tbuckley/cabot-search huggingface dataset:
FDG-PET and Beyond: Molecular Breast Cancer Imaging
Authors: Andrew Quon, Sanjiv S. Gambhir
Journal: Journal of Clinical Oncology (2005)

Positron emission tomography (PET) scanning has gained widespread acceptance for the diagnosis, staging, and management of a variety of malignancies, including breast cancer. This has heralded an exciting new era of molecular imaging research of which using FDG as the primary PET tracer is only the beginning. The fundamental strength of PET over conventional imaging is the ability to convey functional information that even the most exquisitely detailed anatomic image cannot provide. As the standard PET radiotracer in current clinical use, FDG is a glucose analog that is taken up by cells in proportion to their rate of glucose metabolism. The increased glycolytic rate and glucose avidity of malignant cells in comparison to normal tissue is the basis of the ability of FDG-PET imaging to accurately differentiate cancer from benign tissue irregardless of morphology. The level or intensity of FDG uptake on PET is semiquantified and reported as the standardized uptake value (SUV). A multitude of new PET tracers are under development, many of which are aimed at targeting cellular processes that are more specific than glucose metabolism. In relation to breast cancer, these tracers include thymidine analogs such as [F-18]fluoro-L-thymidine (FLT) that target DNA replication as a measure of cell proliferation, annexin V derivatives that evaluate apoptosis, estrogen receptor (ER) tracers such as 16 -[F-18]fluoroestradiol-17 (FES), and engineered antibody fragments that directly target HER-2/neu receptors. In addition to new tracers, scanner technology is also rapidly evolving. Chief among these is the advent of the dual modality PET/CT scanner, which at the very least increases patient convenience by permitting PET and computed tomography (CT) imaging in a single appointment. But perhaps more importantly, initial studies indicate that the sum of the two modalities is better than either used separately and also may be an extremely useful tool in preradiation therapy planning. Other new scanning devices are also being developed, including small gantry PET scanners designed specifically for breast imaging, and handheld PET probes for direct intraoperative localization of tracer-avid tumor foci.
Intra- and intersession variability of the single-breath determination of carbon monoxide diffusing capacity
Authors: Kevin De Soomer, H. Vaerenberg, W. De Backer, E. Oostveen
Journal: European Respiratory Journal (2011)

Background: Some lung function laboratories perform 3 instead of 2 reproducible tests for the single-breath determination of the carbon monoxide diffusing capacity (DLCO) with the underlying assumption that the average of 3 values is more reliable than the average of 2. Recent ATS/ERS guidelines (Eur Respir J 2005) state that the actual number of tests that will provide the best estimate of DLCO is not yet determined.

Aim: To compare the within and between session variability of the DLCO estimate using 2 versus 3 values.

Methods: A DLCO measurement consisted of 3 acceptable tests that met the repeatability requirement according to the ATS/ERS guidelines. DLCO measurements were preferably performed twice a week on fixed, consecutive days just before lunchtime. A total of 10 DLCO measurements were collected in 12 nonsmoking, healthy adults (4M: 8F) during a 6 weeks period of time.

Results: The within and between session coefficients of variability (CoV) are listed in the table.

View this table:



The determination of DLCO using 3 tests did not significantly reduce the within or between CoV compared to the use of only 2 tests. Although adding the third test to estimate DLCO significantly reduced the value of DLCO (p< 0.001), this reduction was not clinically relevant (∼1% reduction in the value of DLCO). For the average healthy subject the DLCO varied as much as ±7% (2 tailed 95% confidence interval) during a 6 weeks period of time.

