tbuckley/cabot-search huggingface dataset:
Abstract 5354: The guilty bystander model for electrochemotherapy of cancer: Verification in vitro
Authors: W Clark Lambert, Gregory J. Tsongalis, Claude E. Gagna, Muriel W. Lambert
Journal: Cancer Research (2015)

Abstract Electroporation (EPR) is the induction of pores in cellular membranes in cells by application of a short application of a high voltage, low amperage electric current. If the cells are immersed in a solution containing a large molecule which is normally impervious to this membrane, it may be introduced into the cells in this manner. Electrochemotherapy (ECT) is a clinical procedure in which a drug, such as bleomicin or cisplatin, is introduced into the blood of or intratumorally into an animal or human subject by intravenous injection followed by application of a short high dose, low amperage electric current into a neoplasm after a delay enabling the drug to reach the neoplasm through the bloodstream or by other means. ECT is normally used for palliative care in human subjects, however there are now a number of reports, numbering well over 10, of unexpected complete clearance of neoplasms following ECT. Many of these reports have come from university centers in Europe and elsewhere. Although ECT is not yet approved in the USA, we believe that these reports can no longer be ignored. We and others have used EPR in culture to introduce large molecules into cells for experimental purposes for decades. Even under the controlled experimental conditions we have employed, however, the proportion of cells into which these molecules have been introduced has been well below 100 per cent. To account for the clearance of some tumors by ECT, in which the proportion of cells in which drug is introduced would be expected to be lower than for EPR, we have proposed a “Guilty Bystander Model”, in which cells adjacent to neoplastic cells into which drug has been introduced are also cleared. To test this model in vitro, we optimized conditions for EPR but were unable to produce more than 88 per cent introduction of labeled large molecules into lymphoblastoid cells (GM 1989A, derived from a healthy 33 year old Caucasian male, and GM 3999, derived from a healthy 8 year old Caucasian female), even under conditions which reduced cell viability from 99 per cent to 79 per cent. Increasing voltage produced a marked loss of viability. We conclude that EPR does not produce 100 per cent introduction of large molecules into human cells, even under optimized conditions in vitro, and that there must remain neoplastic cells in tumors treated by ECT that are eliminated by means other than introduction of the drug. Citation Format: W Clark Lambert, Gregory J. Tsongalis, Claude E. Gagna, Muriel W. Lambert. The guilty bystander model for electrochemotherapy of cancer: Verification in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5354. doi:10.1158/1538-7445.AM2015-5354
Pharmacology of mesocortical dopamine neurons.
Authors: M J Bannon, R H Roth
Journal: Pharmacological Reviews (1983)

The current information on the pharmacology and function of the DA innervation to the prefrontal cortex is a synthesis of data from several initially distinct areas of research. Some possible functions of the mesocortical DA system are suggested from the extensive studies conducted on the role of the prefrontal cortex in behavior, and also from the data on prefrontal cortical modulation of the output of subcortical DA systems. Meanwhile, anatomical, behavioral, biochemical, and electrophysiological studies on mesocortical DA neurons have largely resulted from interest in determining the site(s) and mechanism(s) of action of various psychotropic drugs, and particularly the antipsychotic drugs (DA antagonists). An interrelated field of study has investigated the functional role of DA autoreceptors. The mesocortical DA system possesses many unique characteristics compared to the nigrostriatal/mesolimbic DA systems, including 1) a higher DA turnover rate, 2) a higher rate and different pattern of neuronal discharge, 3) a greatly diminished responsiveness to DA agonists and antagonists, 4) a lack of tolerance to the effect of chronically administered DA antagonists, and 5) a selective activation by footshock stress. These characteristics may be due to the fact that the DA cells projecting to the prefrontal cortex lack DA autoreceptors, an important site for the physiological and pharmacological modulation of subcortical DA systems. This contention is further supported by recent studies on two distinct DA systems innervating, respectively, the anterior cingulate and piriform cortices: the former system, which lacks DA autoreceptors, responds much like the prefrontal cortical DA sy stem; the latter system, which possesses functional DA autoreceptors, manifests a pharmacological responsiveness similar to the nigrostriatal/mesolimbic DA systems (11, 14, 118, 119, 38). Autoreceptors may be an important target for future rational drug design. For example, DA agonists more selective for DA autoreceptors (65, 72) may be useful agents in the treatment of schizophrenia. If, however, these drugs prove ineffective in schizophrenic patients, it might help to explain the equivocal results obtained to date in the treatment of schizophrenia with low (autoreceptor-specific) doses of less selective DA agonists (for a review, see Ref. 97). A lack of clinical efficacy of DA autoreceptor agonists might also suggest that if a DA system is indirectly involved in schizophrenia the site of therapeutic action of antipsychotic drugs is a DA system (such as that innervating the prefrontal cortex) that lacks autoreceptors.
CPAP titration: Correlation between 2 different equations and autoCPAP
Authors: Hernandez Veronica, Cancelo Laura, Bravo David, Sobradillo Patricia, Ribas Francisco Javier, Tomas Laura, Julia A. Garcia, Llaguno Olatz, Lahidalga Begoña, Martinez Cristina, Manjon Jose Luis, Alvarez Ainhoa, Egea Carlos, Duran Joaquin, Latorre Amaia, Lobo Jose Luis
Journal: European Respiratory Journal (2013)

