tbuckley/cabot-search huggingface dataset:
Evaluation of poxviruses targeting the tumor microenvironment for cancer therapy.
Authors: D. Kim, S. Kim-Schulze, G. Deraffele, J. Schlom, H. Kaufman
Journal: Journal of Clinical Oncology (2010)

2600 Background: The tumor microenvironment plays a critical role in mediating anti-tumor immunity following immunotherapy. To overcome the suppressive influence of the microenvironment, recombinant vaccinia and fowlpox viruses were designed to express B7.1 alone or a triad of costimulatory molecules, including B7.1, ICAM-1 and LFA-3 (TRICOM) for direct intra-lesional injection into tumors. The safety profile, immune response and therapeutic efficacy of the four poxviruses are reported herein. Methods: A series of phase I clinical trials were conducted in metastatic cancer patients who have measurable, superficial metastatic lesions (2 colorectal, 35 melanoma). Index tumors were injected with vaccinia virus expressing B7.1 (rV-B7.1, n = 12) or TRICOM (rV-TRICOM, n = 13) or fowlpox virus expressing B7.1 (rF-B7.1, n = 6) or TRICOM (rF-TRICOM, n = 6). Patients were evaluated for toxicity using NCI CTC and clinical response by standard RECIST criteria. Blood and tumor biopsies were collected for analysis of systemic and local immune response of vaccines. Results: There were no serious adverse events in any patient. The three most common adverse events were grade I fever (n = 13), grade I fatigue (n = 13) and grade I injection site pain (n = 16). All viruses induced significant anti-viral antibody titers following intra-tumoral injection, although rV- B7.1 induced the strongest response (2.9 fold increase) and rF-TRICOM the weakest (1.8 fold increase). Although all four viruses induced viral-specific T cell responses, both vaccinia vectors showed the strongest tumor-antigen specific T-cell responses. Objective clinical responses were observed in 3 of 12 (25%) patients treated with rV-B7.1, 5 of 13 (38%) with rV-TRICOM, 0 of 6 with rF-B7.1 and 0 of 6 with rF-TRICOM. Conclusions: Intratumoral injection of recombinant poxviruses is safe and capable of generating tumor-specific immunity in metastatic cancer patients. Vaccinia virus demonstrated better antigen-specific T-cell responses and therapeutic effectiveness in Phase I trials. Further studies using vaccinia vectors in combination with other agents or in prime-boost strategies with fowlpox virus might be considered for targeting the tumor microenvironment. No significant financial relationships to disclose.
HIF2α signaling inhibits adherens junctional disruption in acute lung injury
Authors: Haixia Gong, Jalees Rehman, Haiyang Tang, Kishore Wary, Manish Mittal, Pallavi Chaturvedi, You-Yang Zhao, Yulia A. Komarova, Stephen M. Vogel, Asrar B. Malik
Journal: Journal of Clinical Investigation (2015)
Counselling women with congenital cardiac disease
Authors: Matthew Cauldwell, Philip J Steer, Mark Johnson, Michael Gatzoulis
Journal: BMJ (2016)

They should be empowered to make informed choices

Preconception counselling is particularly important for women with congenital heart disease because these conditions are the leading direct cause of maternal death in many developed countries, including the United Kingdom.1 Recent developments in medicine and the law require us to re-evaluate how preconception counselling is delivered.

The principle of patient autonomy has superseded the traditional paternalistic model of healthcare, with shared decision making the new standard. This involves agreeing the evidence base during the clinical consultation (placing an imperative on the doctor to get the facts right) and joint decision making, taking account of the patient’s preferences and values. Decision support tools facilitate sharing of complex information in some disciplines; however, no such tools exist for heart disease and pregnancy, so clinicians have to rely …
Abstract 14722: Lifelong Exercise Training Demonstrates a Dose Dependent Effect on Left Ventricular Myocardial Compliance and Distensibility
Authors: Jeffrey L Hastings, Paul S Bhella, Graeme C Carrick-Ranson, Naoki Fujimoto, Nainesh Gandhi, Nicole Minniefield, Shigeki Shibata, Kara Boyd, M. Dean Palmer, Benjamin D Levine
Journal: Circulation (2010)

Purpose: Sedentary aging leads to a decrease in left ventricular (LV) chamber compliance and distensibility. Previously we showed that Masters′ athletes who train 6-7 sessions per week throughout t...
Bronchodilator response and airway cytology as parameters for asthma control: A randomized clinical trial Protocol ID: APITA, NCT00597064, on August 1st, 2008
Authors: Ana Luisa Fernandes, Maria Marta Amorim, Lilian Ballini Caetano, Alexandre Araruna, Ilka Lopes Santoro
Journal: European Respiratory Journal (2012)

