tbuckley/cabot-search huggingface dataset:
Polysensitization and increased susceptibility in contact allergy: a review
Authors: A. Schnuch, J. Brasch, W. Uter
Journal: Allergy (2008)

Genetic factors presumably play a role in contact allergy (CA). There is, however, a lack of conclusive evidence from clinical studies. This may be on account of the strongly competing or modifying impact of exogenous factors, namely the potency of allergens and the intensity of exposure, and the fact that – in principle – everybody can be sensitized. Regarding phenotype, in contrast, polysensitization (PS) seems to indicate a subset of individuals at greater risk. In human sensitization experiments with dinitrochlorobenzene, induction was facilitated in PS, and elicitation enhanced. Recent clinical epidemiological data, taking confounders for PS, such as age, sex, and other skin diseases into account, demonstrated the following: (i) PS was the greatest risk factor to be sensitized to a number of (even weak) index allergens, indicating higher susceptibility on the level of induction; (ii) patch test reactions in PS patients were generally stronger indicating higher susceptibility on the level of elicitation. These findings are complemented by reports on polymorphisms of TNF‐α and IL‐16 in PS patients. Future studies on the genetics of CA should be performed in subgroups with PS, focussing on polymorphisms relevant for CA‐specific and nonspecific (inflammatory) processes.
SV40-Dependent AKT Activity Drives Mesothelial Cell Transformation after Asbestos Exposure
Authors: Paola Cacciotti, Dario Barbone, Camillo Porta, Deborah A. Altomare, Joseph R. Testa, Luciano Mutti, Giovanni Gaudino
Journal: Cancer Research (2005)

Abstract Human malignant mesothelioma is an aggressive cancer generally associated with exposure to asbestos, although SV40 virus has been involved as a possible cofactor by a number of studies. Asbestos fibers induce cytotoxicity in human mesothelial cells (HMC), although cell survival activated by key signaling pathways may promote transformation. We and others previously reported that SV40 large T antigen induces autocrine loops in HMC and malignant mesothelioma cells, leading to activation of growth factor receptors. Now we show that SV40 induces cell survival via Akt activation in malignant mesothelioma and HMC cells exposed to asbestos. Consequently, prolonged exposure to asbestos fibers progressively induces transformation of SV40-positive HMC. As a model of SV40/asbestos cocarcinogenesis, we propose that malignant mesothelioma originates from a subpopulation of transformed stem cells and that Akt signaling is a novel therapeutic target to overcome malignant mesothelioma resistance to conventional therapies.
Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With Advanced Lung Adenocarcinoma With <i>EGFR</i> Mutations
Authors: James Chih-Hsin Yang, Vera Hirsh, Martin Schuler, Nobuyuki Yamamoto, Kenneth J. O'Byrne, Tony S.K. Mok, Victoria Zazulina, Mehdi Shahidi, Juliane Lungershausen, Dan Massey, Michael Palmer, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2013)

