tbuckley/cabot-search huggingface dataset:
Phase III Randomized Trial of Docetaxel Plus Cisplatin Versus Vindesine Plus Cisplatin in Patients With Stage IV Non-Small-Cell Lung Cancer: The Japanese Taxotere Lung Cancer Study Group
Authors: Kaoru Kubota, Koshiro Watanabe, Hideo Kunitoh, Kazumasa Noda, Yukito Ichinose, Nobuyuki Katakami, Takahiko Sugiura, Masaaki Kawahara, Akira Yokoyama, Soichiro Yokota, Shuichi Yoneda, Kaoru Matsui, Shinzo Kudo, Masahiko Shibuya, Takeshi Isobe, Yoshihiko Segawa, Yutaka Nishiwaki, Yasuo Ohashi, Hisanobu Niitani
Journal: Journal of Clinical Oncology (2004)

Purpose Few randomized trials have demonstrated survival benefit of combination chemotherapy involving new agents plus cisplatin compared with classic combination chemotherapy in advanced non-small-cell lung cancer (NSCLC). The primary aim of this study was to test whether docetaxel plus cisplatin (DC) improves survival compared with vindesine plus cisplatin (VdsC) in patients with previously untreated stage IV NSCLC. Patients and Methods Eligible, stage IV, chemotherapy-naive patients (n = 311) were randomly assigned to receive docetaxel 60 mg/m 2 intravenously on day 1 plus cisplatin 80 mg/m 2 intravenously on day 1 of a 3- or 4-week cycle, or vindesine 3 mg/m 2 intravenously on days 1, 8, and 15 plus cisplatin 80 mg/m 2 intravenously on day 1 of a 4-week cycle. Cross-over administration of docetaxel and vindesine was prohibited for both treatment groups. Results Overall, 302 patients were eligible for evaluation. The DC arm demonstrated significant improvements compared with the VdsC arm in overall response rates (37% v 21%, respectively; P &lt; .01) and median survival times (11.3 v 9.6 months, respectively; P = .014). Two-year survival rates were 24% for the DC arm compared with 12% for the VdsC arm. The physical domain of the Quality of Life for Cancer Patients Treated with Anticancer Drugs measure was significantly better in the DC arm than in the VdsC arm (P = .020). Toxicity was predominantly hematologic and was more severe in the VdsC arm. Conclusion As first-line treatment for stage IV NSCLC, DC resulted in greater clinical benefit in terms of response rate (with marked improvements in overall and 2-year survival rates) and quality of life than did treatment with VdsC.
The Interaction of Drugs with the Sarcoplasmic Reticulum
Authors: L Herbette, F C Messineo, A M Katz
Journal: The Annual Review of Pharmacology and Toxicology (1982)

Efforts to determine the mechanisms by which drugs interact with membranes can be facilitated by studies of the SR, which has a relatively simple structure. The fact that the SR lacks most of the specific receptors found on other membranes, notably the sarcolemma, is an advantage, as well as a limitation, in that "nonspecific" drug effects can be evaluated readily in the SR. The presence in the SR of a well-characterized calcium pump protein allows the effects of a given drug on membrane function to be analyzed, and drug effects on the functional properties of the SR can now be correlated with their probable sites of action within the membrane. Equally important is the ability to acquire information regarding the relation between the structure of an amphiphilic drug and its mechanism of interaction with the SR membrane, because these interactions depend on the structural properties of both the membrane and the added agent. The potential sites of interaction of amphiphiles schematically portrayed in Figure 3 may be relevant to membranes other than the SR, as the overall structural properties of this membrane appear not to be unique. For this reason, the interaction of drugs with the sarcoplasmic reticulum membrane may provide structural models that are applicable to other biological membranes.
Abnormal Stimulus-Response Intensity Functions in Posttraumatic Stress Disorder: An Electrophysiological Investigation
Authors: Jeffrey David Lewine, Robert J. Thoma, Sherri L. Provencal, Chris Edgar, Gregory A. Miller, Jose M. Canive
Journal: American Journal of Psychiatry (2002)

