tbuckley/cabot-search huggingface dataset:
Localized RhoA GTPase activity regulates dynamics of endothelial monolayer integrity
Authors: Robert Szulcek, Cora M.L. Beckers, Jasmina Hodzic, Jelle de Wit, Zhenlong Chen, Tim Grob, Rene J.P. Musters, Richard D. Minshall, Victor W.M. van Hinsbergh, Geerten P. van Nieuw Amerongen
Journal: Cardiovascular Research (2013)

Endothelial cells (ECs) control vascular permeability by forming a monolayer that is sealed by extracellular junctions. Various mediators modulate the endothelial barrier by acting on junctional protein complexes and the therewith connected F-actin cytoskeleton. Different Rho GTPases participate in this modulation, but their mechanisms are still partly resolved. Here, we aimed to elucidate whether the opening and closure of the endothelial barrier are associated with distinct localized RhoA activities at the subcellular level.Live fluorescence resonance energy transfer (FRET) microscopy revealed spatially distinct RhoA activities associated with different aspects of the regulation of endothelial monolayer integrity. Unstimulated ECs were characterized by hotspots of RhoA activity at their periphery. Thrombin receptor activation in the femoral vein of male wistar rats and in cultured ECs enhanced RhoA activity at membrane protrusions, followed by a more sustained RhoA activity associated with cytoplasmic F-actin filaments, where prolonged RhoA activity coincided with cellular contractility. Unexpectedly, thrombin-induced peripheral RhoA hotspots were not spatially correlated to the formation of large inter-endothelial gaps. Rather, spontaneous RhoA activity at membrane protrusions coincided with the closure of inter-endothelial gaps. Electrical impedance measurements showed that RhoA signalling is essential for this protrusive activity and maintenance of barrier restoration.Spontaneous RhoA activity at membrane protrusions is spatially associated with closure, but not formation of inter-endothelial gaps, whereas RhoA activity at distant contractile filaments contributes to thrombin-induced disruption of junctional integrity. Thus, these data indicate that distinct RhoA activities are associated with disruption and re-annealing of endothelial junctions.
Photochemotherapy in the treatment of psoriasis
Authors: T. LAKSHMIPATHI, P.W. GOULD, L.A. MACKENZIE, B.E. JOHNSON, W. FRAIN-BELL
Journal: British Journal of Dermatology (1977)

This article describes the satisfactory clinical improvement obtained in the majority of a group of 72 patients with psoriasis of various types as a result of the oral and/or topical administration of 8-methoxypsoralen followed by long wavelength ultraviolet irradiation. The irradiation source used was that of conventional longwave UV fluorescent tubes mounted in a specially constructed cubicle. Until such time as the long term effect of this form of photochemotherapy on the cell has been evaluated and the most appropriate regime worked out, it would seem to be important to restrict the amount of irradiation used to that required to produce acceptable maintained clinical improvement.
The role of adrenergic mechanisms in the substrate and hormonal response to insulin-induced hypoglycemia in man.
Authors: A J Garber, P E Cryer, J V Santiago, M W Haymond, A S Pagliara, D M Kipnis
Journal: Journal of Clinical Investigation (1976)

Sequential determinations of glucose outflow and inflow, and rates of gluconeogenesis from alanine, before, during and after insulin-induced hypoglycemia were obtained in relation to alterations in circulating epinephrine, norepinephrine, glucagon, cortisol, and growth hormone in six normal subjects. Insulin decreased the mean (+/-SEM) plasma glucose from 89+/-3 to 39+/-2 mg/dl 25 min after injection, but this decline ceased despite serum insulin levels of 153+/-22 mul/ml. Before insulin, glucose inflow and outflow were constant averaging 125.3+/-7.1 mg/kg per h. 15 min after insulin, mean glucose outflow increased threefold, but then decreased at 25 min, reaching a rate 15% less than the preinsulin rate. Glucose inflow decreased 80% 15 min after insulin, but increased at 25 min, reaching a maximum of twice the basal rate. Gluconeogenesis from alanine decreased 68% 15 min after insulin, but returned to preinsulin rates at 25 min, and remained constant for the next 25 min, after which it increased linearly. A fourfold increase in mean plasma epinephrine was found 20 min after insulin, with maximal levels 50 times basal. Plasma norepinephrine concentrations first increased significantly at 25 min after insulin, whereas significantly increased levels of cortisol and glucagon occurred at 30 min, and growth hormone at 40 min after insulin. Thus, insulin-induced hypoglycemia in man results from both a decrease in glucose production and an increase in glucose utilization. Accelerated glycogenolysis produced much of the initial, posthypoglycemic increment in glucose production. The contribution of glycogenolysis decreased with time, while that of gluconeogenesis from alanine increased. Of the hormones studied, only the increments in plasma catecholamines preceded or coincided with the measured increase in glucose production after hypoglycemia. It therefore seems probable that adrenergic mechanisms play a major role in the initiation of counter-regulatory responses to insulin-induced hypoglycemia in man.
Validity of reported pain as a measure of clinical state in juvenile rheumatoid arthritis.
Authors: C K Ross, J V Lavigne, J R Hayford, A R Dyer, L M Pachman
Journal: Annals of the Rheumatic Diseases (1989)

