tbuckley/cabot-search huggingface dataset:
Randomized Phase 3 Trial of Fluorouracil, Epirubicin, and Cyclophosphamide Alone or Followed by Paclitaxel for Early Breast Cancer
Authors: M. Martin, A. Rodriguez-Lescure, A. Ruiz, E. Alba, L. Calvo, M. Ruiz-Borrego, B. Munarriz, C. A. Rodriguez, C. Crespo, E. de Alava, J. A. Lopez Garcia-Asenjo, M. D. Guitian, S. Almenar, J. F. Gonzalez-Palacios, F. Vera, J. Palacios, M. Ramos, J. M. Gracia Marco, A. Lluch, I. Alvarez, M. A. Segui, J. I. Mayordomo, A. Anton, J. M. Baena, A. Plazaola, A. Modolell, A. Pelegri, J. R. Mel, E. Aranda, E. Adrover, J. V. Alvarez, J. L. Garcia Puche, P. Sanchez-Rovira, S. Gonzalez, J. M. Lopez-Vega
Journal: JNCI Journal of the National Cancer Institute (2008)

Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting. After breast cancer surgery, women with lymph node–positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study—5-year disease-free survival (DFS)—was assessed by Kaplan–Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided. Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) ( P = .017), number of involved axillary lymph nodes ( P < .001), tumor size ( P = .020), hormone receptor status ( P = .004), and HER2 status ( P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment. Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy.
Long acting somatostatin analogue for the treatment of refractory RA
Authors: F Koseoglu
Journal: Annals of the Rheumatic Diseases (2002)

We read with interest the article by Paran and colleagues on a pilot study of a long acting somatostatin analogue for the treatment of refractory rheumatoid arthritis (RA).1 The role of peptidergic sensory neurons and the “neurogenic inflammation” in RA and, particularly, in the involvement of substance P (SP) in the articular destruction in experimental arthritis has been demonstrated.2 High levels of SP have been detected in synovial fluid3 and plasma4 samples of patients with RA. It has also been shown that somatostatin inhibits SP release from sensory nerves.5 Matucci-Cerinic et al have demonstrated that intra-articular somatostatin induces clinical improvement in patients with RA.6

We would like to report our experience, based on a pilot study of treatment for RA with somatostatin analogue (sandostatin). Eleven female patients with classical or definite RA according to American Rheumatism Association criteria were selected for this study with a mean age of 57.4 years and average duration of disease period of 14.5 years. All the patients had previously received multiple disease modifying antirheumatic drugs, but complete remission could not be achieved. Patients who had received any drug except non-steroidal anti-inflammatory drugs during the eight weeks before the start of the study, who had …
The mean predicts the number of deviants
Authors: L S Lewis
Journal: BMJ (1990)