Purpose Patient-reported symptoms and health-related quality of life (QoL) benefits were investigated in a randomized, phase III trial of afatinib or cisplatin/pemetrexed. Patients and Methods Three hundred forty-five patients with advanced epidermal growth factor receptor (EGFR) mutation–positive lung adenocarcinoma were randomly assigned 2:1 to afatinib 40 mg per day or up to six cycles of cisplatin/pemetrexed. Lung cancer symptoms and health-related QoL were assessed every 21 days until progression using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 questionnaires. Analyses of cough, dyspnea, and pain were preplanned, including percentage of patients who improved on therapy, time to deterioration of symptoms, and change in symptoms over time. Results Questionnaire compliance was high. Compared with chemotherapy, afatinib significantly delayed the time to deterioration for cough (hazard ratio [HR], 0.60; 95% CI, 0.41 to 0.87; P = .007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 0.93; P = .015), but not pain (HR, 0.83; 95% CI, 0.62 to 1.10; P = .19). More patients on afatinib (64%) versus chemotherapy (50%) experienced improvements in dyspnea scores (P = .010). Differences in mean scores over time significantly favored afatinib over chemotherapy for cough (P &lt; .001) and dyspnea (P &lt; .001). Afatinib showed significantly better mean scores over time in global health status/QoL (P = .015) and physical (P &lt; .001), role (P = .004), and cognitive (P = .007) functioning compared with chemotherapy. Fatigue and nausea were worse with chemotherapy, whereas diarrhea, dysphagia, and sore mouth were worse with afatinib (all P &lt; .01). Conclusion In patients with lung adenocarcinoma with EGFR mutations, first-line afatinib was associated with better control of cough and dyspnea compared with chemotherapy, although diarrhea, dysphagia, and sore mouth were worse. Global health status/QoL was also improved over time with afatinib compared with chemotherapy.
Lung Inflammation Induced by Lipoteichoic Acid or Lipopolysaccharide in Humans
Authors: Jacobien J. Hoogerwerf, Alex F. de Vos, Paul Bresser, Jaring S. van der Zee, Jennie M. Pater, Anita de Boer, Michael Tanck, Daniel L. Lundell, Chung Her-Jenh, Christian Draing, Sonja von Aulock, Tom van der Poll
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is considered to be important for an appropriate immune response against pathogens that enter the lower airways.We studied the effects of two different TLR agonists relevant for respiratory infections in the human lung: lipoteichoic acid (LTA; TLR2 agonist, component of gram-positive bacteria) and lipopolysaccharide (LPS; TLR4-agonist, component of gram-negative bacteria).Fifteen healthy subjects were given LPS or LTA: by bronchoscope, sterile saline was instilled into a lung segment followed by instillation of LTA or LPS into the contralateral lung. After 6 hours, a bronchoalveolar lavage was performed and inflammatory parameters were determined. Isolated RNA from purified alveolar macrophages was analyzed by multiplex ligation-dependent probe amplification. In addition, spontaneous cytokine release by alveolar macrophages was measured.Marked differences were detected between LTA- and LPS-induced lung inflammation. Whereas both elicited neutrophil recruitment, only LPS instillation was associated with activation of neutrophils (CD11b surface expression, degranulation product levels) and consistent rises of chemo-/cytokine levels. Moreover, LPS but not LTA activated alveolar macrophages, as reflected by enhanced expression of 10 different mRNAs encoding proinflammatory mediators and increased spontaneous cytokine release upon incubation ex vivo. Remarkably, only LTA induced C5a release.This is the first study to report the in vivo effects of LTA in men and to compare inflammation induced by LTA and LPS in the human lung. Our data suggest that stimulation of TLR2 or TLR4 results in differential pulmonary inflammation, which may be of relevance for understanding pathogenic mechanisms at play during gram-positive and gram-negative respiratory tract infection.
Effect of Adding Pharmacists to Primary Care Teams on Blood Pressure Control in Patients With Type 2 Diabetes
Authors: Scot H. Simpson, Sumit R. Majumdar, Ross T. Tsuyuki, Richard Z. Lewanczuk, Richard Spooner, Jeffrey A. Johnson
Journal: Diabetes Care (2010)

OBJECTIVE To evaluate the effect of adding pharmacists to primary care teams on the management of hypertension and other cardiovascular risk factors in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted a randomized controlled trial with blinded ascertainment of outcomes within primary care clinics in Edmonton, Canada. Pharmacists performed medication assessments and limited history and physical examinations and provided guideline-concordant recommendations to optimize medication management. Follow-up contact was completed as necessary. Control patients received usual care. The primary outcome was a ≥10% decrease in systolic blood pressure at 1 year. RESULTS A total of 260 patients were enrolled, 57% were women, the mean age was 59 years, diabetes duration was 6 years, and blood pressure was 129/74 mmHg. Forty-eight of 131 (37%) intervention patients and 30 of 129 (23%) control patients achieved the primary outcome (odds ratio 1.9 [95% CI 1.1–3.3]; P = 0.02). Among 153 patients with inadequately controlled hypertension at baseline, intervention patients (n = 82) were significantly more likely than control patients (n = 71) to achieve the primary outcome (41 [50%] vs. 20 [28%]; 2.6 [1.3–5.0]; P = 0.007) and recommended blood pressure targets (44 [54%] vs. 21 [30%]; 2.8 [1.4–5.4]; P = 0.003). The 10-year risk of cardiovascular disease, based on changes to the UK Prospective Diabetes Study Risk Engine, were predicted to decrease by 3% for intervention patients and 1% for control patients (P = 0.005). CONCLUSIONS Significantly more patients with type 2 diabetes achieved better blood pressure control when pharmacists were added to primary care teams, which suggests that pharmacists can make important contributions to the primary care of these patients.
HOW NEUTROPHILS KILL MICROBES
Authors: Anthony W. Segal
Journal: Annual Review of Immunology (2005)