Reported pain is one valid indicator of clinical state which should be used in the assessment and management of children with juvenile rheumatoid arthritis. Parents9 reports of children9s pain for 101 children with juvenile rheumatoid arthritis differed significantly by type of juvenile rheumatoid arthritis. When multiple regression was used separately for pauciarticular and polyarticular classifications of juvenile rheumatoid arthritis a measure of clinical state, which reflected joint activity, morning stiffness, and overall disease activity as rated by the doctor, had a significant and independent effect upon pain reported by parents. The child9s age was not significantly related to the pain reported by parents. Children9s pain reports did not differ significantly between older and younger children.
Chronic pulmonary sarcoidosis: relationship between lung lavage cell counts, chest radiograph, and results of standard lung function tests.
Authors: Y H Lin, P L Haslam, M Turner-Warwick
Journal: Thorax (1985)

Thirty three consecutive untreated patients with pulmonary sarcoidosis, confirmed histologically or by Kveim test, were investigated to correlate cell counts in bronchoalveolar lavage fluid with clinical features, the chest radiograph, and results of lung function tests. A persistently abnormal radiograph had been observed for one year or more in 26 (79%) and for two years or more in 20 (61%), but only 24% had dyspnoea. Twenty (61%) of 33 patients showed an increased percentage of lymphocytes in bronchoalveolar lavage fluid, although only eight (24%) exceeded 28%. A moderate increase of neutrophils, up to 12%, was found in 14 (42%). Lymphocyte percentage counts were higher in the group of patients without evidence of radiographic contraction suggesting fibrosis, and this contrasted with higher percentage neutrophil counts in those with contraction. There was also a correlation between the percentages of neutrophils and increasing radiographic profusion scores (p less than 0.001), suggesting that neutrophils may reflect the severity of the parenchymal legions as well as fibrotic distortion, and an inverse correlation with vital capacity (p less than 0.001) and transfer factor (TLCO) (p less than 0.1 greater than 0.05). No significant correlation was found between the lymphocyte counts and radiographic profusion scores, vital capacity or TLCO; but it was noted that all eight patients with high lymphocyte counts (greater than 28%) had radiographic profusion scores less than 12. This study shows that, especially in sarcoidosis with more extensive radiographic shadows of long duration, bronchoalveolar lavage neutrophils may be important as well as lymphocytes in clinical assessment of "activity" of disease. These observations are important because they throw doubt on whether the lavage lymphocyte count alone can be used as an indicator of the need to start corticosteroid treatment.
Does early review by a respiratory physician lead to a shorter length of stay for patients with non-severe community-acquired pneumonia?
Authors: T Bewick, V J Cooper, W S Lim
Journal: Thorax (2009)

<h3>Background:</h3> The aim of this study was to evaluate whether patients with non-severe community-acquired pneumonia (CAP) have a shorter length of stay (LOS) when initially seen by a respiratory physician compared with a non-respiratory physician. <h3>Methods:</h3> At Nottingham City Hospital, following nurse triage, acute medical patients who are not severely ill are admitted to the consultant-led emergency short stay unit (ESSU). Records of patients seen on ESSU between January 2004 and December 2007 with a clinical discharge code relating to CAP were retrospectively examined. Patients with a diagnosis of cellulitis over the same time period were used as controls. Patients were grouped depending on whether they were seen on their first post-take ward round by a respiratory consultant physician (group A), non-respiratory consultant physician (group B) or on a Saturday or Sunday (group C). <h3>Results:</h3> Following exclusions, 426 patients with CAP and 935 patients with cellulitis were analysed. The median LOS for patients with CAP in group A was 1.74 days (n = 123, interquartile range (IQR) 0.97–4.09) compared with 3.03 days for patients in group B (n = 174, IQR 1.12–6.23; p&lt;0.01). There was a larger percentage of discharges within 24 h of consultant review in group A (43.1%) compared with group B (31.9%), although this was not statistically significant (p = 0.18). There was no statistically significant difference between groups A and B with cellulitis in LOS or percentage discharged within 24 h of first consultant review. <h3>Conclusion:</h3> Patients with non-severe CAP have a shorter hospital LOS when initially seen by a respiratory compared with a non-respiratory physician.
Developmental Trajectories of Brain Volume Abnormalities in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder
Authors: F. Xavier Castellanos
Journal: JAMA (2002)

