none had grade 4. CONCLUSION TIP had major activity in this setting, with a 58% objective response rate, 17% complete response rate, durable complete responses (six of nine persisting), and relatively well-tolerated toxicity, with no toxic deaths. The activity of TIP, a novel taxol-cisplatin-based regimen, in recurrent or metastatic head and neck SCC should be confirmed in a phase III trial.
APOBEC Enzymes: Mutagenic Fuel for Cancer Evolution and Heterogeneity
Authors: Charles Swanton, Nicholas McGranahan, Gabriel J. Starrett, Reuben S. Harris
Journal: Cancer Discovery (2015)

Abstract Deep sequencing technologies are revealing the complexities of cancer evolution, casting light on mutational processes fueling tumor adaptation, immune escape, and treatment resistance. Understanding mechanisms driving cancer diversity is a critical step toward developing strategies to attenuate tumor evolution and adaptation. One emerging mechanism fueling tumor diversity and subclonal evolution is genomic DNA cytosine deamination catalyzed by APOBEC3B and at least one other APOBEC family member. Deregulation of APOBEC3 enzymes causes a general mutator phenotype that manifests as diverse and heterogeneous tumor subclones. Here, we summarize knowledge of the APOBEC DNA deaminase family in cancer, and their role as driving forces for intratumor heterogeneity and a therapeutic target to limit tumor adaptation. Significance: APOBEC mutational signatures may be enriched in tumor subclones, suggesting APOBEC cytosine deaminases fuel subclonal expansions and intratumor heterogeneity. APOBEC family members might represent a new class of drug target aimed at limiting tumor evolution, adaptation, and drug resistance. Cancer Discov; 5(7); 704–12. ©2015 AACR.
Prospective gene signature study using microRNA to predict the tissue of origin (ToO) in pts with cancer of unknown primary site (CUP).
Authors: G. R. Varadhachary, T. B. Edmonston, S. Karanth, H. R. Carlson, D. Lebanony, S. Rosenwald, R. Lenzi, Y. Spector, D. Cohen, M. N. Raber
Journal: Journal of Clinical Oncology (2010)

4151 Background: CUP patients present with metastatic disease without an identifiable primary. Accurate ToO assignment could help guide use of specific therapy, which may impact survival. MicroRNAs, 22-oligonucleotide RNA molecules involved in gene- expression regulation, are conserved through evolution and can exhibit high tissue specificity. We used a microRNA-based test to prospectively evaluate tumors from CUP pts. Methods: RNA was extracted from FFPE metastatic biopsies. The test measures expression of 48 microRNAs by qRT-PCR. The classifier combines predictions generated by 2 classifiers: a biologically motivated binary decision-tree and K- nearest-neighbors (KNN). Each classifier predicts one of 25 diagnoses. The test reports one predicted tissue origin when the 2 classifiers agree, or the 2 different tissue predictions when the 2 classifiers do not reach a consensus. Results: Tissue from 52 pts was evaluated. 6 failed due to inadequate RNA quality; 46 were processed successfully. Profile predictions were compared with clinical presentation (CP)—imaging, pathology (histology and IHC), and therapeutic response. A “level of agreement” tool was used to describe these results (Table). The microRNA test assigned a single putative primary in 14 (same results from 2 classifiers). In 32 pts, two ToO profiles were predicted, of which the one more concordant with the CP was accepted. Assay prediction was fully concordant with CP and pathology (level 1) in 39% of pts and clinically plausible (levels 2A and 2B) in an additional 43%. Additional samples data will be presented at the Meeting. Conclusions: This prospective study showed feasibility in retrieving microRNA and determining ToO from FFPE tissue of CUP pts and demonstrates concordance with the clinical presentation in 82% of cases. Level of agreement Criteria MicroRNA test results N=46 1 Molecular profile (MP) results concordant with latent primary OR histology and IHC 18 2A MP results with supportive IHC differential AND consistent CP 11 2B MP results with supportive IHC differential and unusual clinical presentation OR unhelpful IHC with consistent CP 9 3 Primary cancer differs from MP OR IHC and CP clearly discordant 8 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Rosetta Genomics Rosetta Genomics Rosetta Genomics