tbuckley/cabot-search huggingface dataset:
Vascular and right ventricular remodelling in chronic thromboembolic pulmonary hypertension
Authors: Marion Delcroix, Anton Vonk Noordegraaf, Elie Fadel, Irene Lang, Gérald Simonneau, Robert Naeije
Journal: European Respiratory Journal (2012)

In chronic thromboembolic pulmonary hypertension (CTEPH) increased pulmonary vascular resistance is caused by fibrotic organisation of unresolved thromboemboli. CTEPH mainly differs from pulmonary arterial hypertension (PAH) by the proximal location of pulmonary artery obliteration, although distal arteriopathy can be observed as a consequence of non-occluded area over-perfusion. Accordingly, there is proportionally more wave reflection in CTEPH, impacting on pressure and flow wave morphology. However, the time constant, i.e. resistance×compliance, is not different in CTEPH and PAH, indicating only trivial effects of proximal wave reflection on hydraulic right ventricular load. More discriminative is the analysis of the pressure decay after pulmonary arterial occlusion, which is more rapid in the absence of significant distal arteriopathy. Structure and function of the right ventricle show a similar pattern to right ventricular hypertrophy, namely dilatation and wall thickening, as well as loss of function in CTEPH and PAH. This is probably related to similar loading conditions. Hyperventilation with hypocapnia is characteristic of both PAH and CTEPH. Ventilatory equivalents for carbon dioxide, as a function of arterial carbon dioxide tension, conform to the alveolar ventilation equation in both conditions, indicating a predominant role of increased chemosensitivity. However, a slight increase in the arterial to end-tidal carbon dioxide tension gradient in CTEPH shows a contribution of increased dead space ventilation.
Advertising of Prescription-Only Medicines to the Public: Does Evidence of Benefit Counterbalance Harm?
Authors: Barbara Mintzes
Journal: Annual Review of Public Health (2012)

Since the global withdrawal of rofecoxib (Vioxx) in 2004, concerns about public health effects of direct-to-consumer advertising (DTCA) have grown. A systematic review of the research evidence on behavioral, health, and cost effects, published in 2005, found four studies meeting inclusion criteria, which showed that DTCA increases prescribing volume and patient demand, and shifts prescribing. From 2005 to 2010, nine studies met similar criteria. These largely confirm previous results. Additional effects include a shift to less appropriate prescribing, differential effects by patient price sensitivity and drug type, switches to less cost-effective treatment, and sustained sales despite a price increase. Claimed effects on adherence do not stand up to scrutiny and are based mainly on negative trials. There is no evidence of improved treatment quality or early provision of needed care. If policy is to be informed by evidence, the strength of research methods and ability to assess causality need to be considered.
Intestinal Barriers to Bacteria and their Toxins
Authors: R L Walker, R L Owen
Journal: Annual Review of Medicine (1990)

Immunologic and nonimmunologic processes work together to protect the host from the multitude of microorganisms residing within the intestinal lumen. Mechanical integrity of the intestinal epithelium, mucus in combination with secretory antibody, antimicrobial metabolites of indigenous microorganisms, and peristalsis each limit proliferation and systemic dissemination of enteric pathogens. Uptake of microorganisms by Peyer's patches and other intestinal lymphoid structures and translocation circumvent the mucosal barrier, especially in immunosuppressed individuals. Improved understanding of the composition and limitation of the intestinal barrier, coupled with advances in genetic engineering of immunogenic bacteria, development of oral delivery systems, and immunomodulators, now make enhancement of mucosal barriers feasible.
Multiple genetic copy number alterations in oral squamous cell carcinoma: study of <i>MYC</i> , <i>TP53</i> , <i>CCDN1, EGFR</i> and <i>ERBB2</i> status in primary and metastatic tumours
Authors: G. Martín-Ezquerra, R. Salgado, A. Toll, M. Gilaberte, T. Baró, F. Alameda Quitllet, M. Yébenes, F. Solé, M. Garcia-Muret, B. Espinet, R.M. Pujol
Journal: British Journal of Dermatology (2010)