Background: Clinical control is hard to define in asthma and there is little experimental data on the optimal timing, sequence and magnitude of treatment. Aim: measuring the effects of short course of oral corticoid in airway inflammation and spirometry values of asymptomatic asthma patients to define control. Methods : a double blind randomized clinical trial to observe the change in spirometry, nasal and sputum cytology in patient under combination therapy, receiving either short course of oral corticoid (OC) or placebo(P). Controlled asthma was defined by ACQ<1·5. They were submitted to clinical evaluation, nasal and sputum cytology, spirometry before and after 15±5 days of randomization. Intervention efficacy was defined by improvement of 200 mL in FEV1. Results: n=70, 73% female, age 46·8±13·1, 35 received OC and 35 P. Who received OC showed significant improvement in all spirometric parameters and abolished their positive bronchodilator response related to P. The eosinophils count in the nasal and induced sputum also reduced in OC arm. The logistic regression model identify for each one year increasing in age there was a 6% decrease in odds of intervention efficacy, associated to 19 times increase in odds related the usage of oral corticoid (related to placebo), and for each increase of 1% in bronchodilator response was associated with 9% increase in odds of efficacy (p= 0·02). Conclusion : The RCT allowed define uncontrolled asthma at baseline and the degree of bronchodilator response, younger age and usage of OC were significant predictors for functional improvement at the end of the trial.

Partially funded by FAPESP.
A phase Ib pharmacokinetic (PK) study of CKD-732 plus capecitabine and oxaliplatin (XELOX) in patients with metastatic colorectal cancer (mCRC) treated with prior irinotecan-based chemotherapy.
Authors: S. J. Shin, J. Ahn, K. Park, Y. Hong, T. Kim, H. Jeung, S. Y. Rha, J. K. Roh, H. Chung
Journal: Journal of Clinical Oncology (2010)

e13567 Background: CKD 732 is an antiangiogenic agent 6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate. Since CKD-732 inhibits angiogenesis which is important to tumor growth and metastasis in human colorectal cancer, we conducted a phase I study to evaluate the safety, tolerability and PK of CKD-732 plus capecitabine and oxaliplatin (XELOX) in patients with metastatic colorectal cancer (mCRC) treated with irinotecan based chemotherapy. Methods: Using a dose-escalation schedule, 9 patients were enrolled at dose levels of CKD-732 2 mg/m2 (Level 1), 5 mg/m2 (Level 2) or 10 mg/m2 (Level 3) given twice weekly for 2 weeks followed by a 1-week rest. Oxaliplatin 130 mg/m2 was administered intravenously on day 1 and capecitabine 1,000 mg/m2 bid was administered orally for 14 days of a 3-week cycle. Results: Nine patients received at least one dose of CKD-732. Of nine patients, one patient was excluded from DLT assessment because suboptimal medicatin adherence. In level 3, two patients experienced a dose limiting toxicity (DLT) (one patient: grade 3 nausea, insomnia, and fatigue, another one: grade 3 insomnia). The maximal tolerated dose (MTD) and recommended dose (RD) of CKD-732 in combination with XELOX was 5 mg/m2. No patient exhibited grade 4 adverse drug reaction (ADR) and treatment related death. Common ADRs in cycle 1 included anorexia (100%), nausea (100%), sensory neuropathy (66.6%), insomnia (66.6%), vomiting (36%), and fatigue (33.3%). Area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased dose dependently with increasing dose. There was no notable effect of administered CKD-732 on the PK of capecitabine and oxaliplatin-derived platinum. Conclusions: The MTD for this combination in mCRC is CKD-732 5 mg/m2 twice a week for 2 weeks, capecitabine 1,000 mg/m2 bid for 14 days and oxaliplatin 130 mg/m2 day. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination of mCRC warrants further investigation. No significant financial relationships to disclose.
Vascular endothelial growth factor receptor-2 (VEGFr-2) genetic polymorphisms as predictors to antiangiogenic therapy
Authors: J. Jurado, J. A. Ortega, P. Iglesias, J. L. García-Puche, J. Belon
Journal: Journal of Clinical Oncology (2009)