TTENTION-DEFICIT/HYPERactivity disorder (ADHD), the most common childhood psychiatric disorder, is thought to reflect subtle abnormalities in central nervous system functioning. 1For this reason, ADHD is being studied increasingly with a variety of brain imaging techniques throughout the life span.Magnetic resonance imaging (MRI) is particularly suitable for the study of pediatric patients, providing high-resolution images without ionizing radiation.Previous MRI neuroimaging studies, most with small samples, have reported smaller anatomic areas and/or volumes in patients with ADHD in regions of the cor-
CD4+ invariant natural killer T cells protect from murine GVHD lethality through expansion of donor CD4+CD25+FoxP3+ regulatory T cells
Authors: Dominik Schneidawind, Antonio Pierini, Maite Alvarez, Yuqiong Pan, Jeanette Baker, Corina Buechele, Richard H. Luong, Everett H. Meyer, Robert S. Negrin
Journal: Blood (2014)
Inactivation of Nuclear Factor κB by Soy Isoflavone Genistein Contributes to Increased Apoptosis Induced by Chemotherapeutic Agents in Human Cancer Cells
Authors: Yiwei Li, Fakhara Ahmed, Shadan Ali, Philip A. Philip, Omer Kucuk, Fazlul H. Sarkar
Journal: Cancer Research (2005)

Abstract Cancer chemotherapeutic strategies commonly require multiple agents. However, use of multiple agents contributes to added toxicity resulting in poor treatment outcome. Thus, combination chemotherapy must be optimized to increase tumor response and at the same time lower its toxicity. Chemotherapeutic agents are known to induce nuclear factor κB (NF-κB) activity in tumor cells, resulting in lower cell killing and drug resistance. In contrast, genistein has been shown to inhibit the activity of NF-κB and the growth of various cancer cells without causing systemic toxicity. We therefore investigated whether the inactivation of NF-κB by genistein before treatment of various cancer cells with chemotherapeutic agents could lead to better tumor cell killing as tested by in vitro studies using gene transfections and also by animal studies. PC-3 (prostate), MDA-MB-231 (breast), H460 (lung), and BxPC-3 (pancreas) cancer cells were pretreated with 15 to 30 μmol/L genistein for 24 hours and then exposed to low doses of chemotherapeutic agents for an additional 48 to 72 hours. We found that 15 to 30 μmol/L genistein combined with 100 to 500 nmol/L cisplatin, 0.5 to 2 nmol/L docetaxel, or 50 ng/mL doxorubicin resulted in significantly greater inhibition of cell growth and induction of apoptosis compared with either agent alone. Moreover, we found that the NF-κB activity was significantly increased within 2 hours of cisplatin and docetaxel treatment and that the NF-κB inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results were also supported, for the first time, by animal experiments, p65 cDNA transfection and p65 small interfering RNA studies, which clearly showed that a specific target (NF-κB) was affected in vivo. Collectively, our results clearly suggest that genistein pretreatment inactivates NF-κB and may contribute to increased growth inhibition and apoptosis induced by cisplatin, docetaxel, and doxorubicin in prostate, breast, lung, and pancreatic cancer cells. Theses results warrant carefully designed clinical studies investigating the combination of soy isoflavones and commonly used chemotherapeutic agents for the treatment of human cancers.
Src: a potential target for the treatment of triple-negative breast cancer
Authors: D. Tryfonopoulos, S. Walsh, D.M. Collins, L. Flanagan, C. Quinn, B. Corkery, E.W. McDermott, D. Evoy, A. Pierce, N. O’Donovan, J. Crown, M.J. Duffy
Journal: Annals of Oncology (2011)
Breast Cancer Incidence Is on the Rise — But Why?
Authors: Patricia A. Newman
Journal: JNCI Journal of the National Cancer Institute (1990)