Neutrophils provide the first line of defense of the innate immune system by phagocytosing, killing, and digesting bacteria and fungi. Killing was previously believed to be accomplished by oxygen free radicals and other reactive oxygen species generated by the NADPH oxidase, and by oxidized halides produced by myeloperoxidase. We now know this is incorrect. The oxidase pumps electrons into the phagocytic vacuole, thereby inducing a charge across the membrane that must be compensated. The movement of compensating ions produces conditions in the vacuole conducive to microbial killing and digestion by enzymes released into the vacuole from the cytoplasmic granules.
Deep phenotypic characterization of NY-ESO TCR engineered T cells and tumor in patients with advanced myeloma
Authors: Eduardo Davila, Luca Melchiori, Ryan Wong, Gwendolyn Binder-Scholl, Rafael Amado, Bent Jakobsen, Aaron Rapoport
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts It is now well established that human tumors express unique antigens, however tumor immune evasion mechanisms often prevent effective naturally occurring anti-tumor immune responses. We hypothesized that infusion of T cells that have been genetically modified to express affinity-
Human CTLs to Wild-Type and Enhanced Epitopes of a Novel Prostate and Breast Tumor-Associated Protein, TARP, Lyse Human Breast Cancer Cells
Authors: SangKon Oh, Masaki Terabe, C. David Pendleton, Anu Bhattacharyya, Tapan K. Bera, Malka Epel, Yoram Reiter, John Phillips, W. Marston Linehan, Claude Kasten-Sportes, Ira Pastan, Jay A. Berzofsky
Journal: Cancer Research (2004)

Abstract Vaccine therapy for prostate and breast cancer may have potential for treating these major causes of death in males and females, respectively. Critical to the development of tumor-specific vaccines is finding and characterizing novel antigens to be recognized by CD8+ T cells. To define new CD8+ T-cell tumor antigens, we determined two wild-type HLA-A2 epitopes from a recently found tumor-associated protein, TARP (T-cell receptor γ alternate reading frame protein), expressed in prostate and breast cancer cells. We were also able to engineer epitope-enhanced peptides by sequence modifications. Both wild-type and enhanced epitopes induced peptide-specific CD8+ T-cell responses in A2Kb transgenic mice. In vitro restimulation of human CD8+ T cells from a prostate cancer patient resulted in CD8+ T cells reactive to the peptide epitopes that could lyse HLA-A2+ human breast cancer cells (MCF-7) expressing TARP. Epitope-specific human CD8+ T cells were also enumerated in patients’ peripheral blood by tetramer staining. Our data suggest that HLA-A2-binding TARP epitopes and enhanced epitopes discovered in this study could be incorporated into a potential vaccine for both breast and prostate cancer.
Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial
Authors: Josep M Llovet, Maria Isabel Real, Xavier Montaña, Ramon Planas, Susana Coll, John Aponte, Carmen Ayuso, Margarita Sala, Jordi Muchart, Ricard Solà, Joan Rodés, Jordi Bruix
Journal: The Lancet (2002)
A Phase I Dose–Escalation Study of Regorafenib (BAY 73–4506), an Inhibitor of Oncogenic, Angiogenic, and Stromal Kinases, in Patients with Advanced Solid Tumors
Authors: Klaus Mross, Annette Frost, Simone Steinbild, Susanne Hedbom, Martin Büchert, Ulrike Fasol, Clemens Unger, Jörn Krätzschmar, Roland Heinig, Oliver Boix, Olaf Christensen
Journal: Clinical Cancer Research (2012)

