tbuckley/cabot-search huggingface dataset:
Pharmacobiologically Based Scheduling of Capecitabine and Docetaxel Results in Antitumor Activity in Resistant Human Malignancies
Authors: Padma Nadella, Charles Shapiro, Gregory A. Otterson, Marsha Hauger, Selnur Erdal, Eric Kraut, Steven Clinton, Manisha Shah, Mike Stanek, Paul Monk, Miguel A. Villalona-Calero
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Capecitabine and docetaxel have demonstrated preclinical antitumor synergy. This synergy is thought to occur from docetaxel-mediated upregulation of thymidine phosphorylase (dThdPase), an enzyme responsible for the relative tumor selectivity of capecitabine. On the basis of the time-dependency and transiency for this upregulation, we performed a phase I study of capecitabine in combination with weekly docetaxel. We hypothesized that weekly docetaxel would result in sustained dThdPase expression and that capecitabine administration at times of maximum dThdPase upregulation would increase the therapeutic index for this combination. PATIENTS AND METHODS: Patients with advanced solid malignancies received docetaxel on days 1, 8, and 15, and capecitabine bid on days 5 to 18, every 4 weeks. Docetaxel was fixed at 36 mg/m 2 /wk, whereas capecitabine was escalated in successive patients cohorts. RESULTS: Sixteen patients received 77 courses at capecitabine doses from 950 to 1,500 mg/m 2 /d. The most common toxicities were hand-foot syndrome, diarrhea, nausea/vomiting, and asthenia. Grades 3 to 4 hematologic toxicities were infrequent and no treatment-related hospitalizations occurred. Three of three patients treated at 1,500/36 mg/m 2 capecitabine/docetaxel developed grade 3 hand-foot syndrome or diarrhea during either their first or second course, whereas only two of 13 patients at 1,250/36 mg/m 2 doses developed significant toxicity. Antitumor responses (n = 7) occurred in patients with hepatocellular, non–small-cell lung, and chemotherapy-refractory breast, bladder, and colorectal carcinomas. Prolonged stabilizations occurred in patients with metastatic mesothelioma (n = 2), chemorefractory non–small-cell lung carcinoma, and bronchioloalveolar carcinoma. CONCLUSION: Capecitabine in combination with weekly docetaxel is well tolerated. Recommended doses are capecitabine 1,250 mg/m 2 /d (625 mg/m 2 bid) with docetaxel 36 mg/m 2 /wk. The acceptable toxicity profile in this dose schedule, and the antitumor activity observed, warrant further evaluation of this regimen.
Long term bradycardia by electrical pacing: a new method for studying heart rate reduction
Authors: M D Brown, M K Davies, O Hudlicka, P Townsend
Journal: Cardiovascular Research (1994)

Objective: The aim was to develop a method of inducing bradycardia on a chronic basis by electrical pacing and to study its effect upon myocardial capillarity in pigs. Methods: Farm pigs were instrumented with Medtronic® dual chamber telemetric pacemakers and two leads, either both atrial or one atrial and one ventricular. Bradycardia was achieved by linking pacing stimuli to endogenous atrial or ventricular events for the different electrode positions respectively, and monitored postoperatively for 4-5 weeks by implanted telemetric ECG devices. Myocardial capillary supply (lectin staining) and myocyte cross sectional areas were then estimated in sections of the left ventricle. Results: Heart rates were reduced by 40-50 beats·min−1 at operation from a resting rate of 110(SEM 3) beats·min−1 in eight animals and bradycardia maintained upon recovery from anaesthesia for up to five weeks, with no obvious limitations for the animals. After this time, heart rates measured under anaesthesia were found to remain low for up to 2 h after pacing had been switched off. There was no evidence of myocyte hypertrophy, yet mean capillary density·mm−2 was significantly increased by pacing, from 1470(50) to 1734(82), p<0.02. Conclusions: It is possible to produce primary heart rate reduction in the pig by a novel means of pacing on a chronic basis, leading to increased myocardial capillary supply without myocyte hypertrophy. This method can provide a basis for future investigations of the beneficial effects of heart rate reduction in the vascularly compromised heart. Cardiovascular Research 1994;28:1774-1779
The human sinus node electrogram: a transvenous catheter technique and a comparison of directly measured and indirectly estimated sinoatrial conduction time in adults.
Authors: J A Reiffel, E Gang, J Gliklich, M B Weiss, J C Davis, J N Patton, J T Bigger
Journal: Circulation (1980)