because they contain added iron and vitamin D and have limited saturated fat and sodium contents, without limiting energy content.Regarding cost we can quibble over figures, but let's accept an extra cost ofE l.43 a week of using a follow on milk (or infant formula) instead of cows' milk.This is the equivalent each day of one to two disposable nappies, or a newspaper, or two cigar- ettes, or 28 ml beer.Nevertheless, for some families even this extra cost may be the proverbial straw-but the answer to this is to change other aspects of public policy, not to continue to recom- mend substandard child feeding customs that are being abandoned by many other countries in the developed world.
Human Breast Cancer Cells Harboring a Gatekeeper T798M Mutation in HER2 Overexpress EGFR Ligands and Are Sensitive to Dual Inhibition of EGFR and HER2
Authors: Brent N. Rexer, Ritwik Ghosh, Archana Narasanna, Mónica Valeria Estrada, Anindita Chakrabarty, Youngchul Song, Jeffrey A. Engelman, Carlos L. Arteaga
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Mutations in receptor tyrosine kinase (RTK) genes can confer resistance to receptor-targeted therapies. A T798M mutation in the HER2 oncogene has been shown to confer resistance to the tyrosine kinase inhibitor (TKI) lapatinib. We studied the mechanisms of HER2-T798M–induced resistance to identify potential strategies to overcome that resistance. Experimental Design: HER2-T798M was stably expressed in BT474 and MCF10A cells. Mutant cells and xenografts were evaluated for effects of the mutation on proliferation, signaling, and tumor growth after treatment with combinations of inhibitors targeting the EGFR/HER2/HER3/PI3K axis. Results: A low 3% allelic frequency of the T798M mutant shifted 10-fold the IC50 of lapatinib. In mutant-expressing cells, lapatinib did not block basal phosphorylation of HER2, HER3, AKT, and ERK1/2. In vitro kinase assays showed increased autocatalytic activity of HER2-T798M. HER3 association with PI3K p85 was increased in mutant-expressing cells. BT474-T798M cells were also resistant to the HER2 antibody trastuzumab. These cells were sensitive to the pan-PI3K inhibitors BKM120 and XL147 and the irreversible HER2/EGFR TKI afatinib but not the MEK1/2 inhibitor CI-1040, suggesting continued dependence of the mutant cells on ErbB receptors and downstream PI3K signaling. BT474-T798M cells showed increased expression of the EGFR ligands EGF, TGFα, amphiregulin, and HB-EGF. Addition of the EGFR neutralizing antibody cetuximab or lapatinib restored trastuzumab sensitivity of BT474-T798M cells and xenografts, suggesting that increased EGFR ligand production was causally associated with drug resistance. Conclusions: Simultaneous blockade of HER2 and EGFR should be an effective treatment strategy against HER2 gene–amplified breast cancer cells harboring T798M mutant alleles. Clin Cancer Res; 19(19); 5390–401. ©2013 AACR.
Single arterial occlusion to locate resistance in patients with pulmonary hypertension
Authors: P. Fesler, A. Pagnamenta, J‐L. Vachiéry, S. Brimioulle, S. Abdel Kafi, A. Boonstra, M. Delcroix, R.N. Channick, L.J. Rubin, R. Naeije
Journal: European Respiratory Journal (2003)

The purpose of this study was to determine the site of increased resistance using the arterial occlusion technique in patients with severe pulmonary hypertension. Pulmonary vascular resistance was partitioned in arterial and venous components based on double exponential fitting analysis of the pulmonary artery pressure decay curve: after balloon occlusion in 36 patients with pulmonary arterial hypertension (PAH); at baseline and during the inhalation of 20 parts per million of nitric oxide (NO); in four patients with chronic thromboembolic pulmonary hypertension; and in two patients with pulmonary veno-occlusive disease. In the patients with PAH, at baseline, mean pulmonary artery pressure was 56±2 mmHg (mean±se), with an arterial component of resistance of 63±1%. Inhaled NO did not change the partition of resistance. The arterial component of resistance amounted on average to 42% and 77% in the patients with veno‐occlusive disease and the patients with thromboembolic pulmonary hypertension, respectively. However, the partitioning of resistance did not discriminate between these three diagnostic categories. The occlusion technique may help to locate the predominant site of increased resistance in patients with severe pulmonary hypertension, but does not allow for a satisfactory differential diagnosis on an individual basis.
Junior doctors' training to include patients' safety
Authors: Owen Dyer
Journal: BMJ (2006)

From this year, junior doctors' training will include education on patient safety, with the creation of a national patient safety education programme aimed at second year foundation trainees.

The “Safe foundations: junior doctors and patient safety” programme has been put together by the Royal College of Physicians on behalf of the National Patient Safety Agency.

The steering group overseeing the project included representatives from the agency, the Academy of Medical Royal Colleges, postgraduate deaneries, clinical tutors, junior doctors, and patients.

