tbuckley/cabot-search huggingface dataset:
CT screening for lung cancer in the UK: position statement by UKLS investigators following the NLST report
Authors: J. K. Field, D. Baldwin, K. Brain, A. Devaraj, T. Eisen, S. W. Duffy, D. M. Hansell, K. Kerr, R. Page, M. Parmar, D. Weller, P. Williamson, D. Whynes
Journal: Thorax (2011)

<h3>Background</h3> The imminent publication of a randomised controlled trial from the USA that suggests CT screening reduces mortality from lung cancer by more than 20%, may potentially lead to one of the most important developments in lung cancer care. However, there remain important questions about the applicability of the results to the UK and the clinical effectiveness of this intervention, including its feasibility and cost-effectiveness. <h3>Objective</h3> To describe the remaining questions that need to be answered by further research and to comment on the use of CT screening in the UK outside a clinical trial. <h3>Methods</h3> The detailed design process of the UKLS protocol and international discussions were used to identify the research questions that remain to be answered and to inform those who may choose to consider offering CT screening, before these questions are answered. <h3>Results</h3> A series of research imperatives have been identified and we advise that CT screening should be part of the ongoing clinical trial in the UK, currently in the pilot phase (UKLS). UKLS is randomising 4,000 individuals for the pilot and a total of 32,000 for the main study. <h3>Conclusion</h3> There remain unresolved issues with respect to CT screening for lung cancer. These include its feasibility, psychosocial and cost-effectiveness in the UK, harmonisation of CT acquisition techniques, management of suspicious screening findings, the choice of screening frequency and the selection of an appropriate risk group for the intervention. UKLS is aimed at resolving these issues.
A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A STAR*D Report
Authors: Maurizio Fava, A. John Rush, Stephen R. Wisniewski, Andrew A. Nierenberg, Jonathan E. Alpert, Patrick J. McGrath, Michael E. Thase, Diane Warden, Melanie Biggs, James F. Luther, George Niederehe, Louise Ritz, Madhukar H. Trivedi
Journal: American Journal of Psychiatry (2006)

Objective: Few controlled studies have addressed the issue of which antidepressant medications should be recommended for outpatients who have not responded to multiple treatment trials. This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant (nortriptyline) following two prospective, consecutive, unsuccessful medication treatments for nonpsychotic major depressive disorder. Method: Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks (first step) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone (second step), adult outpatients (N=235) with nonpsychotic major depressive disorder were randomly assigned to 14 weeks of treatment with mirtazapine (up to 60 mg/day) (N=114) or nortriptyline (up to 200 mg/day) (N=121). The primary outcome, symptom remission, was defined a priori as a total exit score of ≤7 on the 17-item Hamilton Rating Scale for Depression. The 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR 16 ), obtained at treatment visits, provided secondary outcomes of remission (score ≤5 at exit) and response (≥50% reduction in score from baseline). Results: For mirtazapine, remission rates were 12.3% and 8.0% per the Hamilton and QIDS-SR 16 scores, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively. QIDS-SR 16 response rates were 13.4% for mirtazapine and 16.5% for nortriptyline. Neither response nor remission rates statistically differed by treatment, nor did these two treatments differ in tolerability or adverse events. Conclusions: Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials resulted in low remission rates (<20%) among patients with major depressive disorder.
Size of B.M.A. committees.
Authors: E. Walker
Journal: BMJ (1968)

SIR,-Among the letters and articles criti- cal of the B.M.A., of which there has been a minor spate lately, several have made refer- ence direct or implied to the Association's "failing membership."The large majority of doctors who make up the Association readily accept fair criti- cism.Indeed, many of us also accept that part of the raison detre of the Association is to act as whipping-boy for the blows of those who seemingly rely .onthis activity to bolster up their own cause.
Cardiovascular effects of neuropeptide Y in rat brainstem nuclei.
Authors: C J Tseng, R Mosqueda-Garcia, M Appalsamy, D Robertson
Journal: Circulation Research (1989)