Background Oncogenesis in the oral cavity is believed to result from genetic alterations that cause a stepwise transformation of the mucosa to invasive carcinoma. In oral squamous cell carcinoma (OSCC) multiple cytogenetic abnormalities have been reported, but their practical significance remains uncertain. Objective To evaluate the usefulness of the assessment of CCND1, MYC, EGFR, ERBB2 and TP53 in OSCC and lymph node metastases. Methods Fifty-one consecutive samples of OSCC, nine lymph node biopsies showing metastatic spread from OSCC, 16 biopsies diagnosed as oral leucoplakia (OLK), 13 samples corresponding to oral lichen planus (OLP) and 14 samples from normal oral mucosa were included in the study. Clinical and histopathological characteristics were reviewed. The genetic and protein status of the CCND1, MYC, EGFR, ERBB2 oncogenes and the TP53 tumour suppressor gene were assessed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). The obtained results were compared with the clinical characteristics and the outcome of the OSCCs. Results TP53 gene losses and MYC, ERBB2, CCND1 and EGFR copy number gains and amplifications were detected in a higher proportion in OSCC and lymph node samples than in OLK and OLP samples (P < 0·005). Overexpression of p53, Myc, Cyclin D1, c-erbB-2 and epidermal growth factor receptor (EGFR) was more prevalent in malignant samples than benign samples (P < 0·05). Correlation between FISH and IHC results was demonstrated in MYC, EGFR and CCND1 studies. The presence of two or more genetic abnormalities in the studied loci was exclusively detected in primary and metastatic OSCC. Conclusions In our series, genetic abnormalities in TP53, MYC, CCND1, ERBB2 and EGFR detected by FISH were absent in inflammatory lesions, infrequent in precursor lesions and common in tumoral lesions. Evaluation of the genetic status of TP53, MYC, CCND1, ERBB2 and EGFR may be an additional diagnostic tool in distinguishing benign from malignant oral lesions in histopathologically challenging cases.
Single amino acid substitutions within the ion permeation pathway alter single-channel conductance of the human L-type cardiac Ca2+ channel.
Authors: A Yatani, A Bahinski, G Mikala, S Yamamoto, A Schwartz
Journal: Circulation Research (1994)

Voltage-dependent L-type Ca2+ channels select for Ca2+ and other divalent cations by high-affinity Ca2+ binding and ion-ion interactions in the permeation pathway. We have recently identified a series of highly conserved glutamate residues, located within the SS2 segments of each of the four repeats of the human heart Ca2+ channel alpha 1 subunit, as major determinants of ion selectivity of the channel. To further investigate the functional role of these glutamate residues in ion permeation, we have individually neutralized the glutamic acids in repeats II and IV by substitution with alanine or glutamine. Wild-type and mutant Ca2+ channels were expressed in Xenopus oocytes. Apparent affinity for external Ca2+ was assessed by measuring the block by Ca2+ of inward Li+ currents through the Ca2+ channels. Mutations reducing net negative charge at these positions resulted in a 10-fold reduction in the affinity of the channel for external Ca2+. Single-channel conductance was measured with either divalent or monovalent cations as the charge carriers. Substitution of glutamic acid at position 677 with either alanine or glutamine increased single-channel conductance, whereas the same substitutions at position 1387 resulted in a decrease in single-channel conductance with Ba2+ as the charge carrier. In contrast, the unitary current amplitude carried by Na+, in the absence of external divalent cations, was not altered by these mutations. The results suggest that these conserved glutamate residues participate in high-affinity Ca2+ binding within the pore. The different effects on Ba2+ permeation indicate an asymmetric arrangement of the glutamate residues between repeats II and IV.(ABSTRACT TRUNCATED AT 250 WORDS)
Low Levels of Her2/neu Expressed by Ewing's Family Tumor Cell Lines Can Redirect Cytokine-Induced Killer Cells
Authors: Michael R. Verneris, Arash Arshi, Matthias Edinger, Martin Kornacker, Yaso Natkunam, Mobin Karami, Yu-an Cao, Neyssa Marina, Christopher H. Contag, Robert S. Negrin
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To identify novel treatments for pediatric solid tumors and/or for malignancies with low-level Her2/neu expression. Experimental Design: Using fluorescence-activated cell sorting and immunohistochemistry, Her2/neu expression was determined on cell lines derived vfrom Ewing's family tumors (EFT) and neuroblastoma. Sensitivity to trastuzumab treatment was investigated using an in vitro proliferation assay. Cytotoxicity against EFT cell lines was done with either freshly isolated or ex vivo activated and expanded T cells (cytokine-induced killer cells, CIK cells), with or without addition of a CD3xHer2/neu bispecific antibody. The effects of either trastuzumab, CIK cells alone, or CD3xHer2/neu bispecific antibody redirected CIK cells was determined using a SCID/hu model of EFTs and serial, noninvasive bioluminescent imaging. Results: EFT cell lines express 5- to 10-fold lower levels of her2/neu than either breast (BT-474) or ovarian (SK-OV-3) cell lines. Treatment of EFT cell lines with trastuzumab did not induce growth inhibition either in vitro or in vivo. In contrast, Her2/neu could be used to redirect CIK cell to mediate cytotoxicity against EFTs both in vitro and in vivo (using two different treatment schemas). Conclusions: CD3xHer2/neu bispecific antibody and CIK cells may be a suitable approach to treat malignancies with low-level Her2/neu expression not responsive to trastuzumab.
Effects of Bacterially Synthesized Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor in Patients with Advanced Malignancy
Authors: Graham J. Lieschke
Journal: Annals of Internal Medicine (1989)