The programme will form part of a …
Considerations in studying the transient outward K+ current in cells exhibiting the hyperpolarization-activated current
Authors: A Verkerk
Journal: Cardiovascular Research (2001)

Recently, we focussed our research on cellular electro-potential of I [6].A typical voltage-clamp protocol for f physiological changes involved in the modulated sinoatrial measuring the reversal potential is clamping a cell at 280 (SA) node function during heart failure [1] and aging [2].mV or at more negative potentials, for activating I , f Heart failure and age-dependent changes of ionic mem-followed by depolarizing voltage-clamp steps in a range
Cardiac Memory Evolves With Age in Association With Development of the Transient Outward Current
Authors: Alexei N. Plotnikov, Eugene A. Sosunov, Kornelis W. Patberg, Evgeny P. Anyukhovsky, Ravil Z. Gainullin, Iryna N. Shlapakova, Ganga Krishnamurthy, Peter Danilo, Michael R. Rosen
Journal: Circulation (2004)

Calcium-insensitive transient outward current (I(to)) is important to the development of cardiac memory (CM), which itself reflects the capacity of the heart to remodel electrophysiologically. We used cardiac pacing to test the hypothesis that CM evolution can be explained by developmental maturation of I(to).Acutely anesthetized dogs from 1 day old to adult were paced from the left ventricle (VP, n=29) or left atrial appendage (AP, n=12) to induce CM. T-wave vector displacement (TVD) obtained during VP was greater than with AP (adults, 0.39+/-0.06 mV; neonates, 0.04+/-0.01 mV; P<0.05). TVD began to increase at approximately 40 days of age, reaching adult levels by approximately 200 days. Microelectrode studies performed in 18 dogs (ages 3 to 94 days) after completing the CM protocol and 20 additional dogs (1 day old to adult) revealed that the epicardial action potential notch was absent in neonates, became apparent in the young, and was deepest in adults. The relationship between TVD and epicardial notch was such that as notch magnitude increased, TVD increased (r=-0.65, P<0.05). KChIP2 and Kv4.3 mRNA (measured via reverse transcription-polymerase chain reaction) also increased with age.The inducibility of CM gradually increases with age in association with evolution of the epicardial action potential notch and mRNA expression for KChIP2 and Kv4.3. This suggests that the capacity of the heart to remodel electrophysiologically and to manifest memory during development depends in part on evolution of the determinants of I(to).
Exhaled biomarkers in lung cancer
Authors: I. Horváth, Z. Lázár, N. Gyulai, M. Kollai, G. Losonczy
Journal: European Respiratory Journal (2009)

Lung cancer is the leading cause of cancer death. Results of therapeutic interventions are particularly discouraging when the disease is discovered in an advanced stage. Early diagnosis is limited by the fact that the disease usually develops asymptomatically and available screening methods do not fulfil the requirements for reliable discrimination between patients with lung cancer and subjects not suffering from the disease. Breath sampling is completely noninvasive and provides a potentially useful approach to screening lung cancer. Exhaled biomarkers contain both volatile and nonvolatile molecules. The profile of volatile organic compounds is different in patients with lung cancer than in control subjects. In exhaled breath condensate, the proteomic profile of breath from cancer patients differs from that of healthy smokers. We reviewed the scientific evidence demonstrating that a unique chemical signature can be detected in the breath of patients with lung cancer and that the exhaled breath biomarker profile could aid clinical decision making.
An unusual case of ANCA positive disease
Authors: S Delen
Journal: Annals of the Rheumatic Diseases (2003)

A 13 year old girl presented with auricular chondritis and recurrent episodes of unexplained chest pain, arthritis, bronchitis, conjunctivitis, prolonged steroid resistant alopecia areata, and a history of recurrent tonsillitis.Both the mosaic of autoimmunity and relapsing polychondritis were considered in the differential diagnosis.The patient was successfully treated with co-trimoxazole.The significance of co-trimoxazole, which is an antibiotic and an immunomodulatory drug, in the treatment of autoimmune disease is discussed.www.annrheumdis.
Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice
Authors: S. Niki
Journal: Journal of Clinical Investigation (2006)