e14561 Background: Vascular endothelial growth factor (VEGF) and its receptors (VEGFr-2) have important roles in angiogenesis, predicting risk and prognosis in several solids tumor. VEGFr-2 located on chromosome 4 (4q11-q12) is organized into 30 exons separated by 29 introns. Recently the VEGF-2578 AA and VEGF-1154 AA genotypes were associated with a superior median overall survival when using bevacizumab in metastatic breast cancer. We investigated the association of VEGFr-2 polymorphisms to efficacy and toxicity in patients with antiangiogenic therapy. Methods: We performed genotype for selected VEGFr-2 polymorphisms in promoter regions 5’UTR, 3’UTR; in exons 7, 8, 9, 11, 16, 17, 18, 21, 27, 30 and introns 9, 17, 20. DNA was extracted from venous blood of 44 patients with non-curable solid tumors who have received treatment with bevacizumab (B) N=20 (45%) or raf kinase inhibitors 55%; vatalanib (PTK-787) N=3, sunitinib (SU011248) N=6, sorafenib (BAY 43–9006) N= 13, ZD6474 N=1 and AMG706 N= 1. Kaplan-Meier survival analysis was used to assess the association between VEGFr-2 staining and either progression-free survival (PFS) or overall survival (OS). Results: 44 patients have received a median of 6 (1–19) cycles of treatment, 72% was used simultaneously with QT. According to the criteria of NCI-CTC the severe toxicity G3–4 occurred in 47%, 9% with a definite suspension of the drug. The toxicity was not associated with VEGFr-2 genotypes. Efficacy; 5/44 patients (11%) had complete response and 11/ 44 (22%) partial responses by RECIST criteria. With a median follow up of 12 months, the ILP was 8.5 months dt (5.8). The analysis of VEGFr-2 polymorphisms identifies the variant AA of the intron-20 rs2219471 with a significant difference in PFS and OS regarding their ancestral variant AG. Conclusions: Our data suggest that VEGFR polymorphism can be a predictor of clinical outcomes in antiangiogenic therapy. No significant financial relationships to disclose.
A randomized phase I/II trial of antitumor vaccination using the recombinant MAGE-A3 protein loaded on myeloid DC or mixed with adjuvant ASO2B in melanoma patients
Authors: L. Gordower, M. Toungouz, V. Richard, R. Palmantier, M. Trakatelli, V. Vantomme, M. Lambermont, V. Brichard, M. Goldman, T. Velu
Journal: Journal of Clinical Oncology (2005)

2526 Background: The MAGE-A3 gene codes for tumor-specific antigens recognized by CD4+ and CD8+ T-cells. We and others previously reported trials with HLA class I-peptide loaded on autologous dendritic cells (DC) that induced specific T cells and occasional antitumor responses. This immune response was transient, possibly due to the lack of T-cell help. Here, we evaluated the potential advantage of the concurrent presentation of CD4+ and CD8+ epitopes on the recombinant (rec) MAGE-A3 protein loaded on myeloid DC, as compared to the protein combined with adjuvant AS02B. Methods: 19 patients (pts) with evaluable stage III or IV MAGE-A3 expressing melanoma received 4 vaccines (weeks 0, 2, 6, 10) of recMAGE-A3 protein either loaded on autologous non-mature DC (40–100 x 10E6 i.d./s.c.), or mixed with AS02B adjuvant (adj.) (300 μg of protein i.m.). DC were generated from adherent PBMC for 7 days with GM-CSF + IL-4, then pulsed with the protein for 1h. T-cell response was analyzed by Elispot after in vitro restimulation, and Ab response by ELISA. Additional compassionate vaccines (rec protein) were given in case of clinical benefit. Results: From the 19 pts, 18 were eligible and, among them, 14 received the 4 vaccines (3 rapid progressions and 1 technical problem). In both arms, no serious toxicity was reported. We observed in the adj. arm (9 pts): one partial response (7 mo), one mixed response (>34mo, with vitiligo surrounding a responsive lesion), and one stable disease (>26mo); in the DC arm (5 pts): one mixed response (>23mo). Pts showed a strong Ab response against the protein in the adj. arm, while no Ab was detected in the DC arm. Moreover, increase in anti-MAGE-A3 T cell frequency (defined as a minimum of 2.5x baseline frequency) was detected in 4 out of 9 pts in adj. arm, and in 1 out of 5 pts in DC arm (responders: n=5, mean fold increase baseline = 9.7). All but one pt with clinical responses were in the T cell responder group. Conclusions: Vaccines with recMAGE-A3 protein given with AS02B adjuvant or loaded on DC were safe. Although the cohorts are small, clinical and immune responses against MAGE-A3 protein seem to be more frequent in the AS02B adjuvant arm than in the non-mature DC arm. No significant financial relationships to disclose.
Pathologic Changes Associated with Riboflavin Deficiency in the Mouse
Authors: Stuart W. Lippincott, Harold P. Morris
Journal: JNCI Journal of the National Cancer Institute (1942)

