tbuckley/cabot-search huggingface dataset:
Use of Patient-Reported Outcomes in Phase III Cancer Treatment Trials: Lessons Learned and Future Directions
Authors: Patricia A. Ganz, Carolyn C. Gotay
Journal: Journal of Clinical Oncology (2007)

This article examines the challenges, opportunities, and successes that have occurred in the incorporation of patient-reported outcomes (PROs) in phase III cancer clinical trials.An informal survey of the leadership of US cooperative group PRO investigators identified diverse trials in which PROs had been measured. Exemplary trials were selected for lessons learned and for examination of successful strategies.We review four challenging trials in depth, illustrating some of the difficulties in integrating PROs within treatment trials, including issues related to missing data, lack of procedures for monitoring patients and ensuring collection of PRO data, and missed opportunities in publication of treatment and PRO outcomes together. Four examples of successful trials are highlighted.As a result of this review, the authors make specific recommendations related to the use of PROs in phase III trials, focusing on issues related to design, choice of PRO instrument and frequency of administration, analysis, and publication strategies.
Impact of Glycemic and Blood Pressure Variability on Surrogate Measures of Cardiovascular Outcomes in Type 2 Diabetic Patients
Authors: Alessandra Di Flaviani, Fabiana Picconi, Paola Di Stefano, Ilaria Giordani, Ilaria Malandrucco, Paola Maggio, Paola Palazzo, Fabrizio Sgreccia, Carlo Peraldo, Fabrizio Farina, Gaetano Frajese, Simona Frontoni
Journal: Diabetes Care (2011)

The effect of glycemic variability (GV) on cardiovascular risk has not been fully clarified in type 2 diabetes. We evaluated the effect of GV, blood pressure (BP), and oxidative stress on intima-media thickness (IMT), left ventricular mass index (LVMI), flow-mediated dilation (FMD), and sympathovagal balance (low frequency [LF]/high frequency [HF] ratio) in 26 type 2 diabetic patients (diabetes duration 4.41±4.81 years; HbA1c 6.70±1.25%) receiving diet and/or metformin treatment, with no hypotensive treatment or complications.Continuous glucose monitoring (CGM) data were used to calculate mean amplitude of glycemic excursion (MAGE), continuous overall net glycemic action (CONGA)-2, mean blood glucose (MBG), mean postprandial glucose excursion (MPPGE), and incremental area under the curve (IAUC). Blood pressure (BP), circadian rhythm, and urinary 15-F2t-isoprostane (8-iso-prostaglandin F2α [PGF2α]) were also evaluated. Subjects were divided into dipper (D) and nondipper (ND) groups according to ΔBP.IMT and LVMI were increased in ND versus D (0.77±0.08 vs. 0.68±0.13 [P=0.04] and 67±14 vs. 55±11 [P=0.03], respectively). MBG, MAGE, and IAUC were significantly associated with LF/HF ratio at night (r=0.50, P=0.01; r=0.40, P=0.04; r=0.41, P=0.04, respectively), MPPGE was negatively associated with FMD (r=-0.45, P=0.02), and CONGA-2 was positively associated with LVMI (r=0.55, P=0.006). The Δsystolic BP was negatively associated with IMT (r=-0.43, P=0.03) and with LVMI (r=-0.52, P=0.01). Urinary 8-iso-PGF2α was positively associated with LVMI (r=0.68 P<0.001).An impaired GV and BP variability is associated with endothelial and cardiovascular damage in short-term diabetic patients with optimal metabolic control. Oxidative stress is the only independent predictor of increased LV mass and correlates with glucose and BP variability.
Inflammation and Atherosclerosis
Authors: Peter Libby, Paul M. Ridker, Attilio Maseri
Journal: Circulation (2002)

Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.
Fluorescence virus-guided capturing system of human colorectal circulating tumour cells for non-invasive companion diagnostics
Authors: Kunitoshi Shigeyasu, Hiroshi Tazawa, Yuuri Hashimoto, Yoshiko Mori, Masahiko Nishizaki, Hiroyuki Kishimoto, Takeshi Nagasaka, Shinji Kuroda, Yasuo Urata, Ajay Goel, Shunsuke Kagawa, Toshiyoshi Fujiwara
Journal: Gut (2014)