Central catecholaminergic neurons are involved in cardiovascular regulation. Neuropeptide Y (NPY) coexists with adrenaline and noradrenaline in the rat brain, and interactions among these substances have been studied. The purpose of this study was to investigate the possible role of NPY in central cardiovascular control. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Intramedullary microinjection (60 nl) of NPY (0, 46.5 fmol, 465 fmol, 1.5 pmol, and 4.65 pmol) was made into the nucleus tractus solitarii (NTS), into the area postrema, and into the C1 area in the rostroventrolateral medulla. Injection site was identified by L-glutamate administration and confirmed histologically. Unilateral injection of NPY into the NTS produced a prominent dose-related decrease in heart rate and systolic and diastolic blood pressure (-106 +/- 8 beats/min, -56 +/- 2 mm Hg, and -33 +/- 2 mm Hg, respectively after 4.65 pmol NPY, n = 7, p less than 0.001). Maximal changes occurred at 30 seconds and recovered in 10 minutes for blood pressure and 20 minutes for heart rate. Injection into the area postrema produced an initial increase in heart rate and mean blood pressure (+23 +/- 2 beats/min and +18 +/- 2 mm Hg) followed by a prolonged decrease in heart rate and mean blood pressure (-14 +/- 4 beats/min and -15 +/- 2 mm Hg, respectively, n = 7, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Reply to E.A. Rakha et al
Authors: Lajos Pusztai, Takayuki Iwamoto
Journal: Journal of Clinical Oncology (2012)

We thank Rakha et al 1 for their thoughtful comments and the additional dimension that they have provided for our report on borderline estrogen receptor (ER)-positive cancers. 2 We studied gene-expression profiles of breast cancers that were 1% to 9% ER-positive by routine immunohistochemistry (IHC) and found that only a minority of these cancers had molecular features of ER-positive, endocrine-sensitive tumors.Three different types of assessment, including ESR1 mRNA expression, 3 PAM50 molecular class, 4 and sensitivity to endocrine therapy gene signature 5 consistently indicated that the majority of these cancers showed molecular features of ER-negative, basal-like cancers.We concluded that in this rare subset of patients a second RNA-based ER assessment may help to identify the minority of ESR1 mRNA-positive, luminal type cancers, and as a result of the substantial uncertainty about endocrine sensitivity in this population with borderline ERpositive cancer, the safest clinical approach may be to consider both adjuvant endocrine and chemotherapy.Rakha et al 1 point out an alternative method to gauge confidence in the ER status of 1% to 9% IHC-positive cancers through a repeat ER staining on the surgical resection specimen, particularly when the initial hormone-receptor determination was performed on a core needle biopsy.Their own IHC-based reassessment of borderline ERpositive cancers agrees with our finding that only approximately one quarter of these cases showed greater than 10% ER staining on repeat IHC. 6On the basis of their report, we support the conclusion of Rakha et al 1 that a repeat ER IHC on the surgical specimen is a reasonable approach to clarify the receptor status of borderline ER-positive cancers.We could not have possibly made a statement about the value of repeat ER IHC on the basis of our work because we did not study the value of repeat IHC.
Prostate-Specific Antigen Levels as a Predictor of Lethal Prostate Cancer
Authors: K. Fall, H. Garmo, O. Andren, A. Bill-Axelson, J. Adolfsson, H.-O. Adami, J.-E. Johansson, L. Holmberg
Journal: JNCI Journal of the National Cancer Institute (2007)

Rates of long-term survival among patients with untreated localized prostate cancer are high. To avoid unnecessary treatment, tools are needed to identify the small proportion of patients who are destined to develop lethal prostate cancer. To evaluate the accuracy of early changes in prostate-specific antigen (PSA) levels as predictors of prostate cancer outcome, we assessed serial measurements of PSA level among 267 men with localized prostate cancer in a Scandinavian cohort of men who were diagnosed between 1989 and 1999 and who were managed by watchful waiting. We then 1) fitted individual regression lines to the PSA values assessed for each patient during the first 2 years of follow-up by using three different models, 2) evaluated early PSA curve characteristics as determinants of the cumulative incidence of lethal prostate cancer and calculated hazard ratios for baseline PSA value and rate of change in PSA level to prostate cancer outcome, and 3) plotted time-dependent receiver operating characteristic (ROC) curves. All P values are two-sided. During complete follow-up for a mean of 8.5 years, 34 patients (13%) died from prostate cancer, and 18 (7%) developed metastases but were still alive at end of follow-up. In a log-linear model, both PSA value at baseline ( P = .05) and the rate of PSA change ( P <.001) were associated with the development of lethal prostate cancer. In the ROC analysis, however, the accuracy of classifying the disease as either indolent or destined to progress was low, regardless of the cut point chosen for initial PSA level or rate of change in PSA level. Although baseline PSA value and rate of PSA change are prognostic factors for lethal prostate cancer, they are poor predictors of lethal prostate cancer among patients with localized prostate cancer who are managed by watchful waiting.
Failure to Induce Apoptosis via BCL-2 Family Proteins Underlies Lack of Efficacy of Combined MEK and PI3K Inhibitors for KRAS-Mutant Lung Cancers
Authors: Aaron N. Hata, Alan Yeo, Anthony C. Faber, Eugene Lifshits, Zhao Chen, Katherine A. Cheng, Zandra Walton, Kristopher A. Sarosiek, Anthony Letai, Rebecca S. Heist, Mari Mino-Kenudson, Kwok-Kin Wong, Jeffrey A. Engelman
Journal: Cancer Research (2014)