INTRODUCTION  Standard practice for continuous positive airway pressure (CPAP) treatment in sleep apnea and hypopnea syndrome (SAHS) requires pressure titration during attended laboratory polysomnography. However, polysomnographic titration is expensive and time-consuming.  Moreover, there are equations to predict optimal pressure that are not routinely used in clinical practice.  Although there is literature which compares different prediction equations with other forms of CPAP titration with similar results, others, do not find this correlation.  AIM: To compare two predictive equations against autoCPAP  MATERIAL AND METHODS  Retrospective study from Vitoria cohort. All patients who had been titrated by autoCPAP [determining in one single night and using p90 pressure] were included. Two equations were used: Hoffstein [CPAP= (BMI x 0.16)+ (NC x 0.13)  (AHI x 0.04) – 5.12] and Series [CPAP= (BMI x 0.193) + (NC x 0.07) + (AHI x 0.02) – 0.611].  RESULTS  619 patients were included. Mainly men (474-76.4%), mean age was (53.9 + 12.6), mean AHI (45.9 + 23.4), mean BMI (31.6 + 5.4); and mean neck circumference (41.5 + 4.1).  Correlation found between CPAP pressure, measured by autoCPAP (p90, 1 single night), and the 2 equations was not good.  Series equation correlated better with autoCPAP pressure than Hoffstein equation. Despite average pressure was similar to that of autoCPAP (9.9 vs 9.6) a high internal dispersion was found.  Correlation did not improve when pressures were divided into groups ( 12).  CONCLUSION  Given the lack of correlation of prediction equations for CPAP titration with autoCPAP (p90), the application of equations for CPAP titration, in clinical practice, should be cautious.
Late intensification chemotherapy with autologous bone marrow transplantation in selected small-cell carcinoma of the lung: a randomized study.
Authors: Y Humblet, M Symann, A Bosly, L Delaunois, C Francis, J Machiels, M Beauduin, C Doyen, P Weynants, J Longueville
Journal: Journal of Clinical Oncology (1987)

A multicentric randomized prospective trial was conducted to test whether late intensification chemotherapy would increase the remission rate, the relapse-free survival, and the survival of small-cell lung cancer patients responding to induction chemotherapy. Autologous bone marrow transplantation was used as support to reduce the duration of the aplasia induced by very high-dose chemotherapy. As induction chemotherapy, 101 patients received, during a period of 5 months, a total dosage of 120 mg/m2 methotrexate, 4.5 mg/m2 vincristine, 1,800 mg/m2 cyclophosphamide, 180 mg/m2 doxorubicin, 160 mg/m2 cisplatin, 750 mg/m2 VP-16-213, and 30 Gy prophylactic cranial irradiation. Forty-five patients, selected for their sensitivity to this induction treatment, were randomized to a last cycle of chemotherapy that combined cyclophosphamide, BCNU, and VP-16-213 either at a conventional dosage of 750 mg/m2 intravenously (IV), 60 mg/m2 IV, and 600 mg/m2 orally or alternatively at a very high dosage of 6 g/m2 IV, 300 mg/m2 IV, and 500 mg/m2 IV, respectively. In the late intensification group, the complete remission rate increased from 39% before randomization to 79% after high-dose chemotherapy. Median relapse-free survivals after randomization for intensified and control chemotherapy groups were 28 and 10 weeks, respectively (P = .002). Median overall survival after induction therapy was 68 weeks for the intensified group compared with 55 weeks for the conventional therapy group (P = .13). Four patients died during intensification. Patients in both groups relapsed at the primary site. It can thus be concluded that late intensification chemotherapy for sensitive small-cell lung cancer increases the complete remission rate and resulted in a statistically significant increase in the relapse-free survival. However, since relapse occurred at the primary site and toxicity was high, overall survival was not significantly improved.
Symptom Assessment in Knee Osteoarthritis Needs to Account for Physical Activity Level
Authors: Grace H. Lo, Timothy E. McAlindon, Gillian A. Hawker, Jeffrey B. Driban, Lori Lyn Price, Jing Song, Charles B. Eaton, Marc C. Hochberg, Rebecca D. Jackson, C. Kent Kwoh, Michael C. Nevitt, Dorothy D. Dunlop
Journal: Arthritis & Rheumatology (2015)