To improve methods for evaluating human sinus node function (SNF), we developed a transvenous electrode catheter technique for direct recording of sinus node electrograms in adults. Sinus node electrograms (SNE) characterized by low-frequency, anatomically localized pre-P-wave potentials were obtained in 19 of 23 patients. The SNE configuration was similar to that previously found for endocardial SNE recordings in in vitro atrial preparations, in open-chest dogs and during human open heart surgery. In 16 patients with normal SNF, directly recorded sinoatrial conduction times (SACTs) were 46-116 msec. In three patients with sick sinus syndrome, SACT was 110-126 msec. In 15 of the 19 patients, SACT was estimated by the atrial premature stimulus technique and was compared with the directly measured SACT. When atrial premature depolarizations produced no sinus node depression, the mean differences between the direct and estimated SACT was 1.8 +/- 5.6 msec.
The Flexible Broncho-Fiberscope
Authors: S. Borgeskov, J. Becker, A. Pedersen
Journal: Endoscopy (1973)

In the Department of Thoracic Surgery, Bispebjerg Hospital, Copenhagen, 750 patients were examined for pulmonary lesions during the nine-month period from August 1, 1972, to May 1, 1973. All the patients underwent conventional rigid bronchoscopy. in 100 of them accurate diagnosis could not be obtained by this method and they were consequently all examined with the flexible broncho-fiber-scope. the experience gained with the use of the flexible broncho-fiberscope combined with bronchial brushing and forceps biopsy is discussed. It is important to establish the nature of pulmonary lesions in order to avoid unnecessary thoracotomies and possibly serious complications, particularly in persons of advanced age. Broncho-fiberscopy has proved to be the most appropriate method for obtaining a diagnosis in case of central lesions of the upper lobes and of intermediate lung lesions. A diagnosis of peripheral lung lesion is most readily obtained by transthoracic fine-needle biopsy. It is concluded that a combination ...
"Hey, mom, thanks!": use of focus groups in the development of place-specific materials for a community environmental action campaign.
Authors: Lesley Green, Mindy Fullilove, David Evans, Peggy Shepard
Journal: Environmental Health Perspectives (2002)

We examined the relevance of five strategies to reduce the risk of exposure to environmental hazards for African-American and Hispanic children living in Northern Manhattan in New York City. Researchers conducting a community-wide intervention to increase awareness of environmental health hazards identified five strategies for keeping children healthy, preventing asthma, and promoting children's growth and development. These strategies were based on current scientific knowledge of environmental health and were tested and refined through a series of focus groups. The 14 focus groups were conducted with women of childbearing age living in the communities under study. The purpose of the focus groups was to test the relevancy of the five strategies and to obtain data to inform the intervention's social action campaign. Here authors discuss the process of identifying strategies for risk reduction and incorporating community residents' perceptions of risk into health risk messages. The authors argue that broader social and historical contexts are important in shaping community members' interpretations of risk and subsequent response to health education campaigns.
Demonstration of sustained sinus and atrial re-entry as a mechanism of paroxysmal supraventricular tachycardia.
Authors: D Wu, F Amat-y-leon, P Denes, R C Dhingra, R J Pietras, K M Rosen
Journal: Circulation (1975)

Electrophysiological studies in five patients with documented (4) or suspected (1) paroxysmal supraventricular tachycardia (PSVT), suggested sinus or atrial reentrance (SR or AR). Two of the patients had preexcitation, three had evidence of atrial enlargement, and all had organic heart disease. The following observations supported a diagnosis of SR and AR; 1) induction of sustained PSVT with atrial extrastimulus technique allowing definition of an echo zone; 2) induction of sustained PSVT during constant rapid atrial pacing at a rate less than that producing A-V nodal Wenckebach periods, or producing normalization of QRS complex in patients with pre-excitation: 3) P waves preceding each QRS during PSVT with an A-H interval appropriate for the rate of the PSVT; 4) antegrade P wave morphology during PSVT, a normal high to low sequence of right atrial activation (SR), or P wave morphology and atrial activation sequence different from sinus (AR); 5) lack of correlation of PSVT induction with critical A-H interval. The rates of induced sustained PSVT ranged from 114 to 143 beats/min, and were similar to those observed during spontaneous episodes of PSVT in the four patients. PSVT could be terminated with critically timed extra-stimuli or carotid massage. In conclusion, SR and AR appear to be mechanisms of spontaneous PSVT in man. Rates of SR and AR PSVT tend to be relatively slow.
Immune monitoring using the predictive power of immune profiles
Authors: Michael P Gustafson, Yi Lin, Betsy LaPlant, Courtney J Liwski, Mary L Maas, Stacy C League, Philippe R Bauer, Roshini S Abraham, Matthew K Tollefson, Eugene D Kwon, Dennis A Gastineau, Allan B Dietz
Journal: Journal for ImmunoTherapy of Cancer (2013)