The purpose of this study was to explore the relationship between combat-related posttraumatic stress disorder (PTSD) and specific augmentation versus reduction patterns for the N100 and P200 components of auditory event-related potentials evoked by tones of increasing intensity.Event-related potentials of subjects with PTSD (N=36), subjects with no psychopathology (N=20), subjects with major depression but no PTSD (N=10), and subjects with a history of chronic alcohol abuse but no PTSD (N=8) were recorded. Brain responses were evoked by a 2000-Hz tone presented in intensity blocks of 65, 72.5, 80, 87.5, and 95 dB (SPL).Evoked data from five PTSD subjects were of poor quality and excluded from further analyses. For all but one subject with no psychopathology and for all subjects with a history of alcohol abuse or major depression (but no PTSD), the Cz amplitude of the P200 response component showed augmentation as a nearly linear function of tone intensity. As a group, subjects with PTSD showed no such increase in P200 response magnitude. Examination of the data from individual subjects with PTSD showed that 42% exhibited augmentation patterns similar to those seen for subjects in the comparison groups. However, 58% showed evidence of P200 reduction, with the response to the loudest tone being smaller than responses to tones of intermediate intensity.The data suggest that there is a significant subgroup of patients with combat-related PTSD who enter into a state of protective inhibition at relatively low stimulus intensities. It is hypothesized that this is an appropriate adaptive mechanism for these subjects rather than an indication of a core neurobiological abnormality.
Accuracy of the "traffic light" clinical decision rule for serious bacterial infections in young children with fever: a retrospective cohort study
Authors: S. De, G. J. Williams, A. Hayen, P. Macaskill, M. McCaskill, D. Isaacs, J. C. Craig
Journal: BMJ (2013)

<b>Objectives</b> To determine the accuracy of a clinical decision rule (the traffic light system developed by the National Institute for Health and Clinical Excellence (NICE)) for detecting three common serious bacterial infections (urinary tract infection, pneumonia, and bacteraemia) in young febrile children. <b>Design</b> Retrospective analysis of data from a two year prospective cohort study <b>Setting</b> A paediatric emergency department. <b>Participants</b> 15&nbsp;781 cases of children under 5 years of age presenting with a febrile illness. <b>Main outcome measures</b> Clinical features were used to categorise each febrile episodes as low, intermediate, or high probability of serious bacterial infection (green, amber, and red zones of the traffic light system); these results were checked (using standard radiological and microbiological tests) for each of the infections of interest and for any serious bacterial infection. <b>Results</b> After combination of the intermediate and high risk categories, the NICE traffic light system had a test sensitivity of 85.8% (95% confidence interval 83.6% to 87.7%) and specificity of 28.5% (27.8% to 29.3%) for the detection of any serious bacterial infection. Of the 1140 cases of serious bacterial infection, 157 (13.8%) were test negative (in the green zone), and, of these, 108 (68.8%) were urinary tract infections. Adding urine analysis (leucocyte esterase or nitrite positive), reported in 3653 (23.1%) episodes, to the traffic light system improved the test performance: sensitivity 92.1% (89.3% to 94.1%), specificity 22.3% (20.9% to 23.8%), and relative positive likelihood ratio 1.10 (1.06 to 1.14). <b>Conclusion</b> The NICE traffic light system failed to identify a substantial proportion of serious bacterial infections, particularly urinary tract infections. The addition of urine analysis significantly improved test sensitivity, making the traffic light system a more useful triage tool for the detection of serious bacterial infections in young febrile children.
The low-density lipoprotein receptor plays a role in the infection of primary human hepatocytes by hepatitis C virus
Authors: Sonia Molina, Valérie Castet, Chantal Fournier-Wirth, Lydiane Pichard-Garcia, Rachel Avner, Dror Harats, Joseph Roitelman, Ronald Barbaras, Pierre Graber, Paola Ghersa, Moshe Smolarsky, Ada Funaro, Fabio Malavasi, Dominique Larrey, Joliette Coste, Jean-Michel Fabre, Antonio Sa-Cunha, Patrick Maurel
Journal: Journal of Hepatology (2006)
The p53 Homologue ΔNp63α Interacts with the Nuclear Factor-κB Pathway to Modulate Epithelial Cell Growth
Authors: Kathryn E. King, Roshini M. Ponnamperuma, Clint Allen, Hai Lu, Praveen Duggal, Zhong Chen, Carter Van Waes, Wendy C. Weinberg
Journal: Cancer Research (2008)