Objective Pain is not always correlated with severity of radiographic osteoarthritis (OA), possibly because people modify activities to manage symptoms. Measures of symptoms that consider pain in the context of activity level may therefore provide greater discrimination than a measure of pain alone. We undertook this study to compare discrimination provided by a measure of pain alone with that provided by combined measures of pain in the context of physical activity across radiographic OA severity levels. Methods This was a cross‐sectional study nested within the Osteoarthritis Initiative (OAI). The population was drawn from 2,127 persons enrolled in an OAI accelerometer monitoring substudy, including those with and those without knee OA. Two composite pain and activity knee symptom (PAKS) scores were calculated as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (plus 1) divided by a physical activity measure (step count for the first PAKS score [PAKS1 score] and activity count for the second PAKS score [PAKS2 score]). Symptom score discrimination across Kellgren/Lawrence (K/L) grades was evaluated using histograms and quantile regression. Results A total of 1,806 participants (55.5% of whom were women) were included (mean ± SD age 65.1 ± 9.1 years, mean ± SD body mass index 28.4 ± 4.8 kg/m 2 ). The WOMAC pain score, but not the PAKS scores, exhibited a floor effect. The adjusted median WOMAC pain scores by K/L grades 0–4 were 0, 0, 0, 1, and 3, respectively. The adjusted median PAKS1 scores were 24.9, 26.0, 32.4, 46.1, and 97.9, respectively, and the adjusted median PAKS2 scores were 7.2, 7.2, 9.2, 12.9, and 23.8, respectively. The PAKS scores had more statistically significant comparisons between K/L grades than did the WOMAC pain score. Conclusion Symptom assessments incorporating pain and physical activity did not exhibit a floor effect and were better able to discriminate radiographic severity than an assessment of pain alone, particularly in milder disease. Pain in the context of physical activity level should be used to assess knee OA symptoms.
A slower life in a smaller world. Patients' perspective on living with pulmonary arterial hypertension
Authors: Aruni Mulgirigama, Denise Hunt, Ruth Wilson, Joanna Pepke-Zaba
Journal: European Respiratory Journal (2012)

Background : The pulmonary arterial hypertension (PAH) patient management pathway is often defined from the clinician or commissioner perspective. We wanted to gain an in-depth understanding of the patient self reported experience living with PAH.   Objectives : Working to understand how a diagnosis of PAH impacts a patient9s life. Exploring the journey through first symptoms to specialist care and the 9life changes9 needed.   Methods : Over 1000 General Practitioners were approached to put forward patients with PAH to participate in semi-structured, in depth qualitative interviews designed to determine the key themes emerging from the individual experiences of PAH. Interviews were audio-recorded for subsequent analysis using interpretive phenomenological analysis methodology.   Results : A total of 8 patient interviews were analysed who had the following underlying aetiologies: IPAH (n=3) and ACHD (n=5), aged between 30 – 70 years and treated with different targeted PAH therapies. Patients interviewed were being managed at 4 different PAH Specialist Centres in the UK. Areas where patients9 needs were perceived not to be met by healthcare delivery included: 1) patient information materials did not cover PAH impact on co-morbidities, 2) dealing with a crisis on their own, 3) effective counseling when treatment fails, 4) securing disability allowance, 5) being able to live a normal life, 6) minimising the impact on their family.   Conclusions : Specific areas have been highlighted where healthcare delivery does not meet patients9 needs. Living with a rare disease has its own unique challenges requiring careful consideration with potential to further improve the patient experience.
THE EFFECT OF TOLERANCE ON THE SPECIFICITY OF THE ANTIBODY RESPONSE AND ON IMMUNOGENICITY
Authors: J. E. M. St. Rose, B. Cinader
Journal: The Journal of Experimental Medicine (1967)