Abstract Although several groups have demonstrated that concomitant use of MEK and phosphoinositide 3-kinase (PI3K) inhibitors (MEKi/PI3Ki) can induce dramatic tumor regressions in mouse models of KRAS-mutant non–small cell lung cancer (NSCLC), ongoing clinical trials investigating this strategy have been underwhelming to date. While efficacy may be hampered by a narrow therapeutic index, the contribution of biologic heterogeneity in the response of KRAS-mutant NSCLCs to MEKi/PI3Ki has been largely unexplored. In this study, we find that most human KRAS-mutant NSCLC cell lines fail to undergo marked apoptosis in response to MEKi/PI3Ki, which is key for tumor responsiveness in vivo. This heterogeneity of apoptotic response occurs despite relatively uniform induction of growth arrest. Using a targeted short hairpin RNA screen of BCL-2 family members, we identify BIM, PUMA, and BCL-XL as key regulators of the apoptotic response induced by MEKi/PI3Ki, with decreased expression of BIM and PUMA relative to BCL-XL in cell lines with intrinsic resistance. In addition, by modeling adaptive resistance to MEKi/PI3Ki both in vitro and in vivo, we find that, upon the development of resistance, tumors have a diminished apoptotic response due to downregulation of BIM and PUMA. These results suggest that the inability to induce apoptosis may limit the effectiveness of MEKi/PI3Ki for KRAS-mutant NSCLCs by contributing to intrinsic and adaptive resistance to this therapy. Cancer Res; 74(11); 3146–56. ©2014 AACR.
Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis
Authors: Serena Sanna, Maristella Pitzalis, Magdalena Zoledziewska, Ilenia Zara, Carlo Sidore, Raffaele Murru, Michael B. Whalen, Fabio Busonero, Andrea Maschio, Gianna Costa, Maria Cristina Melis, Francesca Deidda, Fausto Pier'Angelo Poddie, Laura Cornelia Clotilde Morelli, Gabriele Farina, Yun Li, Mariano Dei, Sandra Lai, Antonella Mulas, Gianmauro Cuccuru, Elenora Porcu, Liming Liang, Patrizia Zavattari, Loredana Moi, Elisa Deriu, M. Francesca Urru, Michele Bajorek, Maria Anna Satta, Eleonora Cocco, Paola Ferrigno, Stefano Sotgiu, Maura Pugliatti, Sebastiano Traccis, Andrea Angius, Maurizio Melis, Giulio Rosati, Gonçalo Abecasis, Manuela Uda, Maria Giovanna Marrosu, David Schlessinger, Francesco Cucca
Journal: Nature Genetics (2010)
Septo-optic Dysplasia
Authors: C. G. D. Brook, M. D. Sanders, R. D. Hoare
Journal: BMJ (1972)

Four children are described who had hypoplastic optic nerves, absent septa pellucida, and various types of endocrinological dysfunction. The importance is stressed of recognizing this syndrome and of following up the growth of the patient, because now that human growth hormone is available the short stature of some blind children may be susceptible to treatment.
Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism.
Authors: M D Sadick, F P Heinzel, B J Holaday, R T Pu, R S Dawkins, R M Locksley
Journal: The Journal of Experimental Medicine (1990)