<h3>Background</h3> We have developed a novel approach to categorize immunity in patients that uses a combination of whole blood flow cytometry and hierarchical clustering. <h3>Methods</h3> Our approach was based on determining the number (cells/μl) of the major leukocyte subsets in unfractionated, whole blood using quantitative flow cytometry. These measurements were performed in 40 healthy volunteers and 120 patients with glioblastoma, renal cell carcinoma, non-Hodgkin lymphoma, ovarian cancer or acute lung injury. After normalization, we used unsupervised hierarchical clustering to sort individuals by similarity into discreet groups we call immune profiles. <h3>Results</h3> Five immune profiles were identified. Four of the diseases tested had patients distributed across at least four of the profiles. Cancer patients found in immune profiles dominated by healthy volunteers showed improved survival (p &lt; 0.01). Clustering objectively identified relationships between immune markers. We found a positive correlation between the number of granulocytes and immunosuppressive CD14<sup>+</sup>HLA-DR<sup>lo/neg</sup> monocytes and no correlation between CD14<sup>+</sup>HLA-DR<sup>lo/neg</sup> monocytes and Lin<sup>-</sup>CD33<sup>+</sup>HLA-DR<sup>-</sup> myeloid derived suppressor cells. Clustering analysis identified a potential biomarker predictive of survival across cancer types consisting of the ratio of CD4<sup>+</sup> T cells/μl to CD14<sup>+</sup>HLA-DR<sup>lo/neg</sup> monocytes/μL of blood. <h3>Conclusions</h3> Comprehensive multi-factorial immune analysis resulting in immune profiles were prognostic, uncovered relationships among immune markers and identified a potential biomarker for the prognosis of cancer. Immune profiles may be useful to streamline evaluation of immune modulating therapies and continue to identify immune based biomarkers.
S12 Unscheduled healthcare resource utilisation and health-related quality of life before and after omalizumab initiation in UK clinical practice: the apex study
Authors: N. Barnes, A. Radwan, F. Percival
Journal: Thorax (2011)

<h3>Objectives</h3> The efficacy and safety of omalizumab for the treatment of severe persistent allergic asthma have been demonstrated in randomised controlled clinical trials. However, there are limited “real world” data on its effects on healthcare resource utilisation or health-related quality of life (QoL) in UK clinical practice. <h3>Methods</h3> A 10 centre retrospective observational study (APEX) compared 12 months pre- vs 12 months post-omalizumab initiation in patients aged =12 years with severe persistent allergic asthma. All patients received =1 dose of omalizumab. Patients who had received omalizumab in a clinical trial were excluded. Hospital records were reviewed to obtain data on hospital resource use and routinely used QoL measures for example, Asthma Quality of Life Questionnaire (AQLQ) at baseline (pre-omalizumab), 16 weeks and up to 12 months following omalizumab initiation. <h3>Results</h3> Mean in-patient hospital admissions fell by 61% from 1.30 to 0.51 (p&lt;0.001) and mean in-patient bed days fell by 70% from 9.10 to 2.74 (p&lt;0.001) per patient. In the subgroup of patients hospitalised for asthma in the 12 months pre-omalizumab (n=81), mean in-patient hospital admissions fell by 70% from 2.19 to 0.65 (p&lt;0.001) and mean in-patient bed days fell by 74% from 14.86 to 3.83 (p&lt;0.001) per patient. Similarly, mean Accident and Emergency department attendances fell by 70% from 1.52 per patient in the 12 months pre-omalizumab to 0.46 in the 12 months post-omalizumab (p&lt;0.001). Other resource use, such as outpatient attendances (excluding visits made solely for omalizumab administration), nurse appointments and telephone consultations remained unchanged following omalizumab initiation. QoL data were not available for all patients at every time point. However, where data were available, mean AQLQ scores increased from 3.09 at baseline to 5.01 at 16 weeks (n=90) and to 5.22 at 12 months (n=29). <h3>Conclusions</h3> Treatment with omalizumab is associated with a clinically and statistically significant reduction in unplanned hospital resource utilisation and improvements in patients9 QoL.
Human Genome Sequencing in Health and Disease
Authors: Claudia Gonzaga-Jauregui, James R. Lupski, Richard A. Gibbs
Journal: Annual Review of Medicine (2011)