To define the clinical and hematologic effects of subcutaneously administered bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF).Single arm nonrandomized dose escalation study.Twenty-one patients with advanced malignancy who were not receiving concurrent myelosuppressive therapy.Subcutaneous administration of rhGM-CSF by once-daily injection to groups of two to four patients at doses of 0.3 to 30 micrograms/kg body weight.d for 10 consecutive days. Some patients received a second 10-day period of daily rhGM-CSF treatment after a 10-day nontreatment interval followed by alternate-day treatment. Clinical status and hematologic values were monitored frequently.All doses of rhGM-CSF caused an immediate transient fall of 84% to 99% in circulating neutrophils, eosinophils, and monocytes. Continued daily dosing caused a leukocytosis of up to 10-fold with increases in numbers of circulating neutrophils, eosinophils, monocytes, and lymphocytes. There appeared to be a plateau in the increase in neutrophils in the dose range 3 to 15 micrograms/kg.d. Marrow aspirates showed increased proportions of promyelocytes and myelocytes. Alternate-day injection of 15 micrograms/kg maintained a leukocytosis. At doses up to 15 micrograms/kg.d, rhGM-CSF was well tolerated but adverse effects included bone pains, myalgias, rashes, and liver dysfunction. At doses exceeding 15 micrograms/kg.d, pericarditis was a dose-limiting toxicity. Idiopathic thrombocytopenic purpura was reactivated by rhGM-CSF in one patient.Bacterially synthesized rhGM-CSF induces a leukocytosis in the dose range of 3 to 15 micrograms/kg.d. These doses are appropriate for phase II studies.
Effect of Velocity Gradient on the Clotting Time of Blood and on the Consistency of Clots Formed in Vitro
Authors: Leopold Dintenfass
Journal: Circulation Research (1966)

Clotting times of human blood and rheology of blood clots have been determined by means of a cone-in-cone viscometer, a ring-in-ring adapter, and a variable-frequency thromboviscometer. The last represents a variable frequency version of the thrombelastograph. The results of clotting time tests on blood samples from 118 donors indicate clearly that clotting time is a function of the velocity gradient at which clotting takes place. Clotting time decreases as the velocity gradient increases. Consistency of blood coagula depends on the velocity gradient at which coagula are formed. Consistency, or viscosity, of coagula decreases when the velocity gradient increases. While the viscosity of clots formed at low rates of shear is of the order of 100 poises, coagula formed at intermediate rates of shear exhibit viscosity of a few decipoises. Viscosity of blood is not significantly altered if coagulation takes place at rates of shear near 400 sec -1 .
Immunoglobulin Prophylaxis in Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis
Authors: Pia Raanani, Anat Gafter-Gvili, Mical Paul, Isaac Ben-Bassat, Leonard Leibovici, Ofer Shpilberg
Journal: Journal of Clinical Oncology (2008)