<h3>Background</h3> Molecular-based companion diagnostic tests are being used with increasing frequency to predict their clinical response to various drugs, particularly for molecularly targeted drugs. However, invasive procedures are typically required to obtain tissues for this analysis. Circulating tumour cells (CTCs) are novel biomarkers that can be used for the prediction of disease progression and are also important surrogate sources of cancer cells. Because current CTC detection strategies mainly depend on epithelial cell-surface markers, the presence of heterogeneous populations of CTCs with epithelial and/or mesenchymal characteristics may pose obstacles to the detection of CTCs. <h3>Methods</h3> We developed a new approach to capture live CTCs among millions of peripheral blood leukocytes using a green fluorescent protein (GFP)-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401, TelomeScan). <h3>Results</h3> Our biological capturing system can image epithelial and mesenchymal tumour cells with telomerase activities as GFP-positive cells. After sorting, direct sequencing or mutation-specific PCR can precisely detect different mutations in <i>KRAS</i>, <i>BRAF</i> and <i>KIT</i> genes in epithelial, mesenchymal or epithelial–mesenchymal transition-induced CTCs, and in clinical blood samples from patients with colorectal cancer. <h3>Conclusions</h3> This fluorescence virus-guided viable CTC capturing method provides a non-invasive alternative to tissue biopsy or surgical resection of primary tumours for companion diagnostics.
Mechanistic role of heat shock protein 70 in Bcr-Abl–mediated resistance to apoptosis in human acute leukemia cells
Authors: Fei Guo, Celia Sigua, Purva Bali, Prince George, Warren Fiskus, Anna Scuto, Srinivas Annavarapu, Abdelmoughite Mouttaki, Gautam Sondarva, Sheng Wei, Jie Wu, Julie Djeu, Kapil Bhalla
Journal: Blood (2004)
Guidelines for exercise testing in the pediatric age group. From the Committee on Atherosclerosis and Hypertension in Children, Council on Cardiovascular Disease in the Young, the American Heart Association.
Authors: R L Washington, J T Bricker, B S Alpert, S R Daniels, R J Deckelbaum, E A Fisher, S S Gidding, J Isabel-Jones, R E Kavey, G R Marx
Journal: Circulation (1994)

Exercise testing of children differs from adult exercise testing in many ways beyond the technical issues related to test performance that are addressed in this report. Disease processes that produce myocardial ischemia are relatively rare in children compared with adults. Exercise testing may be useful in these cases, but the use of testing to assess functional capacity or cardiac rhythms will be encountered more often. Although the precise role of exercise testing in patient evaluation or long-term management of the cardiac patient will vary somewhat from center to center, exercise testing is often essential to diagnose and to direct treatment in a wide variety of clinical problems. An understanding of the role of exercise testing for children with known or suspected heart abnormalities is an essential part of the training of pediatric cardiologists. The staff of the pediatric exercise laboratory should be available to discuss with the clinician when a test might be of value in a specific case in addition to providing advice about the specifics of the performance of the test and offering age- and size-appropriate normal data from the laboratory with test interpretation.
Physical therapy treatment for adhesive capsulitis: clinical evidence and clinical reasoning
Authors: A Salam, S Hemmings, D Morrissey
Journal: British Journal of Sports Medicine (2011)