Factors that determine the spectrum of target organs involved in autoimmune destruction are poorly understood. Although loss of function of autoimmune regulator (AIRE) in thymic epithelial cells is responsible for autoimmunity, the pathogenic roles of AIRE in regulating target-organ specificity remain elusive. In order to gain insight into this issue, we have established NOD mice, an animal model of type 1 diabetes caused by autoimmune attack against beta cell islets, in which Aire has been abrogated. Remarkably, acinar cells rather than beta cell islets were the major targets of autoimmune destruction in Aire-deficient NOD mice, and this alteration of intra-pancreatic target-organ specificity was associated with production of autoantibody against pancreas-specific protein disulfide isomerase (PDIp), an antigen expressed predominantly by acinar cells. Consistent with this pathological change, the animals were resistant to the development of diabetes. The results suggest that Aire not only is critical for the control of self-tolerance but is also a strong modifier of target-organ specificity through regulation of T cell repertoire diversification. We also demonstrated that transcriptional expression of PDIp was retained in the Aire-deficient NOD thymus, further supporting the concept that Aire may regulate the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus.
Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK)
Authors: A. Pijpe, N. Andrieu, D. F. Easton, A. Kesminiene, E. Cardis, C. Nogues, M. Gauthier-Villars, C. Lasset, J.-P. Fricker, S. Peock, D. Frost, D. G. Evans, R. A. Eeles, J. Paterson, P. Manders, C. J. van Asperen, M. G. E. M. Ausems, H. Meijers-Heijboer, I. Thierry-Chef, M. Hauptmann, D. Goldgar, M. A. Rookus, F. E. van Leeuwen
Journal: BMJ (2012)

<b>Objective</b> To estimate the risk of breast cancer associated with diagnostic radiation in carriers of BRCA1/2 mutations. <b>Design</b> Retrospective cohort study (GENE-RAD-RISK). <b>Setting</b> Three nationwide studies (GENEPSO, EMBRACE, HEBON) in France, United Kingdom, and the Netherlands, <b>Participants</b> 1993 female carriers of BRCA1/2 mutations recruited in 2006-09. <b>Main outcome measure</b> Risk of breast cancer estimated with a weighted Cox proportional hazards model with a time dependent individually estimated cumulative breast dose, based on nominal estimates of organ dose and frequency of self reported diagnostic procedures. To correct for potential survival bias, the analysis excluded carriers who were diagnosed more than five years before completion of the study questionnaire. <b>Results</b> In carriers of BRCA1/2 mutations any exposure to diagnostic radiation before the age of 30 was associated with an increased risk of breast cancer (hazard ratio 1.90, 95% confidence interval 1.20 to 3.00), with a dose-response pattern. The risks by quarter of estimated cumulative dose &lt;0.0020 Gy, ≥0.0020-0.0065 Gy, ≥0.0066-0.0173 Gy, and ≥0.0174 Gy were 1.63 (0.96 to 2.77), 1.78 (0.88 to 3.58), 1.75 (0.72 to 4.25), and 3.84 (1.67 to 8.79), respectively. Analyses on the different types of diagnostic procedures showed a pattern of increasing risk with increasing number of radiographs before age 20 and before age 30 compared with no exposure. A history of mammography before age 30 was also associated with an increased risk of breast cancer (hazard ratio 1.43, 0.85 to 2.40). Sensitivity analysis showed that this finding was not caused by confounding by indication of family history. <b>Conclusion</b> In this large European study among carriers of BRCA1/2 mutations, exposure to diagnostic radiation before age 30 was associated with an increased risk of breast cancer at dose levels considerably lower than those at which increases have been found in other cohorts exposed to radiation. The results of this study support the use of non-ionising radiation imaging techniques (such as magnetic resonance imaging) as the main tool for surveillance in young women with BRCA1/2 mutations.
Percutaneous Left Atrial Appendage Transcatheter Occlusion to Prevent Stroke in High-Risk Patients With Atrial Fibrillation
Authors: Horst Sievert, Michael D. Lesh, Thomas Trepels, Heyder Omran, Antonio Bartorelli, Paola Della Bella, Toshiko Nakai, Mark Reisman, Carlo DiMario, Peter Block, Paul Kramer, Dirk Fleschenberg, Ulrike Krumsdorf, Detlef Scherer
Journal: Circulation (2002)