Regorafenib is a novel oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic kinases (KIT, RET, and RAF). This first-in-man, phase I dose-escalation study assessed the safety, pharmacokinetic, pharmacodynamic, and efficacy profiles of regorafenib in patients with advanced solid tumors.Patients aged 18 years or older with advanced solid tumors refractory to standard treatment were recruited. Regorafenib was administered orally for 21 days on/seven days off in repeating cycles, until discontinuation due to toxicity or tumor progression. Adverse events (AE) were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Pharmacokinetic profiles were measured after a single dose and on day 21. Pharmacodynamic and efficacy evaluations included tumor perfusion assessment using dynamic contrast-enhanced MRI, plasma cytokines, and tumor response using RECIST (v1.0).Fifty-three patients were enrolled into eight cohorts at dose levels from 10 to 220 mg daily. The recommended dose for future studies was determined to be 160 mg daily, with a treatment schedule of 21 days on/seven days off in repeating 28-day cycles. The most common drug-related grade 3 or 4 AEs were dermatologic AEs (hand-foot skin reaction, rash), hypertension, and diarrhea. Pharmacokinetic analysis revealed a similar exposure at steady state for the parent compound and two pharmacologically active metabolites. Tumor perfusion and plasma cytokine analysis showed biologic activity of regorafenib. Three of 47 evaluable patients achieved a partial response (renal cell carcinoma, colorectal carcinoma, and osteosarcoma).Regorafenib showed an acceptable safety profile and preliminary evidence of antitumor activity in patients with solid tumors.
Effects of botulinum toxin A on the sphincter of Oddi: an in vivo and in vitro study
Authors: J Sand, I Nordback, P Arvola, I Porsti, A Kalloo, P Pasricha
Journal: Gut (1998)

<i>Background</i>—Botulinum toxin A is a potent inhibitor of the release of acetylcholine from nerve endings. Local injection of botulinum toxin has recently been suggested to be helpful in sphincter of Oddi dyskinesia by decreasing sphincter of Oddi pressure. <i>Aims</i>—To explore the mechanism of action of botulinum toxin A on sphincter of Oddi (SO) muscle. <i>Methods</i>—Four piglets underwent duodenoscopy and SO manometry was performed. After obtaining a baseline pressure, the SO was injected with normal saline and the experiment repeated after one week. The SO was then injected endoscopically with botulinum toxin (40 U) with follow up manometry one week later. The sphincter of Oddi was removed from 10 pigs, cut into three rings, and placed in an organ bath. The force of contraction was measured and registered on a polygraph. Rings were stimulated by 70 V (10 Hz, 0.5 ms) electrical field stimulation for 20 seconds, exogenous acetylcholine (100 μM), and KCl (125 mM). Botulinum toxin (0.1 U/ml) or atropine (1 μM) was added to the incubation medium and the stimulation was repeated. <i>Results</i>—Mean basal SO pressure in the pigs remained unchanged after saline injection but decreased to about 50% of baseline value following botulinum toxin injection (p=0.04). The contractions induced by direct stimulation of SO smooth muscle with KCl were not significantly affected by either atropine or botulinum toxin. In all rings exogenous acetylcholine induced contractions, which were totally blocked by atropine, but not by botulinum toxin. Electrical field stimulation induced contractions that were inhibited by both atropine and botulinum toxin. <i>Conclusion</i>—Botulinum toxin inhibits pig sphincter of Oddi smooth muscle contractions by a presynaptic cholinergic mechanism, similar to that described in skeletal muscle.
Infopoints: NHS Economic Evaluation Database for healthcare decision makers
Authors: J. Nixon, B. Stoykova, J. Christie, J. Glanville, J. Kleijnen, M. Drummond
Journal: BMJ (2000)

The increasing importance of information on cost effectiveness has been recognised by the National Institute for Clinical Excellence (NICE)1 and will be an integral part of new national guidelines for the NHS. Analyses of the literature on economic evaluations also reveal a rapid increase in the number of published studies.2 Having access to reliable information on the cost effectiveness of competing health technologies is therefore important to decision makers and researchers in the NHS.

The NHS Economic Evaluation Database (NHS EED) project …
Casein kinase 1α–dependent feedback loop controls autophagy in RAS-driven cancers
Authors: Jit Kong Cheong, Fuquan Zhang, Pei Jou Chua, Boon Huat Bay, Andrew Thorburn, David M. Virshup
Journal: Journal of Clinical Investigation (2015)