Pathologic Changes Associated with Riboflavin Deficiency in the Mouse Stuart W. Lippincott, Stuart W. Lippincott passed assistant surgeon National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Harold P. Morris Harold P. Morris senior nutrition chemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 2, Issue 6, June 1942, Pages 601–610, https://doi.org/10.1093/jnci/2.6.601 Published: 01 June 1942
Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages
Authors: Maximilian Schieck, Jan P. Schouten, Sven Michel, Kathrin Suttner, Antoaneta A. Toncheva, Vincent D. Gaertner, Thomas Illig, Simone Lipinski, Andre Franke, Michael Klintschar, Omer Kalayci, Umit M. Sahiner, Esra Birben, Erik Melén, Göran Pershagen, Maxim B. Freidin, Ludmila M. Ogorodova, Raquel Granell, John Henderson, Bert Brunekreef, Henriëtte A. Smit, Christian Vogelberg, Andrea von Berg, Albrecht Bufe, Andrea Heinzmann, Otto Laub, Ernst Rietschel, Burkhard Simma, Jon Genuneit, Danny Jonigk, Dirkje S. Postma, Gerard H. Koppelman, Judith M. Vonk, Wim Timens, H. Marike Boezen, Michael Kabesch
Journal: Journal of Allergy and Clinical Immunology (2016)
Acute respiratory effects in atopic humans exposed to short-term controlled exposure to diluted wood smoke
Authors: Ingunn S. Riddervold, Jakob H. Bønløkke, Anna-Carin Olin, Vivi Schlünssen, Torben Sigsgaard
Journal: European Respiratory Journal (2011)

Growing evidence suggests that particulate air pollution derived from wood stoves causes acute inflammation in the respiratory system and possibly increases the incidence of asthma and other respiratory diseases.

The aim of this study was to evaluate acute respiratory effects from short-term wood smoke exposure in humans. A total of 20 non-smoking atopic subjects with normal lung function and without bronchial responsiveness completed the study. The subjects were monitored during three different experimental exposure sessions, aiming at particle concentrations of 200μg/m3, 400μg/m3, and clean air as control exposure. A balanced cross-over design was applied and the subjects were randomly allocated to exposure orders.

Diluted wood smoke were generated in a wood-burning facility and added to a full-scale climate chamber exposure lasted for 3 hours under controlled environmental conditions. Respiratory effects were evaluated at baseline and follow-up measurements during exposure in relation to changes in lung function and were assessed in relation to changes in airway inflammation status measures by fractional exhaled nitric oxide (FENO), exhaled breath condensate (EBC) and nasal lavage (NAL), samples.

No statistically significant differences between the three exposures were found for any of the lung function outcomes: FEV1 (p=0.6283); and FVC (p=0.8364), or for feNO50 (p=0.3578). Mild signs of airway inflammation were found in few of the analyzed markers of inflammation in the NAL and EBC samples. In conclusion, short term exposure with wood smoke causes only mild inflammatory response.
Molecular evolution of a repetitive region within the per gene of Drosophila.
Authors: A A Peixoto, S Campesan, R Costa, C P Kyriacou
Journal: Molecular Biology and Evolution (1993)

The clock gene period (per) controls a number of biological rhythms in Drosophila. In D. melanogaster, per has a repetitive region that encodes a number of alternating threonine-glycine residues. We sequenced and compared this region from several different Drosophila species belonging to various groups within the Drosophila and Sophophora subgenera. This part of per shows a great variability in both DNA sequence and length. Furthermore, analysis of the data suggests that changes in the length of this variable region might be associated with amino acid replacements in the more conserved flanking sequences.
Definitive chemoradiotherapy (CRT) for elderly patients (pts) with thoracic squamous cell carcinoma (SCC) of the esophagus
Authors: K. Mera, A. Ohtsu, M. Muto, T. Yano, T. Doi, K. Nihei, S. Ishikura
Journal: Journal of Clinical Oncology (2005)