Background Many barriers exist impeding the translation of treatment evidence into practice for adhesive capsulitis (AC). The need for evidence-based practice is unquestionable, with reasoning skills needed to evaluate and apply the evidence. This study aims to combine published evidence and clinical reasoning to optimally guide clinical practice. Objectives The first is to categorise and grade the evidence for each individual physical therapy treatment modality for AC, through a literature review. This informs the second; qualitative exploration of physiotherapists' perceptions of the evidence and its interaction with clinical reasoning. Methods A systematic literature search was conducted for reviews and trials describing a physical therapy treatment for AC. Summaries of each individual modality were generated, and graded on the strength of supporting evidence. Semi-structured interviews were also conducted with experienced physiotherapists until data saturation. Results The literature search yielded 26 studies, from which 19 physical therapy interventions were identified. Strong evidence exists to support the use of education, steroid injection, mobilisations, stretching, supervised exercise, home exercise, acupuncture, heat therapy, transcutaneous electrical nerve stimulation, non-steroidal anti-inflammatory drugs and interferential electrotherapy. Moderate evidence exists for six modalities, and limited evidence for two. Fourteen themes surrounding the assessment, treatment and evidence behind AC were identified from framework analysis of interview transcripts. Conclusion There is relatively little high quality evidence in favour of one modality over another for AC. Until the quality and scope of evidence improves, clinicians will continue to rely heavily on their own expertise for treatment. These results are a meaningful guide to clinical practice, and reveal a number of research questions.
The Translational Research Working Group Developmental Pathway for Image-Based Assessment Modalities
Authors: Gary S. Dorfman, Daniel C. Sullivan, Mitchell D. Schnall, Lynn M. Matrisian
Journal: Clinical Cancer Research (2008)

The Image-based assessment modality (IM) pathway refers to one of six Translational Research Working Group (TRWG) pathways that, together, describe the core domains of early translational cancer research. This pathway focuses on approaches that are based on the interaction of energy and living organisms to analyze tissue noninvasively so as to reveal properties relevant to the detection, diagnosis, or prognosis of cancer and precancer; or the response of the cancer to therapy. Examples include, but are not limited to, magnetic resonance imaging and positron emission tomography, as well as contemporary contrast agents designed to probe specific molecular constituents of tumors. The IM pathway is presented as a general outline of the steps required for the effective development, optimization, testing, and validation of image-based modalities. The distinctive features of the IM pathway and issues encountered that represent obstacles to effective and efficient progress through the pathway are discussed. The IM pathway also forms a framework to identify opportunities to address current barriers and is expected to adapt and evolve as the field advances.
Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells
Authors: J Etchin, Q Sun, A Kentsis, A Farmer, Z C Zhang, T Sanda, M R Mansour, C Barcelo, D McCauley, M Kauffman, S Shacham, A L Christie, A L Kung, S J Rodig, Y M Chook, A T Look
Journal: Leukemia (2012)

Drugs that target the chief mediator of nuclear export, chromosome region maintenance 1 protein (CRM1) have potential as therapeutics for leukemia, but existing CRM1 inhibitors show variable potencies and a broad range of cytotoxic effects. Here, we report the structural analysis and antileukemic activity of a new generation of small-molecule inhibitors of CRM1. Designated selective inhibitors of nuclear export (SINE), these compounds were developed using molecular modeling to screen a small virtual library of compounds against the nuclear export signal (NES) groove of CRM1. The 2.2-Å crystal structure of the CRM1-Ran-RanBP1 complex bound to KPT-251, a representative molecule of this class of inhibitors, shows that the drug occupies part of the groove in CRM1 that is usually occupied by the NES, but penetrates much deeper into the groove and blocks CRM1-directed protein export. SINE inhibitors exhibit potent antileukemic activity, inducing apoptosis at nanomolar concentrations in a panel of 14 human acute myeloid leukemia (AML) cell lines representing different molecular subtypes of the disease. When administered orally to immunodeficient mice engrafted with human AML cells, KPT-251 had potent antileukemic activity with negligible toxicity to normal hematopoietic cells. Thus, KPT-SINE CRM1 antagonists represent a novel class of drugs that warrant further testing in AML patients.
ANTIGENIC PROPERTIES OF THE TYPE-SPECIFIC SUBSTANCE DERIVED FROM GROUP A HEMOLYTIC STREPTOCOCCI
Authors: George K. Hirst, Rebecca C. Lancefield
Journal: The Journal of Experimental Medicine (1939)