Conclusion: A DLCO determination based on 3 instead of 2 tests does not result in a more stable estimate of DLCO.
Prenatal and Postnatal Exposure to Polycyclic Aromatic Hydrocarbons and Asthma: Effect of Atopy at Ages 5-6 yrs in an Urban Birth Cohort
Authors: K. Jung, S. Hsu, K. Moors, K. Bernabe, B. Yan, S.N. Chillrud, R. Whyatt, M. Perzanowski, L. Hoepner, I. Goldstein
Journal: Journal of Allergy and Clinical Immunology (2011)
Where to perform noninvasive ventilation?
Authors: M.W. Elliott, M. Confalonieri, S. Nava
Journal: European Respiratory Journal (2002)

Noninvasive positive-pressure ventilation (NPPV) has been shown to be a means of reducing the need for endotracheal intubation, which when effective reduces the complication rate and improves outcome. Because paralysis and sedation are not needed and because the patient is not necessarily dependent upon a machine for respiration, ventilation outside the intensive care unit (ICU) is an option. A number of studies have shown that NPPV for acute exacerbations of chronic obstructive pulmonary disease (COPD) can be effective in the non-ICU environment, though usually in patients with less severe exacerbations. However, there have been no direct comparisons of the application of NPPV in different locations. The likelihood of success of the technique is an important factor in deciding where NPPV should be performed. Ready access to invasive ventilation is important when NPPV is not indicated from the outset or fails after an initial trial. In acute exacerbations of COPD, NPPV is less likely to be successful the more severe the exacerbation, as measured by the severity of acidosis. Good tolerance of NPPV, which translates into an improvement in pH and a fall in respiratory rate, predicts a successful outcome and is a useful way of monitoring progress. NPPV has been shown to be cost effective both in the ICU and when performed on general wards. A dedicated intermediate care unit with particular expertise in noninvasive modes of ventilation may provide the best environment, both in terms of outcome, but also cost effectiveness. The ideal location for noninvasive positive-pressure ventilation will vary from country to country and indeed from hospital to hospital, depending upon local factors. However, the most important factor is that staff be adequately trained in the technique and be available throughout the 24-h period.
Project Data Sphere to Make Cancer Clinical Trial Data Publicly Available
Authors: K. Hede
Journal: JNCI Journal of the National Cancer Institute (2013)

and proprietary issues that have hampered efforts to share data. He developed Project Data Sphere, which within weeks will go live with cancer trial data from an expected five to seven pharmaceutical companies. The goal, according to Hugh-Jones, is to have Project Data Sphere grow into an interactive platform where investigators can learn from the collective successes and failures of previous trials with the help of powerful analytic tools, which the statistical software giant SAS Institute offered to the project free. “The reality is that we have to do better,” said Hugh-Jones. “You’ve got to get beyond a 5% success rate in bringing new oncology drugs to market. But it’s an economic issue as well. People are realizing there just isn’t the money to keep pumping into trials either at a commercial or at a governmental level.”
Tuberculosis Outbreaks Predicted by Characteristics of First Patients in a DNA Fingerprint Cluster
Authors: Sandra V. Kik, Suzanne Verver, Dick van Soolingen, Petra E. W. de Haas, Frank G. Cobelens, Kristin Kremer, Henk van Deutekom, Martien W. Borgdorff
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: Some clusters of patients who have Mycobacterium tuberculosis isolates with identical DNA fingerprint patterns grow faster than others. It is unclear what predictors determine cluster growth.Objectives: To assess whether the development of a tuberculosis (TB) outbreak can be predicted by the characteristics of its first two patients.Methods: Demographic and clinical data of all culture-confirmed patients with TB in the Netherlands from 1993 through 2004 were combined with DNA fingerprint data. Clusters were restricted to cluster episodes of 2 years to only detect newly arising clusters. Characteristics of the first two patients were compared between small (2–4 cases) and large (5 or more cases) cluster episodes.Measurements and Main Results: Of 5,454 clustered cases, 1,756 (32%) were part of a cluster episode of 2 years. Of 622 cluster episodes, 54 (9%) were large and 568 (91%) were small episodes. Independent predictors for large cluster episodes were as follows: less than 3 months' time between the diagnosis of the first two patients, one or both patients were young (<35 yr), both patients lived in an urban area, and both patients came from sub-Saharan Africa.Conclusions: In the Netherlands, patients in new cluster episodes should be screened for these risk factors. When the risk pattern applies, targeted interventions (e.g., intensified contact investigation) should be considered to prevent further cluster expansion.
Lack of Character Displacement in the Male Recognition Molecule, Bindin, in Altantic Sea Urchins of the Genus Echinometra
Authors: L. B. Geyer, H.A. Lessios
Journal: Molecular Biology and Evolution (2009)