BALB/c mice infected with Leishmania major develop fatal, progressive disease, despite an immune response characterized by expansion of CD4+ T cells in the draining lymph nodes. The immune response has been further characterized by a lack of IFN-gamma mRNA, but increased IL-4 mRNA in lymphoid tissues, and striking elevation of serum IgE. Treatment of infected BALB/c mice with rIFN-gamma at doses shown to be beneficial in other protozoan infections was insufficient to ameliorate L. major infection. In contrast, neutralization of IL-4 by six weekly injections of mAb 11B11 led to attenuation of disease in 100% of animals, and complete cure in 85%. Resolution of disease required the presence of T cells, and recovered mice remained resistant to reinfection at 12 wk. This immunity was adoptively transferable and was dependent on both CD4+ and CD8+ cells. Although administration of anti-IL-4 was associated with fourfold increase in IFN-gamma mRNA in lymph node cells draining the lesion, the coadministration of neutralizing R4 6A2 anti-IFN-gamma mAb had no effect on resistance to disease. This was in marked contrast to resolution of disease in both resistant C57BL/6- and GK1.5-pretreated BALB/c mice that was abrogated by in vivo treatment with anti-IFN-gamma. These data suggest a novel mechanism of cellular immunity established by interference with the development of Th2 cells during infection.
Participation in the Cooperative Family Registry for Breast Cancer Studies: Issues of Informed Consent
Authors: Mary B. Daly, Kenneth Offit, Frederick Li, Gord Glendon, Alice Yaker, Dee West, Barbara Koenig, Margaret McCredie, Vicki Venne, Susan Nayfield, Daniela Seminara
Journal: JNCI Journal of the National Cancer Institute (2000)

No universal surveillance system collects information on all cases of cancer in the United States. Instead, cancer data are assembled in a variety of ways. Several very good populationbased registries collect data in a fairly uniform manner, but different hospital-based registries often have different formats for data reporting, collection, coding, and analysis. Outcomes of interest include estimates of incidence, prevalence, and mortality; the identification of risk factors through epidemiologic analyses; the evaluation of patterns of care; and financial and resource planning. Few of the registries, however, have any genetic information. The recent identification of genes associated with high penetrance for breast cancer has brought a new focus to the study of cancer genetics—one that emphasizes the identification of families with heritable patterns of cancer—and has created the need for the development of registries that are defined by familial cancers.
Inflammatory mediators in nasal lavage, induced sputum and serum of employees with rheumatic and respiratory disorders
Authors: M. Roponen, J. Kiviranta, M. Seuri, H. Tukiainen, R. Myllykangas-Luosujärvi, M-R. Hirvonen
Journal: European Respiratory Journal (2001)

Exposure to microbes present in mould-damaged buildings has been linked to increased frequency of various inflammatory diseases. The current study examined differences in inflammatory mediators in nasal lavage (NAL), induced sputum (IS) and serum of occupants with rheumatic or respiratory disorders and their controls, all working in the same moisture-damaged building. Exhaled nitric oxide (NO) measurements, lung function tests, skin-prick tests and health data collection by questionnaire were performed. Concentrations of NO, interleukin (IL)-1, IL-4, IL-6 and tumour necrosis factor-α in NAL, IS and serum (excluding NO and IL-1) of the subjects were measured during an occupational exposure period and the vacation period without such exposure. The concentrations of IL-4 in NAL fluid were significantly higher among all occupants during the working period (geometric mean 8.5 pg·mL −1 , range 0–206.5 pg·mL −1 ), as compared to that during vacation (0.4 pg·mL −1 , range 0–3.7 pg·mL −1 ) (p=0.008). Absence from the work environment also significantly diminished reporting of symptoms. IL-4 levels in the serum of case subjects were significantly higher than in controls. Moreover, employees with respiratory symptoms had markedly higher exhaled NO values than their controls (p=0.028). In summary, these data suggest that mediators in nasal lavage samples reflect the occupational exposure to moulds, whereas possible indicators of existing disorders are detectable in serum.
Newly identified genetic determinants of lung function
Authors: N. Martin
Journal: Thorax (2010)

It is well established that pulmonary function is in part genetically determined. These authors report a meta-analysis of genome-wide association study (GWAS) results from 20 288 participants and follow-up analyses in 54 276 participants, identifying five novel genome-wide significant loci for pulmonary function. A companion manuscript from the CHARGE Consortium, which reports a GWAS of lung function in 20 890 participants, also identifies significant associations at three of …
Clinicopathological significance and prognostic importance of circulating plasma DNA expression in advanced non-small cell lung cancer and its efficacy as a diagnostic tool
Authors: Abd El Halim Abu-Hamar, Hanan Shawky, Ibrahim Ibrahim, Abdel Khalek Hanan
Journal: European Respiratory Journal (2012)

