tbuckley/cabot-search huggingface dataset:
Paternal Age at Birth of First Child and Risk of Schizophrenia
Authors: Liselotte Petersen, Preben Bo Mortensen, Carsten Bøcker Pedersen
Journal: American Journal of Psychiatry (2010)

Objective: Greater paternal age is associated with increased risk of schizophrenia, and it has been hypothesized that de novo mutations in paternal germ cells are responsible for this association. An alternative hypothesis is that selection into late fatherhood accompanies a predisposition to schizophrenia. However, direct evidence of either hypothesis is lacking. If de novo mutations are responsible, greater paternal age at conception should increase the risk of schizophrenia. Conversely, if selection into late fatherhood is responsible for the association, greater age at which the father had his first child should increase the risk of schizophrenia. The authors aimed to distinguish between these two measures of paternal age. Method: A total of 2.2 million people born in Denmark between 1955 and 1992 were followed up until first diagnosis with schizophrenia. Incidence rate ratios were estimated in a Cox regression. Results: Among second- or later-born children, greater paternal age increased the risk of schizophrenia. However, when paternal age at the time of the father's first child was accounted for, the risk of schizophrenia did not depend on paternal age at the birth of later children. In contrast, the risk of schizophrenia increased significantly with increasing paternal age at the time of the father's first child. Conclusions: Factors related to greater paternal age when the father's first child was born, and not the father's age at conception of later children, are responsible for the association between paternal age and the risk of schizophrenia. These findings do not support the de novo mutation hypothesis.
A Critical Appraisal of the Predictive Value of In Vitro Chemosensitivity Assays
Authors: R. M. Phillips, M. C. Bibby, J. A. Double
Journal: JNCI Journal of the National Cancer Institute (1990)

Journal Article A Critical Appraisal of the Predictive Value of In Vitro Chemosensitivity Assays Get access R. M. Phillips, R. M. Phillips * Clinical Oncology Unit, University of BradfordBradford, West Yorkshire, England *Correspondence to : R. M. Phillips, Ph.D., Clinical Oncology Unit, University of Bradford, Bradford, West Yorkshire BD7 1DP, England. Search for other works by this author on: Oxford Academic PubMed Google Scholar M. C. Bibby, M. C. Bibby Clinical Oncology Unit, University of BradfordBradford, West Yorkshire, England Search for other works by this author on: Oxford Academic PubMed Google Scholar J. A. Double J. A. Double Clinical Oncology Unit, University of BradfordBradford, West Yorkshire, England Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 82, Issue 18, 19 September 1990, Pages 1457–1468, https://doi.org/10.1093/jnci/82.18.1457 Published: 19 September 1990 Article history Received: 19 March 1990 Revision received: 20 June 1990 Accepted: 11 July 1990 Published: 19 September 1990
Response to Letter Regarding Article, “Elevated Levels of Inflammatory Cytokines Predict Survival in Idiopathic and Familial Pulmonary Arterial Hypertension”
Authors: Elaine Soon, Nicholas W. Morrell, Joanna Pepke-Zaba, Carmen M. Treacy, Natalie J. Doughty, Alan M. Holmes, Simon Jennings, Lucy Barker, Paul Nicklin, Christoph Walker, David C. Budd, Laura Southgate, Rajiv D. Machado, Richard C. Trembath
Journal: Circulation (2011)

