tbuckley/cabot-search huggingface dataset:
A Phase I Trial of the Dual Farnesyltransferase and Geranylgeranyltransferase Inhibitor L-778,123 and Radiotherapy for Locally Advanced Pancreatic Cancer
Authors: Neil E. Martin, Thomas B. Brunner, Krystina D. Kiel, Thomas F. DeLaney, William F. Regine, Mohammed Mohiuddin, Ernest F. Rosato, Daniel G. Haller, James P. Stevenson, Debbie Smith, Barnali Pramanik, Joel Tepper, Wesley K. Tanaka, Briggs Morrison, Paul Deutsch, Anjali K. Gupta, Ruth J. Muschel, W. Gillies McKenna, Eric J. Bernhard, Stephen M. Hahn
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. Experimental Design: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. Results: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. Conclusions: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.
Contribution of nasal pathways to low frequency respiratory impedance in infants
Authors: G L Hall
Journal: Thorax (2002)

Background: In infants the impedance of the nasal pathways (Zn) is a significant proportion of the total respiratory impedance (Zrs). Methods: In 11 infants Zrs was partitioned into Zn and lower respiratory system impedance (Zlrs) using a nasal catheter. A low frequency oscillatory signal (0.5–20 Hz) was applied during a pause in breathing to obtain the impedance spectra. A model of the respiratory system containing an airway and tissue compartment was then fitted to Zrs and Zlrs. The airway compartment consisted of a frequency independent resistance (R) and inertance (I), while the tissue compartment was described by coefficients of tissue damping (G) and elastance (H). Results: Zrs could be reliably partitioned into Zn and Zlrs. The nasal pathway acted as a purely resistive-inertive impedance and contributed approximately half of the airway resistance (mean (SE) 44.6 (4.9)%) and most of the respiratory system inertance (71.7 (3.5)%). Conclusion: In studies investigating changes in airway resistance in nasally breathing infants, the separation of nasal and lower respiratory system mechanics will increase the sensitivity of the tests.
Phase I and Pharmacologic Study of Liposomal Lurtotecan, NX 211: Urinary Excretion Predicts Hematologic Toxicity
Authors: Diederik F.S. Kehrer, Annelies M. Bos, Jaap Verweij, Harry J. Groen, Walter J. Loos, Alex Sparreboom, Maja J.A. de Jonge, Marta Hamilton, Terri Cameron, Elisabeth G.E. de Vries
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine the maximum-tolerated and recommended dose, toxicity profile, and pharmacokinetics of the liposomal topoisomerase I inhibitor lurtotecan (NX 211) administered as a 30-minute intravenous infusion once every 3 weeks in cancer patients. PATIENTS AND METHODS: NX 211 was administered by peripheral infusion. Dose escalation decisions were based on all toxicities during the first cycle as well as pharmacokinetic parameters. Serial plasma, whole blood, and urine samples were collected for up to 96 hours after the end of infusion, and drug levels were determined by high-performance liquid chromatography. RESULTS: Twenty-nine patients (16 women; median age, 56 years; range, 39 to 74 years) received 77 courses of NX 211 at dose levels of 0.4 (n = 3), 0.8 (n = 6), 1.6 (n = 3), 3.2 (n = 6), 3.8 (n = 6), and 4.3 mg/m2 (n = 5). Neutropenia and thrombocytopenia were the dose-limiting toxicities and were not cumulative. Other toxicities were mild to moderate. Nine patients had stable disease while undergoing treatment. The systemic clearance of lurtotecan in plasma and whole blood was 0.82 ± 0.78 L/h/m2 and 1.15 ± 0.96 L/h/m2, respectively. Urinary recovery (Fu) of lurtotecan was 10.1% ± 4.05% (range, 4.9% to 18.9%). In contrast to systemic exposure measures, the dose excreted in urine (ie, dose × Fu) was significantly related to the percent decrease in neutrophil and platelet counts at nadir (P < .00001). CONCLUSION: The dose-limiting toxicities of NX 211 are neutropenia and thrombocytopenia. The recommended dose for phase II studies is 3.8 mg/m2 once every 3 weeks. Pharmacologic data suggest a relationship between exposure to lurtotecan and NX 211–induced clinical effects.
Vitiligo-Like Depigmentation in Patients With Stage III-IV Melanoma Receiving Immunotherapy and Its Association With Survival: A Systematic Review and Meta-Analysis
Authors: Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, Rosalie M. Luiten
Journal: Journal of Clinical Oncology (2015)