Lung cancer is commonest neoplasm.Thereis continuous need for new prognostic markers. Circulating plasma DNA levels is over-expressed in many cancers, including lung.  The aim of work  to study the expression of circulating DNA in NSCLC and assessment of its utility as a diagnostic marker and impact on therapeutic efficacy.  Methods : plasma DNA was determined through the use of polymerase chain reaction in 41 patients with advanced NSCLC and 38 age-matched controls. All 41 patients with advanced NSCLC received platinum-based chemotherapy. Circulating plasma DNA levels was correlated with response to therapy, overall survival, and lactate dehydrogenase level.  Results:  There was a significant correlation between circulating plasma DNA levels and stage, LDH levels and tumor status. Plasma DNA levels were significantly inversely correlated with treatment response.  Conclusion:  circulating plasma DNA levels is frequently over-expressed in primary NSCLC, and appears to be potentially useful marker for diagnosis, significant predictor of survival and response to therapy.  Overall survival according to circulating plasma DNA levels.   Ref.  Sher Y-P, Yang P-C, et al.:Prognosis of Non–Small Cell Lung Cancer Patients by Detecting Circulating Cancer Cells in the Peripheral Blood with MultipleMarkerGenes. clincancerres.aacrjournals.org on May 13, 2011.
Steady and Pulsatile Energy Losses in the Systemic Circulation under Normal Conditions and in Simulated Arterial Disease
Authors: M. F. O'Rourke
Journal: Cardiovascular Research (1967)

External left ventricular work was calculated from records of pressure and flow in the ascending aorta of 1 unanaesthetized and 21 anaesthetized dogs. Work was divided into pulsatile and steady components, the former representing energy lost in vascular pulsations and the latter, energy lost in maintaining steady flow. The ratio of pulsatile to total (steady + pulsatile) external work averaged 10% under control conditions but increased markedly when heart rate slowed, when cardiac output rose, or when arterial distensibility was impaired.
Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study
Authors: Marlies JE Kempers, Roland P Kuiper, Charlotte W Ockeloen, Pierre O Chappuis, Pierre Hutter, Nils Rahner, Hans K Schackert, Verena Steinke, Elke Holinski-Feder, Monika Morak, Matthias Kloor, Reinhard Büttner, Eugene TP Verwiel, J Han van Krieken, Iris D Nagtegaal, Monique Goossens, Rachel S van der Post, Renée C Niessen, Rolf H Sijmons, Irma Kluijt, Frans BL Hogervorst, Edward M Leter, Johan JP Gille, Cora M Aalfs, Egbert JW Redeker, Frederik J Hes, Carli MJ Tops, Bernadette PM van Nesselrooij, Marielle E van Gijn, Encarna B Gómez García, Diana M Eccles, David J Bunyan, Sapna Syngal, Elena M Stoffel, Julie O Culver, Melanie R Palomares, Tracy Graham, Lea Velsher, Janos Papp, Edith Oláh, Tsun L Chan, Suet Y Leung, Ad Geurts van Kessel, Lambertus ALM Kiemeney, Nicoline Hoogerbrugge, Marjolijn JL Ligtenberg
Journal: The Lancet Oncology (2010)
Biologic discontinuation studies: a systematic review of methods; comment on the article by Yoshida<i>et al</i>
Authors: Aatke van der Maas, Noortje van Herwaarden, Alfons A den Broeder
Journal: Annals of the Rheumatic Diseases (2013)

<b>Objectives:</b> To investigate the opinions of general practitioners, orthopaedic surgeons, rheumatologists, sport and exercise medicine (SEM) registrars and public health consultants on training, caseload, the most appropriate setting, and the position of SEM within the National Health Service (NHS) in the United Kingdom. <b>Method:</b> A cross-sectional questionnaire-based survey investigated the opinions of the above professionals from three primary care trusts and associated hospitals in London and Birmingham. <b>Results:</b> With a 50% response rate (n=226), 93% (208/224) of participants felt there was a role for SEM in the NHS. 56% (124/223) agreed this role should be in both primary and secondary care. 64% (136/212) of participants felt that their practice would benefit from the input of a SEM physician and 95% (191/202) would consider referring patients to SEM services. 74% (165/222) agreed SEM should have a public health role and 63% (140/222) believed these responsibilities should be evenly balanced with the treatment of sports injuries. Despite the emphasis on public health work from SEM policy makers, none of the SEM registrars selected public health as an important training area. 31% (44/140) of participants felt that a lack of education in the medical profession regarding SEM represented the greatest hindrance to its development in the NHS. <b>Conclusion:</b> Several areas of agreement were demonstrated across the specialties, many of which matched the views of policy makers. This study involved participants from a range of cognate disciplines, and was the first to investigate this issue since SEM was recognised as a specialty in 2005.