Following the "finished," euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges.
Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study
Authors: Nathalie Ylitalo, Per Sørensen, Agnetha M Josefsson, Patrik KE Magnusson, Per Kragh Andersen, Jan Pontén, Hans-Olov Adami, Ulf B Gyllensten, Mads Melbye
Journal: The Lancet (2000)
Akt-Dependent Glucose Metabolism Promotes Mcl-1 Synthesis to Maintain Cell Survival and Resistance to Bcl-2 Inhibition
Authors: Jonathan L. Coloff, Andrew N. Macintyre, Amanda G. Nichols, Tingyu Liu, Catherine A. Gallo, David R. Plas, Jeffrey C. Rathmell
Journal: Cancer Research (2011)

Most cancer cells utilize aerobic glycolysis, and activation of the phosphoinositide 3-kinase/Akt/mTOR pathway can promote this metabolic program to render cells glucose dependent. Although manipulation of glucose metabolism may provide a means to specifically eliminate cancer cells, mechanistic links between cell metabolism and apoptosis remain poorly understood. Here, we examined the role and metabolic regulation of the antiapoptotic Bcl-2 family protein Mcl-1 in cell death upon inhibition of Akt-induced aerobic glycolysis. In the presence of adequate glucose, activated Akt prevented the loss of Mcl-1 expression and protected cells from growth factor deprivation-induced apoptosis. Mcl-1 associated with and inhibited the proapoptotic Bcl-2 family protein Bim, contributing to cell survival. However, suppression of glucose metabolism led to induction of Bim, decreased expression of Mcl-1, and apoptosis. The proapoptotic Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, shows clinical promise, but Mcl-1 upregulation can promote resistance. Importantly, inhibition of glucose metabolism or mTORC1 overcame Mcl-1-mediated resistance in diffuse large B cell leukemic cells. Together these data show that Mcl-1 protein synthesis is tightly controlled by metabolism and that manipulation of glucose metabolism may provide a mechanism to suppress Mcl-1 expression and sensitize cancer cells to apoptosis.
Locus Reference Genomic sequences: an improved basis for describing human DNA variants
Authors: Raymond Dalgleish, Paul Flicek, Fiona Cunningham, Alex Astashyn, Raymond E Tully, Glenn Proctor, Yuan Chen, William M McLaren, Pontus Larsson, Brendan W Vaughan, Christophe Béroud, Glen Dobson, Heikki Lehväslaiho, Peter EM Taschner, Johan T den Dunnen, Andrew Devereau, Ewan Birney, Anthony J Brookes, Donna R Maglott
Journal: Genome Medicine (2010)