Journal Article Breast Cancer Incidence Is on the Rise — But Why? Get access Patricia A. Newman Patricia A. Newman Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 82, Issue 12, 20 June 1990, Pages 998–1000, https://doi.org/10.1093/jnci/82.12.998 Published: 20 June 1990
Regulation of mechanosensitive biliary epithelial transport by the epithelial Na+ channel
Authors: Qin Li, Charles Kresge, Abhijit Bugde, Michelle Lamphere, Jason Y. Park, Andrew P. Feranchak
Journal: Hepatology (2015)

Intrahepatic biliary epithelial cells (BECs), also known as cholangiocytes, modulate the volume and composition of bile through the regulation of secretion and absorption. While mechanosensitive Cl – efflux has been identified as an important secretory pathway, the counterabsorptive pathways have not been identified. In other epithelial cells, the epithelial Na + channel (ENaC) has been identified as an important contributor to fluid absorption; however, its expression and function in BECs have not been previously studied. Our studies revealed the presence of α, β, and γ ENaC subunits in human BECs and α and γ subunits in mouse BECs. In studies of confluent mouse BEC monolayers, the ENaC contributes to the volume of surface fluid at the apical membrane during constitutive conditions. Further, functional studies using whole‐cell patch clamp of single BECs demonstrated small constitutive Na + currents, which increased significantly in response to fluid‐flow or shear. The magnitude of Na + currents was proportional to the shear force, displayed inward rectification and a reversal potential of +40 mV (E Na+ = +60 mV), and were abolished with removal of extracellular Na + ( N ‐methyl‐ d ‐glucamine) or in the presence of amiloride. Transfection with ENaCα small interfering RNA significantly inhibited flow‐stimulated Na + currents, while overexpression of the α subunit significantly increased currents. ENaC‐mediated currents were positively regulated by proteases and negatively regulated by extracellular adenosine triphosphate. Conclusion : These studies represent the initial characterization of mechanosensitive Na + currents activated by flow in biliary epithelium; understanding the role of mechanosensitive transport pathways may provide strategies to modulate the volume and composition of bile during cholestatic conditions. (H epatology 2016;63:538–549)
Molecular Mechanisms of Lymphocyte-Mediated Cytotoxicity and Their Role in Immunological Protection and Pathogenesis In Vivo
Authors: David Kägi, Birgit Ledermann, Kurt Bürki, Rolf M. Zinkernagel, Hans Hengartner
Journal: Annual Review of Immunology (1996)

Studies with perforin-deficient mice have demonstrated that two independent mechanisms account for T cell-mediated cytotoxicity: A main pathway is mediated by the secretion of the pore-forming protein perforin by the cytotoxic T cell, whereas an alternative nonsecretory pathway relies on the interaction of the Fas ligand that is upregulated during T cell activation with the apoptosis-inducing Fas molecule on the target cell. NK cells use the former pathway exclusively. The protective role of the perforin-dependent pathway has been shown for infection with the noncytopathic lymphocytic choriomeningitis virus, for infection with Listeria monocytogenes, and for the elimination of tumor cells by T cells and NK cells. In contrast, perforin-dependent cytotoxicity is not involved in protection against the cytopathic vaccinia virus and vesicular stomatitis virus. LCMV-induced immunopathology and autoimmune diabetes have been found to require perforin-expression. A contribution of perforin-dependent cytotoxicity to the rejection of MHC class I-disparate heart grafts has also been observed. Its absence is efficiently compensated in rejection of fully allogeneic organ or skin grafts. So far, evidence for a role of Fas-dependent cytotoxicity as a T cell effector mechanism in vivo is lacking. Current data suggest that the main function of Fas may be in regulation of the immune response and apparently less at the level of an effector mechanism in host defense. Further analysis is necessary, however, to settle this point finally.
Impact of Treatment End Point Definitions on Perceived Differences in Long-Term Outcome With Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia
Authors: Hagop Kantarjian, Susan O'Brien, Elias Jabbour, Jenny Shan, Farhad Ravandi, Tapan Kadia, Stefan Faderl, Guillermo Garcia-Manero, Gautam Borthakur, Jorge Cortes
Journal: Journal of Clinical Oncology (2011)