Bindin, a protein involved in sea urchin sperm–egg recognition and adhesion, is under positive selection in genera with sympatric species but evolves neutrally in genera in which all species are allopatric. This pattern has led to suggestions that reinforcement may be the source of the observed selection. Reproductive character displacement, or increased divergence of reproductive characters in areas where closely related species overlap, is often a consequence of reinforcement and has been shown to be present in one Indo-Pacific species of the genus Echinometra. In the Atlantic species of the same genus, positive selection has been shown to act on bindin of Echinometra lucunter. To examine whether the source of this selection is reinforcement, we determined variation on the first exon of bindin in E. lucunter in the Caribbean, where it is sympatric with Echinometra viridis, and in the rest of the Atlantic, where E. viridis is absent. There was no differentiation between bindin sequences from the two geographic regions; similar levels of positive selection were found to be acting in both areas. The similarities were not due to gene flow; mitochondrial DNA from the two regions indicates that E. lucunter populations most likely originated in the Atlantic and have not exchanged genes with Caribbean populations for approximately 200,000 years. The lack of evidence of stronger selection on bindin of E. lucunter in areas of sympatry with its sister species suggests that the source of selection is not reinforcement. Processes acting within species, such as sexual selection, sperm competition, or sexual conflict, are more likely to be involved in the evolution of this molecule.
Hypoxic Culture Induces Expression of Sialin, a Sialic Acid Transporter, and Cancer-Associated Gangliosides Containing Non–Human Sialic Acid on Human Cancer Cells
Authors: Jun Yin, Ayako Hashimoto, Mineko Izawa, Keiko Miyazaki, Guo-Yun Chen, Hiromu Takematsu, Yasunori Kozutsumi, Akemi Suzuki, Kimio Furuhata, Feng-Leng Cheng, Chun-Hung Lin, Chihiro Sato, Ken Kitajima, Reiji Kannagi
Journal: Cancer Research (2006)