We appreciate the opportunity to discuss the issues raised by Dr Montani et al.The Kaplan-Meier survival curves were presented according to quartile values for each cytokine to determine whether there was a dose-response effect, which is standard practice for this form of analysis.When we dichotomized the data by median values, it also resulted in significant differences in survival, but the separation of curves given by the median values was not as good as that given by the optimum values stated in Table 4 of our article. 1ecause it is our intention to validate the use of these cytokines as biomarkers in clinical practice, we believe that presentation of both quartiles and optimum values for each cytokine is the best and most transparent method of presenting these data.3][4] We can also confirm that the proportional hazards assumption was respected with regard to the Cox model.Hence, each parameter/cytokine has been given its best opportunity to perform as a predictor of survival in these analyses, particularly given that the optimum values for the classic parameters may vary slightly between different populations.Regarding the impact of pulmonary arterial hypertension (PAH) therapies on cytokine levels, this group of patients was recruited over a 6-year period, and was treated according to their clinical condition over this period.Many patients initially on monotherapy then progressed to combination therapy.Only 13 patients remained on endothelin receptor antagonist monotherapy throughout this period, and only 2 on phosphodiesterase-5 inhibitor monotherapy.There were no significant differences in cytokine levels between patients on endothelin receptor antagonist monotherapy versus those on prostanoids.The impact of specific therapies on cytokine levels would be best evaluated in a longitudinal study measuring levels in treatment-naı ¨ve patients commenced on therapy.Such a study is underway in centers in the United Kingdom.We have also considered the incident patients in this group, who made up 41% of the cases (24 of 58 patients).The cytokine levels we specified were still significant or nearly significant discriminators for survival in incident patients.There were no significant differences in cytokine levels between incident and prevalent PAH patients.Finally, the study population reflected real-life experience, with a mixture of incident and prevalent PAH patients on different PAHtargeted therapies and combinations of therapies.The fact that cytokines are able to act as discriminators in this mixed population offers hope that they may be useful tools in the clinical setting.
Interleukin 5 induces S mu-S gamma 1 DNA rearrangement in B cells activated with dextran-anti-IgD antibodies and interleukin 4: a three component model for Ig class switching.
Authors: R Mandler, C C Chu, W E Paul, E E Max, C M Snapper
Journal: The Journal of Experimental Medicine (1993)

The cellular signals required for induction of immunoglobulin (Ig) class switching are only partially understood. Two processes that are considered to be necessary for such induction are DNA synthesis and germline constant heavy (CH) gene transcription. We now show that an additional signal, as mediated by interleukin 5 (IL-5), is also required. To induce proliferation of resting B cells, but not Ig secretion, we utilized anti-IgD antibodies conjugated to dextran (alpha delta-dex). The addition of IL-4, a well-established switch factor for the IgG1 subclass, to alpha delta-dex-activated cell cultures failed to induce IgG1 secretion or mIgG1+ cells unless IL-5 was also present. While IL-4 stimulated an increase in germline gamma 1 RNA in alpha delta-dex-activated cells, this effect could neither be induced nor enhanced by IL-5. By contrast, IL-5 strongly enhanced steady-state levels of productive gamma 1 RNA induced by alpha delta-dex and IL-4, suggesting that IL-5 stimulated IgG1 switch rearrangement. To test this possibility we measured switch (S) mu-S gamma 1 DNA recombination events using a newly developed assay, digestion circularization polymerase chain reaction (DC-PCR). We demonstrated that IL-5 was necessary for induction of S mu-S gamma 1 DNA rearrangement in alpha delta-dex plus IL-4-activated cells but that it had little effect on rearrangement in the absence of IL-4. Our data strongly suggest, therefore, a three-component model for induction of Ig class switching. This model includes germline CH gene transcription, DNA synthesis, and a third component that is necessary for recombination.
Randomised phase II study comparing topotecan/carboplatin administration for 5 versus 3 days in the treatment of extensive-stage small-cell lung cancer
Authors: U. Seifart, T. Fink, C. Schade-Brittinger, K. Hans, C. Mueller, G. Koschel, H. Schroeder, R. Lorenz, J. Dethling, M. Wolf
Journal: Annals of Oncology (2006)
Phase III, Randomized, Double-Blind Study of Epoetin Alfa Compared With Placebo in Anemic Patients Receiving Chemotherapy
Authors: Thomas E. Witzig, Peter T. Silberstein, Charles L. Loprinzi, Jeff A. Sloan, Paul J. Novotny, James A. Mailliard, Kendrith M. Rowland, Steven R. Alberts, James E. Krook, Ralph Levitt, Roscoe F. Morton
Journal: Journal of Clinical Oncology (2004)

To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy.This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly.The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, -3.8 to +5.3) compared with 2.8 g/dL (range, -2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a > or = 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with -2.1 for the nonresponders (P = .006).Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.
An Assessment of Radical Prostatectomy
Authors: Grace L. Lu-Yao
Journal: JAMA (1993)