As our knowledge of the complexity of gene architecture grows, and we increase our understanding of the subtleties of gene expression, the process of accurately describing disease-causing gene variants has become increasingly problematic. In part, this is due to current reference DNA sequence formats that do not fully meet present needs. Here we present the Locus Reference Genomic (LRG) sequence format, which has been designed for the specific purpose of gene variant reporting. The format builds on the successful National Center for Biotechnology Information (NCBI) RefSeqGene project and provides a single-file record containing a uniquely stable reference DNA sequence along with all relevant transcript and protein sequences essential to the description of gene variants. In principle, LRGs can be created for any organism, not just human. In addition, we recognize the need to respect legacy numbering systems for exons and amino acids and the LRG format takes account of these. We hope that widespread adoption of LRGs - which will be created and maintained by the NCBI and the European Bioinformatics Institute (EBI) - along with consistent use of the Human Genome Variation Society (HGVS)-approved variant nomenclature will reduce errors in the reporting of variants in the literature and improve communication about variants affecting human health. Further information can be found on the LRG web site: http://www.lrg-sequence.org.
NCIC-CTG phase II study of gemcitabine in patients with malignant glioma (IND.94)
Authors: S Z Gertler, D MacDonald, M Goodyear, P Forsyth, D J Stewart, K Belanger, J Perry, D Fulton, W Steward, N Wainman, L Seymour
Journal: Annals of Oncology (2000)
Efficacy of Adjuvant Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer and Tumors ≤ 2 cm: A Meta-Analysis of the Randomized Trastuzumab Trials
Authors: Ciara C. O'Sullivan, Ian Bradbury, Christine Campbell, Marc Spielmann, Edith A. Perez, Heikki Joensuu, Joseph P. Costantino, Suzette Delaloge, Priya Rastogi, Dimitrios Zardavas, Karla V. Ballman, Eileen Holmes, Evandro de Azambuja, Martine Piccart-Gebhart, Jo Anne Zujewski, Richard D. Gelber
Journal: Journal of Clinical Oncology (2015)

We compared efficacy of trastuzumab versus no trastuzumab in patients with small (≤ 2 cm) human epidermal growth factor receptor 2 (HER2) -positive breast cancer treated in randomized trials.A meta-analysis was conducted using data from five of the six adjuvant trastuzumab trials. Efficacy end points were disease-free survival (DFS) and overall survival (OS). Separate analyses were prospectively planned for hormone receptor (HR) -positive and HR-negative cohorts. Random effect models and Yusuf-Peto fixed effects models assessed the impact of heterogeneity on baseline hazards and treatment effects across studies. Peto-Pike cumulative incidence estimates were stratified by study and nodal status.Median follow-up time was 8 years. For 2,263 patients with HR-positive disease, 8-year cumulative incidence rates comparing trastuzumab versus no trastuzumab were 17.3% versus 24.3% (P < .001) for DFS and 7.8% versus 11.6% (P = .005) for OS, respectively; for 1,092 HR-positive patients with zero or one positive lymph nodes, results were 12.7% versus 19.4% (P = .005) for DFS and 5.3% versus 7.4% (P = .12) for OS, respectively. For 1,957 patients with HR-negative disease, 8-year cumulative incidence rates were 24.0% versus 33.4% (P < .001) for DFS and 12.4% versus 21.2% (P < .001) for OS, respectively; for 1,040 HR-negative patients with zero or one positive lymph nodes, results were 20.4% versus 26.3% (P = .05) for DFS and 8.2% versus 12.2% (P = .084) for OS, respectively.Women with HER2-positive tumors ≤ 2 cm in the randomized trastuzumab trials derived substantial DFS and OS benefit from adjuvant trastuzumab. Trastuzumab-treated patients with HR-positive disease and ≤ one positive lymph node may be candidates for trials assessing less aggressive treatment approaches.
Nebulization and anti-Pseudomonas aeruginosa activity of colistin
Authors: P Diot, F Gagnadoux, C Martin, H Ellataoui, Y Furet, M Breteau, E Boissinot, E Lemarie
Journal: European Respiratory Journal (1997)

Colistin aerosols are frequently administered to patients with cystic fibrosis. However, questions arise concerning the effect of both jet and ultrasonic nebulizers on the properties of the drug. The aim of this study was to characterize the anti-Pseudomonas aeruginosa (PA) activity of colistin after jet (Pari LL) and ultrasonic (DP100) nebulization. A bench study was performed by capturing the aerosols, determining the drug mass, and assessing its anti-PA activity. Because the inhaled mass of colistin had to be entirely recovered for the bacteriological study, it was assessed by isotopic methods, mixing the drug with a 99mTc-labelled tracer and demonstrating that 99mTc activity accurately predicted the mass of colistin. Colistin was extracted from the filters and its antibiotic activity was determined using the method employed for the study of the bacteriostatic and bactericidal power of serum on the ATCC 27853 PA strain. The postnebulization minimum inhibitory concentrations (MIC) were 1.9 micrograms.mL-1 with DP100 and 0.5 microgram.mL-1 with Pari LL. These values were less than two dilutions different from the 1 microgram.mL-1 MIC of non-nebulized colistin. We conclude that neither jet nebulization nor ultrasonic nebulization alter the antibiotic properties of colistin and that both systems can be used to nebulize colistin.