Vitiligo-like depigmentation in patients with melanoma may be associated with more favorable clinical outcome. We conducted a systematic review of patients with stage III to IV melanoma treated with immunotherapy to determine the cumulative incidence of vitiligo-like depigmentation and the prognostic value of vitiligo development on survival.We systemically searched and selected all studies on melanoma immunotherapy that reported on autoimmune toxicity and/or vitiligo between 1995 and 2013. Methodologic quality of each study was appraised using adapted criteria for systematic reviews in prognostic studies. Random-effect models were used to calculate summary estimates of the cumulative incidence of vitiligo-like depigmentation across studies. The prognostic value of vitiligo-like depigmentation on survival outcome was assessed using random-effects Cox regression survival analyses.One hundred thirty-seven studies were identified comprising 139 treatment arms (11 general immune stimulation, 84 vaccine, 28 antibody-based, and 16 adoptive transfer) including a total of 5,737 patients. The overall cumulative incidence of vitiligo was 3.4% (95% CI, 2.5% to 4.5%). In 27 studies reporting individual patient data, vitiligo development was significantly associated with both progression-free-survival (hazard ratio [HR], 0.51; 95% CI, 0.32 to 0.82; P < .005) and overall survival (HR, 0.25; 95% CI, 0.10 to 0.61; P < .003), indicating that these patients have two to four times less risk of disease progression and death, respectively, compared with patients without vitiligo development.Although vitiligo occurs only in a low percentage of patients with melanoma treated with immunotherapy, our findings suggest clear survival benefit in these patients. Awareness of vitiligo induction in patients with melanoma is important as an indicator of robust antimelanoma immunity and associated improved survival.
Use of the Method of Generalized Least Squares in Reconstructing Phylogenies from Sequence Data
Authors: Michael Bulmer
Journal: Molecular Biology and Evolution (1991)

The method of generalized least squares provides a flexible method of phylogenetic reconstruction from sequence data, after reducing them to pairwise distances between species, corrected for multiple and back mutation.It gives efficient estimates of the branch lengths of a given tree.It also provides a natural measure of the departure of the observed from the predicted set of distances which has a x2 distribution under the true topology; this fact is used to construct a significance test on the topology and so to determine a "confidence interval" for the set of trees which are compatible with the data.To use this method it is necessary to know the variances and covariances of the corrected pairwise distances.A new method of estimating these variances and covariances empirically is described.The methodology is illustrated using data on the phylogeny of four mammalian orders (with the conclusion that rodents and lagomorphs are not sister groups) and of six primates (with the conclusion that the human/chimp/gorilla trichotomy cannot be resolved with these data alone).' z (dij-S,)* .This is the method proposed by Cavalli-Sforza and Edwards ( 1967) ; it has been used recently as part of the neighbor-joining method of Saitou and Nei ( 1987) for finding the best-supported tree and as part of the method of Li ( 1989) for testing phylogenetic trees.
Nuclear Shape, Mechanics, and Mechanotransduction
Authors: Kris Noel Dahl, Alexandre J.S. Ribeiro, Jan Lammerding
Journal: Circulation Research (2008)

In eukaryotic cells, the nucleus contains the genome and is the site of transcriptional regulation. The nucleus is the largest and stiffest organelle and is exposed to mechanical forces transmitted through the cytoskeleton from outside the cell and from force generation within the cell. Here, we discuss the effect of intra- and extracellular forces on nuclear shape and structure and how these force-induced changes could be implicated in nuclear mechanotransduction, ie, force-induced changes in cell signaling and gene transcription. We review mechanical studies of the nucleus and nuclear structural proteins, such as lamins. Dramatic changes in nuclear shape, organization, and stiffness are seen in cells where lamin proteins are mutated or absent, as in genetically engineered mice, RNA interference studies, or human disease. We examine the different mechanical pathways from the force-responsive cytoskeleton to the nucleus. We also highlight studies that link changes in nuclear shape with cell function during developmental, physiological, and pathological modifications. Together, these studies suggest that the nucleus itself may play an important role in the response of the cell to force.
Epidemiology, Public Health, and the Rhetoric of False Positives
Authors: Aaron Blair, Rodolfo Saracci, Paolo Vineis, Pierluigi Cocco, Francesco Forastiere, Philippe Grandjean, Manolis Kogevinas, David Kriebel, Anthony McMichael, Neil Pearce, Miquel Porta, Jonathan Samet, Dale P. Sandler, Adele Seniori Costantini, Harri Vainio
Journal: Environmental Health Perspectives (2009)