Activating mutations in the RAS oncogene are common in cancer but are difficult to therapeutically target. RAS activation promotes autophagy, a highly regulated catabolic process that metabolically buffers cells in response to diverse stresses. Here we report that casein kinase 1α (CK1α), a ubiquitously expressed serine/threonine kinase, is a key negative regulator of oncogenic RAS-induced autophagy. Depletion or pharmacologic inhibition of CK1α enhanced autophagic flux in oncogenic RAS-driven human fibroblasts and multiple cancer cell lines. FOXO3A, a master longevity mediator that transcriptionally regulates diverse autophagy genes, was a critical target of CK1α, as depletion of CK1α reduced levels of phosphorylated FOXO3A and increased expression of FOXO3A-responsive genes. Oncogenic RAS increased CK1α protein abundance via activation of the PI3K/AKT/mTOR pathway. In turn, elevated levels of CK1α increased phosphorylation of nuclear FOXO3A, thereby inhibiting transactivation of genes critical for RAS-induced autophagy. In both RAS-driven cancer cells and murine xenograft models, pharmacologic CK1α inactivation synergized with lysosomotropic agents to inhibit growth and promote tumor cell death. Together, our results identify a kinase feedback loop that influences RAS-dependent autophagy and suggest that targeting CK1α-regulated autophagy offers a potential therapeutic opportunity to treat oncogenic RAS-driven cancers.
Effect of Raloxifene on the Incidence of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis Categorized by Breast Cancer Risk
Authors: Marc E. Lippman, Steven R. Cummings, Damon P. Disch, John L. Mershon, Sherie A. Dowsett, Jane A. Cauley, Silvana Martino
Journal: Clinical Cancer Research (2006)

To assess the effect of raloxifene, indicated for osteoporosis treatment and prevention, on invasive breast cancer in subgroups of postmenopausal women defined by risk factors for breast cancer.Data from the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial (N=7,705) and a follow-up study, the 4-year Continuing Outcomes Relevant to Evista (CORE) trial (N=4,011), were analyzed. Prespecified subgroups were defined by age (>or=65 versus<65 years), age at menopause (>or=49 versus<49 years), body mass index (>or=25 versus<25 kg/m2), family history of breast cancer (yes/no), serum estradiol level (5-10 versus<5, >10 versus<5 pmol/L), prior estrogen therapy (yes/no), and bone mass at MORE baseline, and 5-year predicted risk, assessed using the modified Gail model (>or=1.67 versus<1.67%), at CORE baseline. Time-to-first invasive breast cancer was analyzed using Cox proportional hazards models.In the placebo group, older age, higher estradiol level, and a family history of breast cancer were associated with an increased breast cancer risk (P<0.05). Raloxifene therapy was associated with a reduced breast cancer risk in both women at lower and those at higher breast cancer risk. Hazard ratio point estimates were 0.11 to 0.67, corresponding to a 33% to 89% reduction in breast cancer risk with raloxifene versus placebo. The therapy by family history interaction was significant (P=0.04).Raloxifene therapy was associated with a reduced risk of invasive breast cancer in postmenopausal women irrespective of the presence/absence of risk factors; its effect was greater in women with a family history of breast cancer.
Novel, Magnetically Guided Catheter for Endocardial Mapping and Radiofrequency Catheter Ablation
Authors: Mitchell N. Faddis, Walter Blume, Jennifer Finney, Andrew Hall, John Rauch, Jon Sell, Kyongtae Ty Bae, Michael Talcott, Bruce Lindsay
Journal: Circulation (2002)

Background— Ablation of complex arrhythmias would be greatly facilitated by more precise control of ablation catheters. A feasibility study was performed in animals to evaluate a novel magnetic guidance system (MGS) that generates a magnetic field to control the movement and position of a magnetic ablation catheter. Methods and Results— The MGS is composed of a digital biplanar fluoroscope within an array of superconducting electromagnets that surround the torso of the experimental animal and a computer control system that generates a composite magnetic field for directional catheter deflection. Magnetic catheter navigation was performed in dogs and pigs (20 to 30 kg). A 7F magnetic ablation catheter was used for intracardiac navigation and radiofrequency ablation. The performance of a standard 7F deflectable catheter was not affected by the MGS. The magnetic catheter was navigated successfully to 51 predefined targets throughout the heart in 6 animals. In 5 animals, the magnetic catheter, guided by a 3D computed tomogram, was successfully navigated to all pulmonary veins. Navigation accuracy was estimated as &lt;1 mm displacement from the target. The magnetic catheter was used to ablate the atrioventricular node in 4 animals and to perform linear ablations across the endocardial surface underlying an epicardial multielectrode recording plaque in 4 animals. Conclusions— These results demonstrate that the MGS can navigate and stabilize an ablation catheter at endocardial targets. Linear or focal radiofrequency ablation with the magnetic catheter is not compromised by the magnetic field. This technology provides precise control of endocardial catheters.