The p53 homologue DeltaNp63alpha is overexpressed and inhibits apoptosis in a subset of human squamous cell carcinomas (SCC). Here, we report that in normal keratinocytes overexpressing DeltaNp63alpha and in human squamous carcinoma cells, DeltaNp63alpha physically associates with phosphorylated, transcriptionally active nuclear c-Rel, a nuclear factor-kappaB family member, resulting in increased c-Rel nuclear accumulation. This accumulation and the associated enhanced proliferation driven by elevated DeltaNp63alpha are attenuated by c-Rel small interfering RNA or overexpression of mutant IkappaBalphaM, indicating that c-Rel-containing complex formation is critical to the ability of elevated DeltaNp63alpha to maintain proliferation in the presence of growth arresting signals. Consistent with a role in growth regulation, DeltaNp63alpha-c-Rel complexes bind a promoter motif and repress the cyclin-dependent kinase inhibitor p21WAF1 in both human squamous carcinoma cells and normal keratinocytes overexpressing DeltaNp63alpha. The relationship between DeltaNp63alpha and activated c-Rel is reflected in their strong nuclear staining in the proliferating compartment of primary head and neck SCC. This is the first report indicating that high levels of DeltaNp63alpha interact with activated c-Rel in keratinocytes and SCC, thereby promoting uncontrolled proliferation, a key alteration in the pathogenesis of cancers.
A Defect in Nucleosome Remodeling Prevents <i>IL-12(p35)</i> Gene Transcription in Neonatal Dendritic Cells
Authors: Stanislas Goriely, Carine Van Lint, Réza Dadkhah, Myriam Libin, Dominique De Wit, Dominique Demonté, Fabienne Willems, Michel Goldman
Journal: The Journal of Experimental Medicine (2004)

To gain insight into the inability of newborns to mount efficient Th1 responses, we analyzed the molecular basis of defective IL-12(p35) expression in human neonatal monocyte-derived dendritic cells (DCs). Determination of IL-12(p35) pre-mRNA levels by real-time RT-PCR revealed that transcriptional activation of the gene in lipopolysaccharide-stimulated neonatal DCs was strongly impaired compared with adult DCs. We next showed that p50/p65 and p65/p65 dimers interact with kB#1 site, a critical cis-acting element of the IL-12(p35) promoter. We found that LPS-induced p65 activation was similar in adult and newborn DCs. Likewise, in vitro binding activity to the Sp1#1 site, previously shown to be critical for IL-12(p35) gene activation, did not differ in adults and newborns. Since the accessibility to this Sp1#1 site was found to depend on nucleosome remodeling, we used a chromatin accessibility assay to compare remodeling of the relevant nucleosome (nuc-2) in adult and neonatal DCs. We observed that nuc-2 remodeling in neonatal DCs was profoundly impaired in response to lipopolysaccharide. Both nuc-2 remodeling and IL-12(p35) gene transcription were restored upon addition of recombinant interferon-γ. We conclude that IL-12(p35) transcriptional repression in neonatal DCs takes place at the chromatin level.
Juvenile psoriatic arthritis and HLA antigens.
Authors: M L Hamilton, D D Gladman, A Shore, R M Laxer, E D Silverman
Journal: Annals of the Rheumatic Diseases (1990)

The clinical, laboratory, and radiological features, including histocompatibility typing, of 28 patients with juvenile psoriatic arthritis are reported. The most common presentation was that of psoriasis preceding or occurring simultaneously with arthritis. The most common course of juvenile psoriatic arthritis was to start as an oligoarthritis and progress, usually to polyarthritis. No patients with juvenile psoriatic arthritis had uveitis. Overall, most patients had a good outcome (93% in functional class I and II), though 8/28 (29%) did require disease modifying drugs over a mean period of 8.8 years of follow up. The clinical features of these patients were very similar to those of a group of 158 adult patients with psoriatic arthritis with the same disease duration followed up in the clinic. Although there was an increased prevalence of B17 in both juvenile and adult psoriatic arthritis, juvenile psoriatic arthritis showed increased prevalence of A2, whereas adult psoriatic arthritis showed increased prevalence of B27, Bw39, and Cw6. This HLA association differed from that reported in other forms of juvenile arthritis.
Beta Blockers and Breast Cancer Mortality: A Population- Based Study
Authors: Thomas I. Barron, Roisin M. Connolly, Linda Sharp, Kathleen Bennett, Kala Visvanathan
Journal: Journal of Clinical Oncology (2011)