1. A substance extracted from group A hemolytic streptococcus is described, which induces active immunity in mice, and in rabbits gives rise to precipitins and to protective antibodies passively transferable to mice. 2. The active immunity in mice is principally type-specific, but some degree of non-type-specific immunity is also developed. The passively transferable protective antibodies are type-specific with only a slight suggestion of non-type specificity. In the precipitin test, the rabbit immune sera give both type-specific and non-type-specific reactions which have not been fully analyzed serologically. 3. Substances contained in the extract absorb the protective antibodies from the serum of rabbits immunized with whole hemolytic streptococci. 4. The most satisfactory method of extraction so far developed is fully described. Chemical tests on the material are consistent with the presence of protein and nucleic acid. 5. The type-specific M substance, prepared as previously described, was compared in some of its antigenic properties with the above mentioned substance. It was found capable of inducing active immunity in mice and of absorbing protective antibody from anti-bacterial immune serum in a manner qualitatively similar to that obtained with the preparations made by the newer methods.
Maternal Smoking During Pregnancy and Bipolar Disorder in Offspring
Authors: Ardesheer Talati, Yuanyuan Bao, Jake Kaufman, Ling Shen, Catherine A. Schaefer, Alan S. Brown
Journal: American Journal of Psychiatry (2013)

Objective Maternal smoking during pregnancy is associated with a number of adverse externalizing outcomes for offspring from childhood to adulthood. The relationship between maternal smoking and bipolar disorder in offspring, which includes externalizing symptoms among its many manifestations, has not been investigated in depth. The authors examined whether offspring exposed to maternal smoking in utero would be at increased lifetime risk for bipolar disorder after accounting for other factors related to maternal smoking. Method Individuals with bipolar disorder (N=79) were ascertained from the birth cohort of the Child Health and Development Study. Case subjects were identified by a combination of clinical, database, and direct mailing sources; all case subjects were directly interviewed and diagnosed using DSM-IV criteria. Comparison subjects (N=654) were matched to case subjects on date of birth (±30 days), sex, membership in the cohort at the time of illness onset, and availability of maternal archived sera. Results After adjusting for potential confounders, offspring exposed to in utero maternal smoking exhibited a twofold greater risk for bipolar disorder (odds ratio=2.014, 95% confidence interval=1.48–2.53, p=0.01). The associations were noted primarily among bipolar offspring without psychotic features. Conclusions Prenatal tobacco exposure may be one suspected cause of bipolar disorder. However, it will be necessary to account for other unmeasured familial factors before causal teratogenic effects can be suggested.
Disruptive <i>TP53</i> Mutation Is Associated with Aggressive Disease Characteristics in an Orthotopic Murine Model of Oral Tongue Cancer
Authors: Daisuke Sano, Tong-Xin Xie, Thomas J. Ow, Mei Zhao, Curtis R. Pickering, Ge Zhou, Vlad C. Sandulache, David A. Wheeler, Richard A. Gibbs, Carlos Caulin, Jeffrey N. Myers
Journal: Clinical Cancer Research (2011)

To characterize tumor growth and metastatic potential in head and neck squamous cell carcinoma (HNSCC) cell lines in an orthotopic murine model of oral tongue cancer and to correlate TP53 mutation status with these findings.Cells from each of 48 HNSCC cell lines were orthotopically injected into the oral tongues of nude mice. Tumor volume, cervical lymph node metastasis, and mouse survival were recorded. Direct sequencing of the TP53 gene and Western blot analysis for the p53 protein after induction with 5-fluorouracil was conducted. Cell lines were categorized as either mutant TP53 or wild-type TP53, and lines with TP53 mutation were further categorized on the basis of type of mutation (disruptive or nondisruptive) and level of p53 protein expression. The behavior of tumors in these different groups was compared.These 48 HNSCC cell lines showed a wide range of behavior from highly aggressive and metastatic to no tumor formation. Mice injected with cells harboring disruptive TP53 mutations had faster tumor growth, greater incidence of cervical lymph node metastasis, and shorter survival than mice injected with cells lacking these mutations.HNSCC cell lines display a wide spectrum of behavior in an orthotopic model of oral cancer. Cell lines with disruptive TP53 mutations are more aggressive in this system, corroborating clinical reports that have linked these mutations to poor patient outcome.
Factor XIII Deficiency Causes Cardiac Rupture, Impairs Wound Healing, and Aggravates Cardiac Remodeling in Mice With Myocardial Infarction
Authors: Matthias Nahrendorf, Kai Hu, Stefan Frantz, Farouc A. Jaffer, Ching-Hsuan Tung, Karl-Heinz Hiller, Sabine Voll, Peter Nordbeck, David Sosnovik, Stefan Gattenlöhner, Mikhail Novikov, Gerhard Dickneite, Guy L. Reed, Peter Jakob, Anthony Rosenzweig, Wolfgang R. Bauer, Ralph Weissleder, Georg Ertl
Journal: Circulation (2006)