As an observational science, epidemiology is regarded by some researchers as inherently flawed and open to false results. In a recent paper, Boffetta et al. [Boffetta P, McLaughlin JK, LaVecchia C, Tarone RE, Lipworth L, Blot WJ. False-positive results in cancer epidemiology: a plea for epistemological modesty. J Natl Cancer Inst 100:988-995 (2008)] argued that "epidemiology is particularly prone to the generation of false-positive results." They also said "the tendency to emphasize and over-interpret what appear to be new findings is commonplace, perhaps in part because of a belief that the findings provide information that may ultimately improve public health" and that "this tendency to hype new findings increases the likelihood of downplaying inconsistencies within the data or any lack of concordance with other sources of evidence." The authors supported these serious charges against epidemiology and epidemiologists with few examples. Although we acknowledge that false positives do occur, we view the position of Boffetta and colleagues on false positives as unbalanced and potentially harmful to public health.We aim to provide a more balanced evaluation of epidemiology and its contribution to public health discourse.Boffetta and colleagues ignore the fact that false negatives may arise from the very processes that they tout as generating false-positive results. We further disagree with their proposition that false-positive results from a single study will lead to faulty decision making in matters of public health importance. In practice, such public health evaluations are based on all the data available from all relevant disciplines and never to our knowledge on a single study.The lack of balance by Boffetta and colleagues in their evaluation of the impact of false-positive findings on epidemiology, the charge that "methodological vigilance is often absent" in epidemiologists' interpretation of their own results, and the false characterization of how epidemiologic findings are used in societal decision making all undermine a major source of information regarding disease risks. We reaffirm the importance of epidemiologic evidence as a critical component of the foundation of public health protection.
Immunohistochemical and Genetic Evaluation of Deoxycytidine Kinase in Pancreatic Cancer: Relationship to Molecular Mechanisms of Gemcitabine Resistance and Survival
Authors: Valeria Sebastiani, Francesca Ricci, Belen Rubio-Viquiera, Piotr Kulesza, Charles J. Yeo, Manuel Hidalgo, Alison Klein, Daniel Laheru, Christine A. Iacobuzio-Donahue
Journal: Clinical Cancer Research (2006)

Abstract Gemcitabine is considered the standard first-line therapy for patients with advanced pancreatic cancer. More recent strategies have focused on improving the efficacy of gemcitabine by either improving the method of delivery or by combining gemcitabine with other non-cross-resistant chemotherapy agents or with small-molecule drugs. However, the clinical benefits, response rates, and duration of responses have been modest. Deoxycytidine kinase (dCK) is the rate-limiting enzyme involved in the metabolism of gemcitabine. The expression of dCK has been postulated to be correlative of gemcitabine resistance. We determined the relationship of dCK immunohistochemical protein expression and/or genetic status of dCK in a panel of human pancreatic cancer tissues and pancreatic cancer cell lines and determined the relationship of these variables to the clinical outcome of patients treated with gemcitabine. We report that dCK protein expression is expressed in the majority of pancreatic cancers analyzed (40 of 44 cases, 91%) and showed a range of labeling intensities ranging from 1+ (labeling weaker in intensity than normal lymphocytes present in same section) to 3+ (labeling greater in intensity than normal lymphocytes present in same section). When labeling intensity was compared with survival, low dCK expression (1+ labeling) was correlated with both overall survival (P &amp;lt; 0.009) and progression-free survival following gemcitabine treatment (P &amp;lt; 0.04). Low dCK labeling intensity was also significantly correlated with patient age (70.3 ± 8.1 versus 59.8 ± 7.4 years; P &amp;lt; 0.0006), suggesting that age-related methylation of the dCK gene may account in part for the observed differences. Sequencing of the entire dCK coding sequence in 17 cell lines and 9 patients' cancer tissues with disease progression while on gemcitabine did not identify any mutations, suggesting that genetic alterations of dCK are not a common mechanism of resistance to gemcitabine for this tumor type. Moreover, dCK labeling showed similar patterns and intensities of labeling among matched pretreatment and post-treatment tissues. In summary, pretreatment levels of dCK protein are most correlated with overall survival following gemcitabine treatment and are stable even after resistance to gemcitabine is clinically documented.
Effects of shock strengths on ventricular defibrillation failure
Authors: N Chattipakorn
Journal: Cardiovascular Research (2003)

Background: The mechanism of defibrillation is controversial. Reentry appearing immediately after the shock has been shown to be responsible for defibrillation failure in some studies while other studies have demonstrated that a rapid train of focal activations with the first focus appearing >50 ms after the shock is responsible for failed defibrillation. We tested the hypothesis that both patterns can occur, but at different shock strengths. Methods and results: Biphasic 6/4 ms shocks of 100–900 V in 100-V increments were given after 10 s of ventricular fibrillation from electrodes in right ventricular apex and right atrium in five isolated pig hearts. Transmembrane activity was optically mapped from the anterior and posterior epicardium using two CCD cameras. The defibrillation threshold (DFT) was 786±199 V. The interval from the shock to the earliest post-shock activation was zero for shocks <400 V but increased with increasing shock voltage to 62±6 ms at 800 V. The number of post-shock phase singularities, which is related to reentry incidence, decreased continuously from pre-shock values for 100-V shocks to zero as the shock strength increased to 600 V. Focal activations were observed after shocks >600 V with no epicardial reentry present. Conclusion: Reentry is responsible for defibrillation failure for low-strength shocks. As the shock strength approaches the DFT, a focal epicardial activation pattern becomes responsible for failed defibrillation. Thus, the mechanism of defibrillation failure depends on shock strength, with focal activation as the mechanism for the clinically important near-DFT strength shocks.
THE DETECTION OF POLIOMYELITIS VIRUS IN SO CALLED ABORTIVE TYPES OF THE DISEASE
Authors: John R. Paul, J. D. Trask
Journal: The Journal of Experimental Medicine (1932)