Objectives.  —To examine temporal trends and geographic variation in radical prostatectomy rates and short-term outcomes.  Design.  —Population-based study of radical prostatectomy for the years 1984 through 1990. Poisson regression was used to estimate temporal and regional effects.  Setting.  —The 50 states and the District of Columbia.  Participants.  —A 20% national sample of male Medicare beneficiaries aged 65 years or older.  Main Outcome Measures.  —Rate of radical prostatectomy; 30-day mortality; and major cardiopulmonary complications, vascular complications, or surgical repairs within 30 days of radical prostatectomy.  Results.  —A total of 10598 radical prostatectomies were identified. The adjusted rate of radical prostatectomy in 1990 was 5.75 times that in 1984. The relative increase was similar in all age groups. Substantial geographic variation existed in rates from 1988 through 1990: all states in the New England and Mid-Atlantic regions had rates equal to or below 60 per 100 000 male Medicare beneficiaries, while all states in the Pacific and Mountain regions had rates equal to or above 130 per 100 000. The mortality and morbidity after radical prostatectomy are not trivial for older men (aged 75 years and older)—almost 2% died and nearly 8% suffered major cardiopulmonary complications within 30 days of the operation.  Conclusion.  —The sharp increase and wide geographic variation in radical prostatectomy rates make the evaluation of this surgical procedure a pressing issue. The rising rate of radical prostatectomy among men aged 75 years and older merits special attention.  ( JAMA . 1993;269:2633-2636)
Airway PI3K Pathway Activation Is an Early and Reversible Event in Lung Cancer Development
Authors: Adam M. Gustafson, Raffaella Soldi, Christina Anderlind, Mary Beth Scholand, Jun Qian, Xiaohui Zhang, Kendal Cooper, Darren Walker, Annette McWilliams, Gang Liu, Eva Szabo, Jerome Brody, Pierre P. Massion, Marc E. Lenburg, Stephen Lam, Andrea H. Bild, Avrum Spira
Journal: Science Translational Medicine (2010)

A cancer-associated signaling pathway is reversibly activated in the normal airways of smokers before they develop lung cancer, presenting an opportunity for preventive therapy.
Genomic Analysis of Tumors by Array Comparative Genomic Hybridization: More Is Better
Authors: Donna G. Albertson, Antoine M. Snijders, Jane Fridlyand, Richard Jordan, Daniel Pinkel, Brian L. Schmidt
Journal: Cancer Research (2006)

To the Editor: 

We read with interest the article by Baldwin et al. ( [1][1]), which describes the use of an array of 32,433 bacterial artificial chromosome clones tiled across the genome ( [2][2], [3][3]) to map genomic aberrations in 20 oral squamous cell carcinoma samples by array comparative
Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): short-term outcomes of an open-label randomised controlled trial
Authors: Sung-Bum Kang, Ji Won Park, Seung-Yong Jeong, Byung Ho Nam, Hyo Seong Choi, Duck-Woo Kim, Seok-Byung Lim, Taek-Gu Lee, Dae Yong Kim, Jae-Sung Kim, Hee Jin Chang, Hye-Seung Lee, Sun Young Kim, Kyung Hae Jung, Yong Sang Hong, Jee Hyun Kim, Dae Kyung Sohn, Dae-Hyun Kim, Jae Hwan Oh
Journal: The Lancet Oncology (2010)
The risk of asthma in relation to occupational exposures: a case-control study from a Swedish city
Authors: K Torén, B Balder, J Brisman, N Lindholm, O Löwhagen, M Palmqvist, A Tunsäter
Journal: European Respiratory Journal (1999)