4048 Background: Definitive CRT is one of the most common treatment modality for esophageal carcinoma (EC). However, there is only limited data about CRT applied for elderly pts. The aim of this retrospective study was to clarify the feasibility and efficacy of definitive CRT for elderly pts. Methods: Subjects of this study were newly diagnosed thoracic EC between Aug ’92 and Dec ’02, and fulfilled the following criteria; PS ≤ 2, no prior therapy, histologically confirmed SCC, no distant metastatis (M1b) and no serious complication. This analysis compared the efficacy, toxicities and outcome between pts aged ≥ 71 years with those < 70 years. Pts were treated with 5-FU+CDDP+radiotherapy 60Gy (JCO 17, ’99). Results: There were 331 pts who met the recruitment criteria, 58 for ≥ 71 years and 273 for < 70 years. Their characteristics were (≥ 71 vs < 70): male/female: 50/8 vs 232/41, median age (range): 75(71–79) vs 61(39–70), PS 0/1/2: 25/23/0 vs 219/50/4, clinical stage (CS) I/II/III(non T4)/T4 and/or IVA: 8/18/15/17 vs 31/63/84/95. 88% of ≥ 71 years and 94% of < 70 years completed CRT. 43% of ≥ 71 years were required dose reduction and relative dose intensity of CDDP and 5-FU were 0.83 and 0.85 for ≥ 71 years, 0.92 and 0.92 for < 70 years, respectively. Although ≥ 71 years were associated with more leukopenia than < 70 years (62% vs 44%), there were no differences in the rest of all grades 3/4 hematological toxicities and grades 3/4 non-hematological toxicities. No significant differences were identified in tumor response between the age groups, CR rates for ≥ 71 and < 70 years were 62% and 56%, respectively (p=0.4). Estimated 5-year survival rates according to CS in ≥ 71 and < 70 years were, CS I.: 62.5% vs 65.5%, II: 37.0% vs 56.8%, III (non T4): 17.5% vs 25.9%, T4 and/or IVA: 0% vs 13.4%. Death on other diseases were observed in 10(17%) in ≥ 71 years and 43(16%) in < 70 years, possible treatment related death were 0% and 2(0.7%), respectively (p=0.5). Conclusions: Selected elderly pts with thoracic EC treated with CRT obtain the almost identical tumor regression to < 70 years without increased toxicities, though the dose reductions are required. CRT is considered to be feasible and have potential to provide survival benefit in elderly pts. No significant financial relationships to disclose.
Masitinib mesylate in imatinib-resistant advanced GIST: A randomized phase II trial.
Authors: Antoine Adenis, Axel Le Cesne, Binh Bui Nguyen, Olivier Bouche, Julien Domont, Isabelle Ray-Coquard, Nicolas Penel, Aurore Blesius, Francois Montestruc, Alain Moussy, Olivier Hermine, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2012)

10007 Background: Masitinib is an oral tyrosine kinase inhibitor with greater in vitro activity and selectivity than imatinib against wild-type and juxtamembrane mutations of KIT (Dubreuil, 2009, PLoSONE). This trial studied efficacy and safety of masitinib at 12 mg/kg/day and sunitinib at 50 mg/day for the treatment of imatinib-resistant GIST. Methods: Patients with inoperable, locally advanced or metastatic GIST and showing disease progression while treated with imatinib 400 mg/day received either masitinib or sunitinib until progression. Primary endpoint was PFS evaluated with RECIST with OS as a secondary endpoint. Based upon an 80% power to detect with a Fleming design a median PFS ≥3 months (alpha 10%, unilateral), a population of 44 patients (22 per arm) was required. Stratification was applied based on mutation status. Results: 44 patients (exon 11 [66%], exon 9 [11%], wild-type or other [5%], not done at baseline [18%]) were randomized into masitinib (n=23) or sunitinib (n=21) treatment-arms from 9 centers between 02/2009 and 09/2011. After a median follow-up of 14 months, median PFS was 3.9 months (95%CI [2.6;8.1]) for masitinib vs 3.8 months [1.9;11] for sunitinib. Of those patients progressing under masitinib, 88% received sunitinib in third line. Median OS was not reached (NR) (95%CI [21;NR]) for masitinib vs 15 months [9.4;22] for sunitinib. The 18-month and 24-month OS rates for masitinib vs sunitinib were 79% (95%CI [53;92]) vs 20% [1.5;55], and 53% (95%CI [9.5;84]) vs 0%, respectively. Similar results were seen in the exon 11 subpopulation with median OS for masitinib NR (95%CI [NR;NR]) vs 15 months [9.6;22] for sunitinib. The safety profile of masitinib was better than sunitinib with a lower occurrence of severe related adverse events (AEs) (17% vs 52%) and related AEs leading to discontinuation (0% vs 9.5%). In masitinib treated patients, nausea, diarrhea and asthenia were the most common related AEs. Conclusions: Although PFS curves looked similar, this study apparently showed a longer survival in the masitinib treatment-arm with a better safety profile than sunitinib. Masitinib may potentially offer patients a new active compound for advanced GIST in the second-line setting.