Thromboembolism due to atrial fibrillation (AF) is a frequent cause of stroke. More than 90% of thrombi in AF form in the left atrial appendage (LAA). Obliteration of the appendage may prevent embolic complications.We evaluated the feasibility and safety of implanting a novel device for percutaneous left atrial appendage transcatheter occlusion (PLAATO). LAA occlusion using the PLAATO system was attempted in 15 patients with chronic AF at high risk for stroke, who are poor candidates for long-term warfarin therapy. The implant consists of a self-expanding nitinol cage covered with a polymeric membrane (ePTFE). The LAA was successfully occluded in 15/15 patients (100%). Angiography and transesophageal echocardiography (TEE) during the procedure showed that the device was well-seated in all patients and that there was no evidence of perforation, device embolization, or interference with surrounding structures. In 1 patient, the first procedure was complicated by a hemopericardium, which occurred during LAA access. A second attempt 30 days later was successful with no untoward sequela. No other complications occurred. At 1-month follow-up, chest fluoroscopy and TEE revealed continued stable implant position with smooth atrial-facing surface and no evidence of thrombus.Thus, transcatheter closure of the LAA is feasible in humans. This novel implant technology may be appropriate for patients with AF who are not suitable candidates for anticoagulation therapy. Further trials are needed to show the long-term safety and its efficacy in reducing stroke.
Representational theory emerges unscathed
Authors: Dennis Lomas
Journal: Behavioral and Brain Sciences (1998)

Representationalism emerges unscathed from Pessoa et al.'s attack. They fail to undermine a key reason for its influence: it has the theoretical resources to explain many illusory visual experiences such as illusory contours and features. Furthermore, in attempting to undermine representationalism, the authors seem to erect an unduly inflated distinction between neural accounts of perception and personal-level accounts of perception.
Histone deacetylase inhibition synergistically enhances pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer
Authors: Donatella Del Bufalo, Marianna Desideri, Teresa De Luca, Marta Di Martile, Chiara Gabellini, Valentina Monica, Simone Busso, Adriana Eramo, Ruggero De Maria, Michele Milella, Daniela Trisciuoglio
Journal: Molecular Cancer (2014)

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Pemetrexed, a multi-target folate antagonist, has demonstrated efficacy in NSCLC histological subtypes characterized by low thymidylate synthase (TS) expression. Among many other potential targets, histone deacetylase inhibitors (HDACi) modulate TS expression, potentially sensitizing to the cytotoxic action of anti-cancer drugs that target the folate pathway, such as pemetrexed. Since high levels of TS have been linked to clinical resistance to pemetrexed in NSCLC, herein we investigated the molecular and functional effects of combined pemetrexed and ITF2357, a pan-HDACi currently in clinical trials as an anti-cancer agent. In NSCLC cell lines, HDAC inhibition by ITF2357 induced histone and tubulin acetylation and downregulated TS expression at the mRNA and protein level. In combination experiments in vitro ITF2357 and pemetrexed demonstrated sequence-dependent synergistic growth-inhibitory effects, with the sequence pemetrexed followed by ITF2357 inducing a strikingly synergistic reduction in cell viability and induction of both apoptosis and autophagy in all cell line models tested, encompassing both adenocarcinoma and squamous cell carcinoma. Conversely, simultaneous administration of both drugs achieved frankly antagonistic effects, while the sequence of ITF2357 followed by pemetrexed had additive to slightly synergistic growth-inhibitory effects only in certain cell lines. Similarly, highly synergistic growth inhibition was also observed in patient-derived lung cancer stem cells (LCSC) exposed to pemetrexed followed by ITF2357. In terms of molecular mechanisms of interaction, the synergistic growth-inhibitory effects observed were only partially related to TS modulation by ITF2357, as genetic silencing of TS expression potentiated growth inhibition by either pemetrexed or ITF2357 and, to a lesser extent, by their sequential combination. Genetic and pharmacological approaches provided an interesting link between the autophagic and apoptotic pathways, and showed that sequential pemetrexed/ITF2357 causes a toxic form of autophagy with consequent activation of a caspase-dependent apoptotic program. In vivo experiments in NSCLC xenografts confirmed that sequential pemetrexed/ITF2357 is feasible and results in increased inhibition of tumor growth and increased mice survival. Overall, these data provide a strong rationale for the clinical development of sequential schedules employing pemetrexed followed by HDACi in NSCLC.