The purpose of this study was to estimate the risk of adult asthma in relation to certain occupational exposures. The study was designed as a case-control study in Goteborg, including 321 subjects with asthma, born between 1926 and 1970. Controls (n=1,459) were randomly selected from the same area from registers of the 1986 population. Questionnaire information was collected in 1996, and included occupational exposures and smoking habits. Odds ratios were calculated for exposure before asthma onset, stratified by sex and age-class. The highest risks for asthma were associated with exposure to grain dust (odds ratio (OR) 4.2, 95% confidence interval (CI) 1.6-10.7) and flour dust (OR 2.8, 95% CI 1.1-7.2). Among males, significantly increased risks were observed after exposure to flour dust, welding fumes, man-made mineral fibres, and solvents. Among females, increased risks for asthma were associated with exposures to paper dust and textile dust. In logistic regression models controlling for age, smoking, sex and interacting exposures, increased risks were seen for welding fumes (OR 2.0, 95% CI 15-3.4), man-made mineral fibres (OR 2.6, 95% CI 1.4-7.3) and solvents (OR 2.2, 95% CI 1.2-3.2). The fraction of asthma attributed to occupational exposures after adjusting for sex, smoking and age was 11% (95% CI 7-14%). In conclusion, exposure to welding fumes, man-made mineral fibres, solvents and textile dust is associated with increased risk for asthma.
Relaxation of distal colonic circular smooth muscle by nitric oxide derived from human leucocytes.
Authors: S J Middleton, M Shorthouse, J O Hunter
Journal: Gut (1993)

The role of nitric oxide (NO) as a mediator of colonic circular smooth muscle relaxation by human leucocytes was investigated. Granulocytes and mononuclear cells were obtained by gradient centrifugation of venous blood from healthy volunteers. Both cell types relaxed precontracted distal colonic circular smooth muscle in a concentration dependent manner. Muscle relaxation was inhibited by preincubation of cells with NG-monomethyl-L-arginine (100 microM/l) but not by preincubation with NG-monomethyl-D-arginine (100 microM/l). Muscle relaxation by cells was reduced by 200 nM oxyhaemoglobin and 10 microM methylene blue but was increased by 60 units/ml superoxide dismutase. Non-viable cells did not produce muscle relaxation. Activation of mononuclear cells by incubation with 100 nM/l FMet-Leu-Phe increased muscle relaxation, whereas activation of granulocytes did not. Granulocytes and mononuclear cells relax precontracted distal colonic circular smooth muscle in vitro by the release of NO that may contribute to motility disorders of the gut associated with inflammation.
Function and Dysfunction of Hypocretin/Orexin: An Energetics Point of View
Authors: Xiao-Bing Gao, Tamas Horvath
Journal: Annual Review of Neuroscience (2014)

The basic elements of animal behavior that are critical to survival include energy, arousal, and motivation: Energy intake and expenditure are fundamental to all organisms for the performance of any type of function; according to the Yerkes-Dodson law, an optimal level of arousal is required for animals to perform normal functions; and motivation is critical to goal-oriented behaviors in higher animals. The brain is the primary organ that controls these elements and, through evolution, has developed specialized structures to accomplish this task. The orexin/hypocretin system in the perifornical/lateral hypothalamus, which was discovered 15 years ago, is one such specialized area. This review summarizes a fast-growing body of evidence discerning how the orexin/hypocretin system integrates internal and external cues to regulate energy intake that can then be used to generate sufficient arousal for animals to perform innate and goal-oriented behaviors.
A Novel Inhibitor of Signal Transducers And Activators Of Transcription 3 Activation Is Efficacious Against Established Central Nervous System Melanoma and Inhibits Regulatory T Cells
Authors: Ling-Yuan Kong, Mohamed K. Abou-Ghazal, Jun Wei, Arup Chakraborty, Wei Sun, Wei Qiao, Gregory N. Fuller, Izabela Fokt, Elizabeth A. Grimm, Robert J. Schmittling, Gary E. Archer, John H. Sampson, Waldemar Priebe, Amy B. Heimberger
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Activation of signal transducers and activators of transcription 3 (STAT3) has been identified as a central mediator of melanoma growth and metastasis. We hypothesized that WP1066, a novel STAT3 blockade agent, has marked antitumor activity, even against the melanoma metastasis to brain, a site typically refractory to therapies. Experimental Design: The antitumor activities and related mechanisms of WP1066 were investigated both in vitro on melanoma cell lines and in vivo on mice with subcutaneously syngeneic melanoma or with intracerebral melanoma tumors. Results: WP1066 achieved an IC50 of 1.6, 2.3, and 1.5 μmol/L against melanoma cell line A375, B16, and B16EGFRvIII, respectively. WP1066 suppressed the phosphorylation of Janus-activated kinase 2 and STAT3 (Tyr705) in these cells. Tumor growth in mice with subcutaneously established syngeneic melanoma was markedly inhibited by WP1066 compared with that in controls. Long-term survival (&amp;gt;78 days) was observed in 80% of mice with established intracerebral syngeneic melanoma treated with 40 mg/kg of WP1066 in contrast to control mice who survived for a median of 15 days. Although WP1066 did not induce immunologic memory or enhance humoral responses to EGFRvIII, this compound reduced the production of immunosuppressive cytokines and chemokines (transforming growth factor-β, RANTES, MCP-1, vascular endothelial growth factor), markedly inhibited natural and inducible Treg proliferation, and significantly increased cytotoxic immune responses of T cells. Conclusions: The antitumor cytotoxic effects of WP1066 and its ability to induce antitumor immune responses suggest that this compound has potential for the effective treatment of melanoma metastatic to brain.
Abstract S1-2: ATLAS – 10 v 5 years of adjuvant tamoxifen (TAM) in ER+ disease: Effects on outcome in the first and in the second decade after diagnosis
Authors: C Davies, H Pan, J Godwin, R Gray, R Peto
Journal: Cancer Research (2012)