Experiments are reported which describe the isolation of poliomyelitis virus from the throats of two patients during an attack of so called abortive poliomyelitis (Wickman type), or what we have termed characteristic minor illnesses in association with poliomyelitis. This finding represents added evidence in favor of the belief, previously held by many observers, that certain types of minor illness, which accompany an epidemic of poliomyelitis, probably represent mild cases of the disease.
Association between leptin and asthma in adults
Authors: A Sood
Journal: Thorax (2006)

Leptin, a pro-inflammatory cytokine produced by adipose tissue, has previously been shown to be associated with asthma in children. We hypothesised that high serum leptin concentrations would also be associated with asthma in adults.The Third National Health and Nutrition Examination Survey is a cross sectional study that included fasting serum leptin concentrations and self-report of doctor diagnosed asthma. Data were analysed using multivariable logistic regression analysis.Of 5876 participants, those with current asthma had a higher mean unadjusted leptin concentration than those who had never had asthma (geometric mean (SE) 9.2 (0.6) microg/l v 7.6 (0.2) microg/l; p = 0.02). After adjustment for triceps skinfold thickness and other covariates, the association between leptin and asthma appeared stronger in women than in men, and in premenopausal women than in postmenopausal women. Body mass index (BMI) was also associated with current asthma in women, but this association was not significantly affected by adjustment for leptin concentrations.The results of this large population based study support the hypothesis that leptin is associated with asthma in women. In addition, while BMI also is related to asthma in women, this study does not support the suggestion that leptin contributes significantly to this association.
Serological response to the 2009 H1N1 influenza vaccination in patients with inflammatory bowel disease
Authors: Garret Cullen, Caroline Bader, Joshua R Korzenik, Bruce E Sands
Journal: Gut (2011)

<h3>Background</h3> Influenza vaccination is recommended for patients with inflammatory bowel disease (IBD). The 2009 H1N1 influenza vaccine produced seroprotection rates of &gt;85% in the general population but there are no data on the immunogenicity of the vaccine in patients with IBD. <h3>Methods</h3> An observational prospective open-label study was conducted to examine the immunogenicity of the 2009 H1N1 influenza vaccine in 108 patients with IBD. Patient details, medications and disease activity were recorded. Pre- and post-vaccination haemagglutinin inhibition titres and geometric mean titres were measured. A functional assay of T lymphocyte activity was measured at vaccination in a subset of patients as an alternative measure of immunosuppression. Subjects were followed for 6 months post-vaccination. <h3>Results</h3> Of 108 patients enrolled, 105 completed the study. The post-vaccination seroprotection rate was 50%. Immunosuppressed subjects had a lower rate of seroprotection than non-immunosuppressed subjects (44% vs 64%, p=0.06). The proportion with seroprotection was significantly lower in subjects on combination immunosuppression than in those receiving no immunosuppression (36% vs 64%, p=0.02). Patients receiving combined immunosuppression had a significantly lower fold increase in geometric mean titres than those on monotherapy immunosuppression (3.5 vs 11.5, p=0.03). An assay of T lymphocyte activity was performed in a subgroup of 48 subjects. Those with intermediate activity had lower seroprotection than those with high activity (28% vs 61%, p=0.02). The vaccine was well tolerated. <h3>Conclusions</h3> Patients with IBD vaccinated with the 2009 H1N1 influenza vaccine had a low rate of seroprotection, particularly among those who were immunosuppressed. Although there is a need for studies of the clinical benefit of vaccines in this population, patients with IBD need to be aware of this reduced immunogenicity.
Mutations in RPE65 cause autosomal recessive childhood–onset severe retinal dystrophy
Authors: Su-min Gu, Debra A. Thompson, C.R. Srisailapathy Srikumari, Birgit Lorenz, Ulrich Finckh, Aileen Nicoletti, K.R. Murthy, Michaela Rathmann, Govindasamy Kumaramanickavel, Michael J. Denton, Andreas Gal
Journal: Nature Genetics (1997)