Different definitions of progression-free survival (PFS) and event-free survival (EFS) may result in perceived differences in outcomes with tyrosine kinase inhibitor (TKI) therapies in chronic myelogenous leukemia (CML).We analyzed the outcome of 435 patients with early chronic-phase, Philadelphia chromosome-positive CML treated with imatinib (n = 281), nilotinib (n = 78), and dasatinib (n = 76) using definitions of PFS and EFS used in the International Randomized Study of Interferon Versus STI571 (IRIS), Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENEST-nd), Dasatinib Versus Imatinib Study in Treatment-Naïve CML Patients (DASISION), and MD Anderson Cancer Center (MDACC) trials. Definitions for EFS-IRIS, time without progression in ENEST-nd, PFS-DASISION, and EFS-MDACC were as previously reported. The EFS-MDACC considered an event any instance of toxicity or death from any cause on or off therapy (if not counted before death as progression/event).Of the 435 patients, 123 (28%) were taken off TKI therapy (resistance/loss of response, n = 33; blastic phase on TKI therapy, n = 6; intolerance/toxicity, n = 29; other causes, n = 55). Thirty-three patients (7.6%) have died; eight patients died on TKI therapy, two patients died within 60 days of being off TKIs, and 23 patients died after being off TKIs for more than 60 days. Of the 33 deaths, 19 deaths (eight deaths on TKI, two deaths within 60 days, and nine deaths off for resistance/relapse/transformation) would be counted as progression/events on the IRIS/ENEST-nd/DASISION studies, whereas 14 deaths would be censored at time off TKI. On the basis of the four definitions used by IRIS, ENEST-nd, DASISION, and MDACC trials, the corresponding 5-year PFS/EFS rates were 96%, 90%, 89%, and 81%.Uniform definitions of PFS and EFS are needed to compare the long-term efficacy and potential use of different TKIs in CML.
Dreams have meaning but no function
Authors: Mark Blagrove
Journal: Behavioral and Brain Sciences (2000)

Solms shows the cortical basis for why dreams reflect waking concerns and goals, but with deficient volition. I argue the latter relates to Hobson et al.'s process I as well as M. A memory function for REM sleep is possible, but may be irrelevant to dream characteristics, which, contrary to Revonsuo, mirror the range of waking emotions, positive and negative. [Hobson et al.; Nielsen; Solms; Revonsuo; Vertes &amp; Eastman]
Copenhagen City Heart Study: longitudinal analysis of ventilatory capacity in diabetic and nondiabetic adults
Authors: P. Lange, J. Parner, P. Schnohr, G. Jensen
Journal: European Respiratory Journal (2002)

The natural history of lung function in diabetes is unknown due to the lack of longitudinal observations. The decline of forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC) was studied over 15 yrs in the 17,506 adult participants of The Copenhagen City Heart Study, which included 266 individuals with diabetes. Multiple linear regression and a mixed-effects model were used, taking into account correlation between repeated measurements and adjusting for relevant confounders. In both sexes, FEV 1 and FVC were consistently lower in diabetic individuals, compared with healthy individuals, with an average reduction of ∼8% of the predicted value. Longitudinal analyses showed that the decline of FEV 1 and FVC in diabetic individuals was similar to that observed in nondiabetic subjects. It was concluded that although diabetic subjects have, on average, a lower forced expiratory volume in one second and forced vital capacity than individuals without diabetes, this deficit seems not to be progressive in the long term. These observations may be of importance with regard to diabetes treatment with inhaled pulmonary insulin, which is likely to become available within a few years.
Collaboration of Kras and Androgen Receptor Signaling Stimulates EZH2 Expression and Tumor-Propagating Cells in Prostate Cancer
Authors: Houjian Cai, Sanaz Memarzadeh, Tanya Stoyanova, Zanna Beharry, Andrew S. Kraft, Owen N. Witte
Journal: Cancer Research (2012)

Abstract Elevation of the chromatin repression factor enhancer of zeste homolog (EZH2) is associated with progression and poor prognosis in several human cancers including prostate cancer. However, the mechanisms driving EZH2 expression are not fully understood. In this study, we investigated the functional synergy in prostate cancers in mice resulting from activation of the androgen receptor, Kras, and Akt, which drives three of the most frequently activated oncogenic signaling pathways in prostate cancer. Although, any two of these three events were sufficient to promote the formation and progression of prostate cancer, only the synergy of androgen receptor and Kras signaling could elevate EZH2 expression and expand prostate cancer progenitor cells in vivo. Our findings have revealed a genetic mechanism resulting in enhanced EZH2 expression during the progression of aggressive prostate cancer, with important implications for understanding how to target advanced disease where cancer progenitor cells may be critical. Cancer Res; 72(18); 4672–81. ©2012 AACR.