Animals were rendered tolerant to human albumin and were then immunized with azo derivatives of human albumin which differed in the number of hapten groups per molecule and in the extent of conformational change. The incidence and specificity of the resulting antibody response was studied and the presence of antibody to azo groups and to conformationally altered protein determinants was demonstrated. Reactivity with the tolerance-inducing antigen was shown to be due to antibodies directed against conformationally altered protein determinants. The difference in the response of tolerant animals to hapten-poor and hapten-rich derivatives was attributed to the extent of conformational alteration. A genetic factor appeared to be implicated in the capacity of tolerant animals to respond to an antigen which cross-reacts with tolerance-inducing macromolecules.
Limited evidence that cancer susceptibility regions are preferential targets for somatic mutation
Authors: Mitchell J. Machiela, Brian M. Ho, Victoria A. Fisher, Xing Hua, Stephen J. Chanock
Journal: Genome biology (2015)

Genome wide-association studies have successfully identified several hundred independent loci harboring common cancer susceptibility alleles that are distinct from the more than 110 cancer predisposition genes. The latter are generally characterized by disruptive mutations in coding genes that have been established as 'drivers' of cancer in large somatic sequencing studies. We set out to determine whether, similarly, common cancer susceptibility loci map to genes that have altered frequencies of mutation. In our analysis of the intervals defined by the cancer susceptibility markers, we observed that cancer susceptibility regions have gene mutation frequencies comparable to background mutation frequencies. Restricting analyses to genes that have been determined to be pleiotropic across cancer types, genes affected by expression quantitative trait loci, or functional genes indicates that most cancer susceptibility genes classified into these subgroups do not display mutation frequencies that deviate from those expected. We observed limited evidence that cancer susceptibility regions that harbor common alleles with small estimated effect sizes are preferential targets for altered somatic mutation frequencies. Our findings suggest a complex interplay between germline susceptibility and somatic mutation, underscoring the cumulative effect of common variants on redundant pathways as opposed to driver genes. Complex biological pathways and networks likely link these genetic features of carcinogenesis, particularly as they relate to distinct polygenic models for each cancer type.
Abstract 12035: Text and Data Mining of Longitudinal Electronic Health Records (EHRs) in a Primary Care Population Can Identify Heart Failure (HF) Patients Months to Years Prior to Formal Diagnosis Using the Framingham Criteria
Authors: Steven R Steinhubl, Brent A Williams, Jimeng Sun, Roy J Byrd, Zahra S Daar, Shahram Ebadollahi, Walter F Stewart
Journal: Circulation (2011)

Introduction: The societal and individual health burden of HF is enormous. While its early recognition offers the possibility of initiating preventive action, earlier detection of HF can be challen...
Prevalence of menopausal symptoms among women with a history of breast cancer and attitudes toward estrogen replacement therapy.
Authors: R J Couzi, K J Helzlsouer, J H Fetting
Journal: Journal of Clinical Oncology (1995)