Abstract Tumor hypoxia figures heavily in malignant progression by altering the intracellular glucose metabolism and inducing angiogenic factor production, thus, selecting and expanding more aggressive cancer cell clones. Little is known, however, regarding hypoxia-induced antigenic changes in cancers. We investigated the expression of N-glycolyl sialic acid (NeuGc)-GM2, a cancer-associated ganglioside containing non–human sialic acid, NeuGc, in human cancers. Cancer tissues prepared from patients with colon cancers frequently expressed NeuGc-GM2, whereas it was virtually absent in nonmalignant colonic epithelia. Studies on cultured cancer cells indicated that the non–human sialic acid was incorporated from culture medium. Hypoxic culture markedly induced mRNA for a sialic acid transporter, sialin, and this accompanied enhanced incorporation of NeuGc as well as N-acetyl sialic acid. Transfection of cells with sialin gene conferred accelerated sialic acid transport and induced cell surface expression of NeuGc-GM2. We propose that the preferential expression of NeuGc-GM2 in cancers is closely associated with tumor hypoxia. Hypoxic culture of tumor cells induces expression of the sialic acid transporter, and enhances the incorporation of non–human sialic acid from the external milieu. A consequence of this is the acquisition of cancer-associated cell surface gangliosides, typically GM2, containing non–human sialic acid (NeuGc), which is not endogenously synthesized through CMP-N-acetyl sialic acid hydroxylase because humans lack the gene for the synthetic enzyme. As hypoxia is associated with diminished response to radiotherapy and chemotherapy, NeuGc-GM2 is a potential therapeutic target for hypoxic cancer cells. (Cancer Res 2006; 66(6): 2937-45)
Inhibition of Protein Kinase Cβ by Enzastaurin Enhances Radiation Cytotoxicity in Pancreatic Cancer
Authors: Aaron C. Spalding, Richard Watson, Mary E. Davis, Alex C. Kim, Theodore S. Lawrence, Edgar Ben-Josef
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Aberrant activation of protein kinase Cβ (PKCβ) by pancreatic cancer cells facilitates angiogenesis and tumor cell survival. Targeting PKCβ with enzastaurin, a well-tolerated drug in clinical trials, would be expected to radiosensitize pancreatic tumors through direct antitumor and antivascular effects. Experimental Design: We tested the hypothesis that enzastaurin radiosensitizes pancreatic cancer cells in culture and in vivo through inhibition of PKCβ. We analyzed pancreatic cancer xenografts for growth delay and microvessel density after treatment with enzastaurin, radiation, or both. We determined the effect of radiation and enzastaurin on glycogen synthase kinase 3β, a mediator of cell death in culture and in vivo. Results: At concentrations attained in patients, enzastaurin reduced levels of active PKCβ measured by phosphorylation at Thr500 in culture and in xenografts. Enzastaurin alone did not affect pancreatic cancer cell survival, proliferation, or xenograft growth. However, enzastaurin radiosensitized pancreatic cancer cells in culture by colony formation assay. Enzastaurin alone decreased microvessel density of pancreatic cancer xenografts without appreciable effects on tumor size. When combined with radiation, enzastaurin increased radiation-induced tumor growth delay with a corresponding decrease in microvessel density. Enzastaurin inhibited radiation-induced phosphorylation of glycogen synthase kinase 3β at Ser9 in pancreatic cancer cells in culture and in tumor xenografts, suggesting a possible mechanism for the observed radiosensitization. Conclusions: Enzastaurin inhibits PKCβ in pancreatic cancer cells in culture, enhancing radiation cytotoxicity. Additional antivascular effects of enzastaurin were observed in vivo, resulting in greater radiosensitization. These results provide the rationale for a clinical trial in locally advanced pancreatic cancer combining enzastaurin with radiation.
Molecular Target Modulation, Imaging, and Clinical Evaluation of Gastrointestinal Stromal Tumor Patients Treated with Sunitinib Malate after Imatinib Failure
Authors: George D. Demetri, Michael C. Heinrich, Jonathan A. Fletcher, Christopher D.M. Fletcher, Annick D. Van den Abbeele, Christopher L. Corless, Cristina R. Antonescu, Suzanne George, Jeffrey A. Morgan, Ming Hui Chen, Carlo L. Bello, Xin Huang, Darrel P. Cohen, Charles M. Baum, Robert G. Maki
Journal: Clinical Cancer Research (2009)

To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules.In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-d-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed.Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease > or =6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-d-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity.Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy.
Multivariate Prognostic Factor Analysis in Locally Advanced and Metastatic Esophago-Gastric Cancer—Pooled Analysis From Three Multicenter, Randomized, Controlled Trials Using Individual Patient Data
Authors: Ian Chau, Andy R. Norman, David Cunningham, Justin S. Waters, Jacqui Oates, Paul J. Ross
Journal: Journal of Clinical Oncology (2004)

Purpose To identify baseline prognostic factors and assess whether pretreatment quality of life (QoL) predicts survival in patients with locally advanced or metastatic esophago-gastric cancer. Patients and Methods Between 1992 and 2001, 1,080 patients were enrolled into three randomized, controlled trials assessing fluorouracil-based combination chemotherapy. All patients were required to complete the European Organization for Research and Treatment of Cancer core QoL questionnaire before random assignment. Results Of the 1,080 patients randomly assigned, 979 (91%) died. Four independent poor prognostic factors were identified by multivariate analysis: performance status ≥ 2 (hazard ratio [HR], 1.58; 99% CI, 1.25 to 1.98), liver metastases (HR, 1.41; 99%CI, 1.14 to 1.74), peritoneal metastases (HR, 1.33; 99%CI, 1.01 to 1.74) and alkaline phosphatase ≥ 100 U/L (HR, 1.41; 99% CI, 1.14 to 1.76). A prognostic index was constructed dividing patients into good (no risk factor), moderate (one or two risk factors) or poor (three or four risk factors) risk groups. One-year survival for good, moderate, and poor risk groups were 48.5%, 25.7%, and 11%, respectively, and the survival differences among these groups were highly significant (P &lt; .00001). Compared with the good risk group, the moderate risk group had nearly twice the risk of death, and the poor risk group had 3.5-fold increased risk of death. Pretreatment physical (P = .003), role functioning (P &lt; .001), and global QoL (P &lt; .001) predicted survival. Conclusion Four poor prognostic factors were identified and a simple prognostic index was devised. Information from this analysis can be used to aid clinical decision-making, help individual patient risk stratification, and serve as benchmark for the planning for future phase III trials.
Lactoferrin Down-Regulates G1 Cyclin-Dependent Kinases during Growth Arrest of Head and Neck Cancer Cells
Authors: Yan Xiao, Constance L. Monitto, Khalid M. Minhas, David Sidransky
Journal: Clinical Cancer Research (2004)