Purpose Because the role of immunoglobulins (IVIG) prophylaxis in patients undergoing hematopoietic stem-cell transplantation (HSCT) has not been established in terms of survival and infection prevention, we conducted a meta-analysis evaluating these issues. Methods Systematic review and meta-analysis of randomized-controlled trials comparing prophylaxis with polyvalent IVIG or cytomegalovirus (CMV)-IVIG and control or another preparation or dose. PUBMED, Cochrane Library, LILACS, and conference proceedings were searched. Two reviewers appraised the quality of trials and extracted data. Relative risks (RRs) with 95% CIs were estimated and pooled. Results Thirty trials including 4,223 patients undergoing bone marrow transplantation (BMT) were included. There was no difference in all-cause mortality when polyvalent IVIG or CMV-IVIG was compared to control (RR, 0.99; 95% CI, 0.88 to 1.12; and RR, 0.86; 95% CI, 0.63 to 1.16, respectively). There was no difference in clinically documented infections when polyvalent IVIG was compared with control (RR, 1.00; 95% CI, 0.90 to 1.10; five trials). CMV infections were not significantly reduced with either polyvalent IVIG or CMV-IVIG. Interstitial pneumonitis was reduced with polyvalent IVIG in older studies but not in the more recent ones, nor in studies assessing CMV-IVIG. Polyvalent IVIG increased the risk for veno-occlusive disease (RR, 2.73; (95% CI, 1.11 to 6.71). Graft-versus-host disease was not affected. Conclusion Because there is no advantage in terms of survival or infection prevention, IVIG does not have a role in HSCT.
Nocturnal evolution of respiratory effort in obstructive sleep apnoea syndrome: influence on arousal threshold
Authors: E Sforza, J Krieger, C Petiau
Journal: European Respiratory Journal (1998)

It has been recently described that the overnight increase in maximal end-apnoeic oesophageal pressure (P(oes,max)), considered as an index of the arousal threshold to occlusion, mostly contributes to apnoea lengthening during the night. However, the rise in apnoea duration could also be caused by changes in hypoxaemia, chemosensitivity and upper airway resistance. To better define the relative contributions of each of these factors, we examined the recordings of nine patients. Before apnoea, the mean pulmonary resistance at peak inspiratory flow (RPIF) was computed. During apnoea, all swings in oesophageal pressure (P(oes)) were measured to define the P(oes,max), the increase from the minimum to the maximum (deltaP(oes)), the rate of increase in P(oes) (RP(oes)) and the P(oes) at the first occluded breath (P(oes,1)). A gradual and significant increase in apnoea duration (p=0.02), P(oes,max) (p=0.02) and deltaP(oes) (p=0.006) was present across the night without any changes in oxygen saturation, RPIF, and P(oes,1). The slope of increase in P(oes,max), apnoea duration and deltaP(oes) was correlated with the apnoea/hypopnoea index. We conclude that in obstructive sleep apnoea, the nocturnal rise in apnoea duration is attributable more to an increase in the arousal threshold related to apnoea recurrence than to changes in chemosensitivity and upper airway resistance.
Quality-Adjusted Time Without Symptoms or Toxicity Analysis of Adjuvant Chemotherapy in Non–Small-Cell Lung Cancer: An Analysis of the National Cancer Institute of Canada Clinical Trials Group JBR.10 Trial
Authors: Raymond W. Jang, Aurélie Le Maître, Keyue Ding, Tim Winton, Andrea Bezjak, Lesley Seymour, Frances A. Shepherd, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2009)

Purpose National Cancer Institute of Canada Clinical Trials Group JBR.10 demonstrated that adjuvant vinorelbine and cisplatin after resection of stage IB-II non–small-cell lung cancer (NSCLC) improved relapse-free and overall survival. However, many patients either are not referred for chemotherapy or decline treatment. To aid in treatment decision making, quality-adjusted survival estimates of the JBR.10 trial were derived using a quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis. Methods Survival curves for treatment (N = 242) and observation groups (N = 240) were partitioned into three health states: time with ≥ grade 2 (early or late) chemotherapy-related toxicity (TOX), time in relapse (REL), and time without toxicity or relapse (TWiST). Q-TWiST = u TOX × TOX + u TWiST × TWIST + u REL × REL, where weights u TOX , u TWIST , and u REL range from 0 to 1. Threshold utility analysis was performed to test the sensitivity of the results to changes in the weights. Weights were derived in an exploratory fashion using different methods. Methods included use of arbitrary values, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) quality-of-life data prospectively collected in JBR.10 (global assessment questions and symptom-based questions), and lastly weights European Quality of Life–Five Dimensions questionnaire collected from early-stage NSCLC (nontrial) patients after resection with discounting for toxicity and relapse. The α level was .05. Results Threshold utility analysis revealed that adjuvant chemotherapy was preferred for all possible weight values for relapse and toxicity (u REL , u TOX ), although the result was not always statistically significant. The adjuvant chemotherapy group had better Q-TWiST in the range of 5 to 6 additional months, which was statistically significant using all methods. Conclusion Adjuvant chemotherapy in early-stage NSCLC improves quality-adjusted survival despite chemotherapy toxicity.
Patterns of Recurrence and Outcome According to Breast Cancer Subtypes in Lymph Node–Negative Disease: Results From International Breast Cancer Study Group Trials VIII and IX
Authors: Otto Metzger-Filho, Zhuoxin Sun, Giuseppe Viale, Karen N. Price, Diana Crivellari, Raymond D. Snyder, Richard D. Gelber, Monica Castiglione-Gertsch, Alan S. Coates, Aron Goldhirsch, Fatima Cardoso
Journal: Journal of Clinical Oncology (2013)