Abstract Background: In ER+ early breast cancer, 5 years of tamoxifen greatly reduces recurrence throughout the first decade (years 0–9) with little further gain later, and reduces breast cancer mortality (BCM) substantially throughout years 0–14 (EBCTCG, Lancet 2011; 378: 771–84 – see Table). It is not known how 10 years TAM compares with the current standard of just 5 years TAM. Methods: In 1996–2005 the international ATLAS trial randomized 6846 women with ER+ disease who had had ∼5 years of adjuvant TAM to continue another 5 years (to year 10) or stop at year 5 (control). Annual follow-ups recorded compliance, hospital admissions, breast cancer recurrence (including new contralateral), any other new primary cancer and cause of death. Results: Compliance was ∼80%, as after 2 years 84% of those allocated continue and 4% of those allocated stop were still taking endocrine treatment (&amp;gt;99% TAM). With mean 7.1 woman-years follow-up (30,000 w-y in years 5–9, 16,000 in years 10–14, 2000 later), 1328 recurrences were reported (900 in years 5–9, 379 in years 10–14). Recurrence was significantly lower with10 than 5 years TAM (Table: logrank 2p = 0.002, rate ratio (RR)=0.90 se 0.06 in years 5–9 and 0.75 se 0.08 in years 10+). So were both BCM (2p = 0.01, RR = 0.97 se 0.10 in years 5–9 and 0.71 se 0.09 in years 10+) and all-cause mortality (2p = 0.01, with no increase in non-BCM). Proportional risk reductions were homogeneous by country, age and stage. Kaplan-Meier risks in years 5–14 (K-M) were: recurrence 21.4 vs 25.1%, BCM 12.2 vs 15.0%. Uterine cancer K-Ms in those randomized at age 50+ were: incidence 2.6 vs 1.6% (2p = 0.08), mortality 0.2 vs 0.2%. In pre-menopausal women (where AIs are not an alternative to TAM) there was no apparent excess of uterine cancer. Discussion: Compared with just 5 years TAM, continuing TAM to year 10 safely protects further against recurrence and, particularly during the second decade, BCM. Combining results from ATLAS and the EBCTCG meta-analyses of 5 years TAM vs none (both had ∼80% compliance), in a hypothetical trial of 10 vs 0 years TAM with ∼80% compliance, 15-year BCM would be reduced by at least one-third. Hence, full compliance with 10 years TAM would yield even greater benefit (Table). Further follow-up of ATLAS will assess more reliably the apparently substantial mortality reduction in the second decade after diagnosis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-2.