Purpose Preclinical studies have demonstrated that antagonism of β 2 -adrenergic signaling inhibits several pathways necessary for breast tumor progression and metastasis. A series of population-based observational studies were conducted to examine associations between beta blocker use and breast tumor characteristics at diagnosis or breast cancer–specific mortality. Patients and Methods Linked national cancer registry and prescription dispensing data were used to identify women with a diagnosis of stage I to IV invasive breast cancer between January 1, 2001, and December 31, 2006. Women taking propranolol (β 1 /β 2 antagonist; n = 70) or atenolol (β 1 antagonist; n = 525), in the year before breast cancer diagnosis were matched (1:2) to women not taking a beta blocker (n = 4,738). Associations between use of propranolol or atenolol and risk of local tumor invasion at diagnosis (T4 tumor), nodal or metastatic involvement at diagnosis (N2/N3/M1 tumor), and time to breast cancer–specific mortality were assessed. Results Propranolol users were significantly less likely to present with a T4 (odds ratio [OR], 0.24, 95% CI, 0.07 to 0.85) or N2/N3/M1 (OR, 0.20; 95% CI, 0.04 to 0.88) tumor compared with matched nonusers. The cumulative probability of breast cancer–specific mortality was significantly lower for propranolol users compared with matched nonusers (hazard ratio, 0.19; 95% CI, 0.06 to 0.60). There was no difference in T4 or N2/N3/M1 tumor incidence or breast cancer–specific mortality between atenolol users and matched nonusers. Conclusion The results provide evidence in humans to support preclinical observations suggesting that inhibiting the β 2 -adrenergic signaling pathway can reduce breast cancer progression and mortality.
Th2 cell clonal anergy as a consequence of partial activation.
Authors: J Sloan-Lancaster, B D Evavold, P M Allen
Journal: The Journal of Experimental Medicine (1994)

We have demonstrated Th2 clonal anergy as a consequence of partial T cell activation by immunogenic peptide and chemically fixed APC, as well as by altered peptide ligand and live antigen-presenting cells (APC). Either stimulation resulted in a profound inability of the T cells to proliferate upon restimulation with antigen and functional APC, a similar phenomenon to that found with Th1 cells. The anergic state was long lasting and was restricted to proliferation, since the T cells retained the ability to produce cytokines upon restimulation, albeit at slightly reduced levels. Th2 anergy induction was inhibited by cyclosporine A, but not by provision of exogenous costimulation or growth factors. The data presented unify Th1 and Th2 cells with regard to anergy and suggest that the fundamental control during anergy for both subsets is prevention of clonal expansion, thus blocking amplification of the immune response.
Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-γ release assay vs. tuberculin skin test
Authors: E. Laffitte, J.P. Janssens, P. Roux-Lombard, A.M. Thielen, C. Barde, G. Marazza, R.G. Panizzon, J.-H. Saurat
Journal: British Journal of Dermatology (2009)

Antitumour necrosis factor (anti-TNF) treatments may reactivate latent tuberculosis infection (LTBI). For detecting LTBI, the tuberculin skin test (TST) has low sensitivity and specificity. Interferon-gamma release assays (IGRA) have been shown to be more sensitive and specific than TST.To compare the TST and the T-SPOT.TB IGRA for identifying LTBI in patients with psoriasis before anti-TNF treatment.A retrospective study was carried out over a 4-year period on patients with psoriasis requiring anti-TNF treatment. All were subjected to the TST, T-SPOT.TB and chest X-ray. Risk factors for LTBI and history of bacillus Calmette-Guérin (BCG) vaccination were recorded. The association of T-SPOT.TB and TST results with risk factors for LTBI was tested through univariate logistic regression models. Agreement between tests was quantified using kappa statistics. Treatment for LTBI was started 1 month before anti-TNF therapy when indicated.Fifty patients were included; 90% had prior BCG vaccination. A positive T-SPOT.TB was strongly associated with a presumptive diagnosis of LTBI (odds ratio 7.43; 95% confidence interval 1.38-39.9), which was not the case for the TST. Agreement between the T-SPOT.TB and TST was poor, kappa = 0.33 (SD 0.13). LTBI was detected and treated in 20% of the patients. In 20% of the cases, LTBI was not retained in spite of a positive TST but a negative T-SPOT.TB. All patients received an anti-TNF agent for a median of 56 weeks (range 20-188); among patients with a positive TST/negative T-SPOT.TB, no tuberculosis was detected with a median follow-up of 64 weeks (44-188). One case of disseminated tuberculosis occurred after 28 weeks of adalimumab treatment in a patient with LTBI in spite of treatment with rifampicin.This study is the first to underline the frequency of LTBI in patients with psoriasis (20%), and to support the use of IGRA instead of the TST for its detection. Nevertheless, there is still a risk of tuberculosis under anti-TNF therapy, even if LTBI is correctly diagnosed and treated.
Association of Hepatitis C with Posttransplant Diabetes in Renal Transplant Patients on Tacrolimus
Authors: Roy D. Bloom, Vinaya Rao, Francis Weng, Robert A. Grossman, Debbie Cohen, Kevin C. Mange
Journal: Journal of the American Society of Nephrology (2002)