The molecular mechanism of lactoferrin-induced cell growth inhibition is incompletely understood. Studying head and neck cancer cells treated with human lactoferrin, we observed growth arrest in three of four cell lines tested. This growth arrest was caused by cell cycle inhibition at the G0-G1 checkpoint. Lactoferrin-induced growth inhibition was associated with a large increase in p27 protein, accompanied by decreased phosphorylation of retinoblastoma protein, and suppression of cyclin E. Decreased levels of phosphorylated Akt were also observed in lactoferrin-sensitive cell lines after treatment. These findings suggest that in head and neck cancer cells the growth inhibitory effects of lactoferrin are mediated through a p27/cyclin E-dependent pathway that may be modulated in part by changes in Akt phosphorylation.
Importance of behaviour in LTP research
Authors: Donald Peter Cain
Journal: Behavioral and Brain Sciences (1997)

Shors and Matzel's evaluation of approaches to the behavioural function of LTP is welcome, and should encourage a widening of conceptual approaches to this problem. In addition to their call for increased sophistication in thinking about LTP, there needs to be a parallel increase in sophistication in the study of behaviour. Changes in emotional state or tone may be a better function for LTP than attention mechanisms.
OP07 Phenotypic description of a large cohort of PSC patients in the UK
Authors: B. Srivastava, A. Muriithi, M. Brown, G. Alexander, T. H. Karlsen, S. Rushbrook, R. W. Chapman
Journal: Gut (2011)

<h3>Introduction</h3> Primary Sclerosing cholangitis (PSC), a chronic cholestatic liver disease of unknown aetiology or pathogenesis, remains an area for active research. <h3>Aim</h3> The demographic and phenotypic characteristics of a UK cohort of 1194 patients with PSC are described. <h3>Method</h3> All patients were recruited as part of an ongoing national collaborative effort (PSC-UK) between October 2008 and May 2011. The diagnosis of PSC was confirmed on the basis of characteristic ERCP, MRCP or histology. Patients with small-duct PSC were also included. All patients completed a descriptive phenotypic questionnaire sent at recruitment. Demographic, phenotypic data and family history were extracted from the participant questionnaires. <h3>Results</h3> 1194 patients have returned completed questionnaires. Median age at recruitment was 59 years and 63% were male (male to female ratio =1.7:1). 64% of patients were lifelong non-smokers and only 4.3% were smoking at recruitment. 63.5% reported inflammatory bowel disease, split into 87% with Ulcerative colitis and 13% with Crohn9s disease. 1.5% had a sibling with PSC and 14% had a sibling with inflammatory bowel disease. Further, 0.5% had one or more children with PSC and 4.6% had children with inflammatory bowel disease. 24% were asymptomatic, but over 50% reported itching and fatigue as the presenting symptom. Jaundice was present in 35%. The most common associated autoimmune disease was thyroid disease, present in 9% followed by Coeliac disease in 2.1% and type 1 diabetes mellitus in 1.8%. 16% of patients reported pan-procto or sub-total colectomy and 12.2% had undergone cholecystectomy. 2.7% of patients reported a history of colon cancer and 1.25% patients had a history of skin cancer. <h3>Conclusion</h3> This is the largest reported demographic and phenotypic description of a single cohort of PSC patients. PSC is more common in young, non-smoking male patients. The frequency of associated inflammatory bowel disease is similar to that reported in other studies. It is plausible that siblings of patients with PSC have an increased risk of not only PSC but also inflammatory bowel disease. These data are consistent with increasing evidence pointing to a role of genetic factors in the pathogenesis of PSC.