Purpose To retrospectively evaluate the pattern of recurrence and outcome of node-negative breast cancer (BC) according to major subtypes. Patients and Methods In all, 1,951 patients with node-negative, early-stage BC randomly assigned in International Breast Cancer Study Group Trials VIII and IX with centrally reviewed pathology data were included. BC subtypes were defined as triple negative (TN; n = 310), human epidermal growth factor receptor 2 (HER2) positive (n = 369), and hormone receptor positive with high (luminal B–like [LB-like]; n = 763) or low (luminal A–like [LA-like]; n = 509) proliferative activity by Ki-67 labeling index. BC-free interval (BCFI) events were invasive BC recurrence in local, contralateral breast, nodal, bone, or visceral sites. Time to first site–specific recurrence was evaluated by using cumulative incidence and competing risks regression analysis. Results Median follow-up was 12.5 years. The 10-year BCFI was higher for patients with LA-like (86%) BC compared with LB-like (76%), HER2 (73%), and TN (71%; P &lt; .001) BC. TN and HER2 cohorts had higher hazard of BCFI event in the first 4 years after diagnosis (pre-trastuzumab). LB-like cohorts had a continuously higher hazard of BCFI event over time compared with LA-like cohorts. Ten-year overall survival was higher for LA-like (89%) compared with LB-like (83%), HER2 (77%), and TN (75%; P &lt; .001) BC. LB-like subtypes had higher rates of bone as first recurrence site than other subtypes (P = .005). Visceral recurrence as first site was lower for the LA-like subgroup, with similar incidence among the other subgroups when treated with chemotherapy (P = .003). Conclusion BC subtypes have different distant recurrence patterns over time. Defining different patterns of BC recurrence can improve BC care through surveillance guidelines and can guide the design of clinical studies.
Premeal Injection of Rapid-Acting Insulin Reduces Postprandial Glycemic Excursions in Type 1 Diabetes
Authors: Yoeri M. Luijf, Arianne C. van Bon, Joost B. Hoekstra, J. Hans DeVries
Journal: Diabetes Care (2010)

OBJECTIVE To assess the effect of three premeal timings of rapid-acting insulin on postprandial glucose excursions in type 1 diabetes. RESEARCH DESIGN AND METHODS Ten subjects participated in a three-way randomized crossover trial. Mean ± SD age was 45.5 ± 12.1 years, A1C was 8.55 ± 1.50%, duration of diabetes was 23.8 ± 7.8 years, and duration of continuous subcutaneous insulin infusion therapy was 8.5 ± 6.1 years. Insulin aspart was administered at 30, 15, or 0 min before mealtime. RESULTS Area under the curve was lower in the −15 stratum (0.41 ± 0.51 mmol/l/min) than that in the −30 stratum (1.89 ± 0.72 mmol/l/min, P = 0.029) and 0 stratum (2.11 ± 0.66 mmol/l/min, P = 0.030). Maximum glucose excursion was lower in the −15 stratum (4.77 ± 0.52 mmol/l) than that in the −30 (6.48 ± 0.76 mmol/l, P = 0.025) and 0 stratum (6.93 ± 0.76 mmol/l, P = 0.022). Peak glucose level was lower in the −15 stratum (9.26 ± 0.72 mmol/l) than that in the −30 stratum (11.74 ± 0.80 mmol/l, P = 0.007) and the 0 stratum (12.29 ± 0.93, P = 0.009). Time spent in the 3.5–10 mmol/l range was higher in the −15 stratum (224.5 ± 25.0 min) than that in the 0 stratum (90.5 ± 23.2 min, P = 0.001). There was no significant difference in occurrence of glucose levels &amp;lt;3.5 mmol/l between strata (P = 0.901). CONCLUSIONS Administration of rapid-acting insulin analogs 15 min before mealtime results in lower postprandial glucose excursions and more time spent in the 3.5–10.0 mmol/l range, without increased risk of hypoglycemia.