PURPOSE To determine the prevalence and severity of vasomotor, gynecologic, and other symptoms among breast cancer patients, their health concerns, beliefs about estrogen replacement therapy (ERT), and willingness to take estrogen under medical supervision. MATERIALS AND METHODS A questionnaire was mailed to 320 women aged 40 to 65 years and diagnosed with in situ or invasive locoregional breast cancer in the years 1988 to 1992. RESULTS Of 222 eligible respondents, 190 were postmenopausal. The prevalence of symptoms among the postmenopausal women was as follows: hot flashes, 65%; night sweats, 44%; vaginal dryness, 48%; dyspareunia, 26%; difficulty sleeping, 44%; and feeling depressed, 44%. The latter two symptoms increased in frequency with increasing severity of vasomotor symptoms (P for trend &lt; or = .001). Forty-one percent of menopausal women perceived that they had experienced, since their breast cancer diagnosis, a physical or emotional problem related to menopause. Of these women, 50% felt they needed treatment. Overall, 31% of postmenopausal women would consider taking estrogen. Those who perceived that they had experienced a menopausal problem were more likely to consider estrogen than those who did not (42% v 22%, P = .003). The proportions willing to take estrogen increased with increasing severity of symptoms, particularly feelings of depression and sleep disturbance (P for trend = .008 and .007, respectively). Awareness that estrogen decreases the risks of heart disease and osteoporosis was not associated with an increased willingness to take it. However, beliefs that estrogen increases the risks of recurrent breast cancer and uterine cancer were associated with a decreased willingness to take it (P = .003 and .08, respectively). CONCLUSION Vasomotor symptoms have a significant impact on the quality of life of breast cancer patients. Clinical trials to determine the safest and the most effective ways to relieve these symptoms are needed.
Tachykinin receptors and airway pathophysiology
Authors: CA Maggi
Journal: European Respiratory Journal (1993)

The mammalian tachykinins (TKs), substance P and neurokinin A, are present in sensory nerve fibres in the upper and lower airways of various mammalian species, including humans. TKs are released from these afferent nerves in an "efferent" mode at peripheral level, especially in response to irritant stimuli. TKs exert a variety of biological effects (bronchoconstriction, plasma protein extravasation, stimulation of mucus secretion), collectively known as "neurogenic inflammation", and this process is thought to be of potential pathogenic relevance for various airway diseases. The recent development of potent and selective TK receptor antagonists on the one hand provides important new tools for the understanding of basic airway physiology and pathophysiology and, on the other, opens new possibilities for therapy of airway diseases.
Tumour necrosis factor alpha impairs function of liver derived T lymphocytes and natural killer cells in patients with primary sclerosing cholangitis
Authors: X Bo
Journal: Gut (2001)

<h3>BACKGROUND</h3> Primary sclerosing cholangitis (PSC) is considered to be a chronic autoimmune disease where infiltrating T lymphocytes have been implicated in the destruction of bile ducts. Altered function of these T cells may reflect abnormalities in the immune response leading to tissue damage. <h3>AIM</h3> We investigated the proliferative and functional capacity of freshly isolated liver derived T lymphocytes (LDLs) and natural killer (NK) cells from PSC patients. <h3>METHODS</h3> The proliferative responses to common mitogens such as phytohaemagglutinin (PHA), concanavalin A (Con A), and lipopolysaccharide (LPS) were studied, and the cytotoxic function of T lymphocytes was measured using allogeneic target cells. NK (CD56<sup>+</sup>/16<sup>+</sup>) cytotoxic function was measured using the two cell lines K562 (NK sensitive) and Raji lymphoma cells (NK resistant). <h3>RESULTS</h3> Compared with patients with primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and normal controls (without liver disease), in PSC: (1) LDLs contained a low percentage of T cells; (2) there was significantly decreased expression of interleukin (IL)-2 receptor (p&lt;0.001) on activated T cells (HLA-DR<sup>+</sup>); (3) LDLs but not peripheral blood lymphocytes had significantly impaired proliferative responses to mitogens such as PHA, Con A, and LPS (p&lt; 0.001); (4) no cytotoxic activity of PSC liver T and NK cells was recorded; (5) significantly higher levels of tumour necrosis factor α (TNF-α) and IL-1β but lower levels of IL-2, IL-10, and interferon γ were found in the supernatants of mitogen stimulated LDL cultures (p&lt;0.001); (6) higher percentages of freshly isolated PSC LDLs contained intracytoplasmic TNF-α and IL-1β; and (7) pretreatment of PSC LDLs in vitro with neutralising TNF antibodies significantly enhanced proliferative responses and allowed IL-2 receptor expression following stimulation. In addition, the impaired cytolytic activity of both NK and T cells was partially restored. Impaired proliferative or functional capacity of liver derived T cells was not observed in either PBC or AIH patients. <h3>CONCLUSIONS</h3> We suggest that reduced T cell reactivity in liver infiltrating cells obtained from patients with PSC is due to high local production of TNF-α. Our findings indicate that the use of anti-TNF antibodies as an alternative treatment for PSC patients should be evaluated.