Posttransplant diabetes mellitus (PTDM) remains a common complication of immunosuppression. Although multiple risk factors have been implicated, none have been clearly identified as predisposing to the increased PTDM frequency observed in patients on tacrolimus. Hepatitis C virus (HCV) has been associated with diabetes and is a significant renal transplant comorbidity. In this study, records of 427 kidney recipients who had no known diabetes before transplantation were retrospectively examined. A multivariate logistic regression model was fit with covariates that had unadjusted relationships with PTDM to examine the independent relationship of HCV and the odds of development of PTDM by 12 mo posttransplant. A potential interaction between HCV and the use of tacrolimus as maintenance therapy on the odds of the development of PTDM was examined. Overall, PTDM occurred more frequently in HCV(+) than HCV(-) patients (39.4% versus 9.8%; P = 0.0005). By multivariate logistic regression, HCV (adjusted odds ratio [OR], 5.58; 95% confidence interval [CI], 2.63 to 11.83; P = 0.0001), weight at transplantation (adjusted OR 1.028; 95% CI, 1.00 to 1.05; P = 0.001), and tacrolimus (adjusted OR, 2.85; 95% CI, 1.01 to 5.28; P = 0.047) were associated with PTDM. A significant interaction (P = 0.0001) was detected between HCV status and tacrolimus use for the odds of PTDM. Among the HCV(+) cohort, PTDM occurred more often in tacrolimus-treated than cyclosporine A-treated patients (57.8% versus 7.7%; P < 0.0001). PTDM rates in HCV(-) patients were similar between the two calcineurin inhibitors (10.0% versus 9.4%; P = 0.521, tacrolimus versus cyclosporine A). In conclusion, HCV is strongly associated with PTDM in renal transplant recipients and appears to account for the increased diabetogenicity observed with tacrolimus.
Pistillata—Duplications as a Mode for Floral Diversification in (Basal) Asterids
Authors: Tom Viaene, Dries Vekemans, Vivian F. Irish, Anke Geeraerts, Suzy Huysmans, Steven Janssens, Erik Smets, Koen Geuten
Journal: Molecular Biology and Evolution (2009)

Basal asterid families, and to a lesser extent the asterids as a whole, are characterized by a high variation in petal and stamen morphology. Moreover, the stamen number, the adnation of stamens to petals, and the degree of sympetaly vary considerably among basal asterid taxa. The B group genes, members of the APETALA3 (AP3) and PISTILLATA (PI) gene lineages, have been shown to specify petal and stamen identities in several core eudicot species. Duplicate genes in these lineages have been shown in some cases to have diversified in their function; for instance in Petunia, a PI paralog is required for the fusion of stamens to the corolla tube, illustrating that such genes belonging to this lineage are not just involved in specifying the identity of the stamens and petals but can also specify novel floral morphologies. This motivated us to study the duplication history of class B genes throughout asterid lineages, which comprise approximately one-third of all flowering plants. The evolutionary history of the PI gene subfamily indicates that the two genes in Petunia result from an ancient duplication event, coinciding with the origin of core asterids. A second duplication event occurred before the speciation of basal asterid Ericales families. These and other duplications in the PI lineage are not correlated with duplications in the AP3 lineage. To understand the molecular evolution of the Ericales PI genes after duplication, we have described their expression patterns using reverse transcription polymerase chain reaction and in situ hybridization, reconstructed how selection shaped their protein sequences and tested their protein interaction specificity with other class B proteins. We find that after duplication, PI paralogs have acquired multiple different expression patterns and negative selective pressure on their codons is relaxed, whereas substitutions in sites putatively involved in protein–protein interactions show positive selection, allowing for a change in the interaction behavior of the PI paralogs after duplication. Together, these observations suggest that the asterids have preferentially recruited PI duplicate genes to diverse and potentially novel roles in asterid flower development.