Identification of key molecular players in myocardial healing could lead to improved therapies, reduction of scar formation, and heart failure after myocardial infarction (MI). We hypothesized that clotting factor XIII (FXIII), a transglutaminase involved in wound healing, may play an important role in MI given prior clinical and mouse model data.To determine whether a truly causative relationship existed between FXIII activity and myocardial healing, we prospectively studied myocardial repair in FXIII-deficient mice. All FXIII(-/-) and FXIII(-)(/+) (FXIII activity <5% and 70%) mice died within 5 days after MI from left ventricular rupture. In contradistinction, FXIII(-/-) mice that received 5 days of intravenous FXIII replacement therapy had normal survival rates; however, cardiac MRI demonstrated worse left ventricular remodeling in these reconstituted FXIII(-/-) mice. Using a FXIII-sensitive molecular imaging agent, we found significantly greater FXIII activity in wild-type mice and FXIII(-/-) mice receiving supplemental FXIII than in FXIII(-/-) mice (P<0.05). In FXIII(-/-) but not in reconstituted FXIII(-/-) mice, histology revealed diminished neutrophil migration into the MI. Reverse transcriptase-polymerase chain reaction studies suggested that the impaired inflammatory response in FXIII(-/-) mice was independent of intercellular adhesion molecule and lipopolysaccharide-induced CXC chemokine, both important for cell migration. After MI, expression of matrix metalloproteinase-9 was 650% higher and collagen-1 was 53% lower in FXIII(-/-) mice, establishing an imbalance in extracellular matrix turnover and providing a possible mechanism for the observed cardiac rupture in the FXIII(-/-) mice.These data suggest that FXIII has an important role in murine myocardial healing after infarction.
mTNF reverse signalling induced by TNFα antagonists involves a GDF-1 dependent pathway: implications for Crohn's disease
Authors: Stefanie Derer, Andreas Till, Robert Haesler, Christian Sina, Nils Grabe, Sascha Jung, Susanna Nikolaus, Tanja Kuehbacher, Joachim Groetzinger, Stefan Rose-John, Philip C Rosenstiel, Stefan Schreiber
Journal: Gut (2012)

<h3>Objective</h3> Mechanisms of action (MoA) of anti-tumour necrosis factor α (TNFα) therapies in Crohn9s disease (CD) may critically involve induction of immune cell apoptosis via membrane-bound TNFα (mTNFα) binding. Certolizumab pegol (CZP), which is effective in induction and maintenance of remission in CD lacks the ability to induce apoptosis. The aim of this study was to analyse transcriptomal responses of reverse signalling induced by the TNFα binding agents infliximab (IFX) and CZP in myelomonocytic cells. <h3>Design</h3> Induction of transcriptional patterns upon anti-TNFα stimulation was assessed using oligonucleotide microarrays. mRNA expression of <i>GDF-1/ LASS1</i>, which was identified as a shared target, was studied in inflammatory bowel disease by real-time PCR, while signalling pathways induced by growth and differentiation factor 1 (GDF-1) were investigated using western blots and ELISA. <h3>Results</h3> IFX and CZP induced a common signature of 20 transcripts that could be categorised into control of cell cycle, transcription activation and pre-mRNA processing. We selected <i>GDF-1/LASS1</i> for functional follow-up, which was found to be upregulated in inflamed CD tissues. We show that downregulation of <i>GDF-1/LASS1</i> depends on autocrine release of transforming growth factor β after mTNFα ligation. We demonstrate that GDF-1 itself acts as a novel proinflammatory factor via induction of interleukin 6 and signal transducer and activator of transcription 3 and is downregulated after IFX treatment. <h3>Conclusion</h3> Commonalities in the MoA of IFX and CZP comprise modulation of non-apoptotic pathways through downregulation of proinflammatory GDF-1. Further characterisation of the molecular role of GDF-1 in complex inflammatory processes in vivo is warranted to decide whether this proinflammatory molecule is a promising therapeutic target in patients with CD.