tbuckley/cabot-search huggingface dataset:
Electrophysiological effects of magnesium on cells in the canine sinus node and false tendon.
Authors: W T Woods, R E Katholi, F Urthaler, T N James
Journal: Circulation Research (1979)

Sinus node cells in the isolated perfused canine right atrium and cells of the right ventricular false tendons were used to assess the effects of extracellular Mg* + concentration ([Mg 1 *],) on cardiac electrical activity.Removal of Mg* + from the perfusate into the sinus node led to an increase of 36% in sinus rate that was sustained for as long as Mg* + was absent; doubling [Mg* + ]o to 2 mmol/liter caused the sinus rate to decrease by 19%.During Mg* + -free perfusion, the accelerated sinus rate could be depressed by the addition of certain substances; verapamil and Mn 1 * produced the same percent depression regardless of [Mg* + ]<» but tetrodotoxin and reduced [Na*] in the solution each brought about significantly greater depression of sinus rate when Mg* + was absent.No change in maximum diastolic potential was observed in the sinus node cells when Mg* + was withheld.In false tendon cells, on the other hand, removal of Mg* + was accompanied by depolarization of the transmembrane potential to a stable level of approximately -4 0 mV, at which potential action potentials could not be elicited.Increasing [Mg* + ]<, to 4 mmol/liter caused slight hyperpolarization of false tendon cells, but maximum upstroke velocity of the action potential and overshoot were reduced in spite of the more negative resting transmembrane potential.In both types of tissue, sinus node and false tendon, all changes clearly began to reverse within 30 minutes after restoration of normal [Mg* + ]o, and recovery was complete by 60 minutes.Since neither atropine, 5 /ig/ml, nor propranolol, 15 ftg/ml, modified the responses to Mg* + alteration, these results indicate that Mg* + has a direct effect on transmembrane electrical processes.The functional response to changes in concentration of this cation depends upon the specific type of cell acted upon.
Prognostic Significance of Activated AKT Expression in Soft-Tissue Sarcoma
Authors: Yasuhiko Tomita, Takaya Morooka, Yoshihiko Hoshida, Binglin Zhang, Ying Qiu, Itsuko Nakamichi, Ken-ichiro Hamada, Takafumi Ueda, Norifumi Naka, Ikuo Kudawara, Katsuyuki Aozasa
Journal: Clinical Cancer Research (2006)

Abstract Purpose: AKT is a serine/threonine kinase which is important in tumorigenesis. Several molecules involved in AKT pathway are dysregulated in various kinds of human cancers. Patients and Methods: Ninety-three patients (53 males and 40 females), ages ranging from 19 to 77 years (median, 57 years), with localized soft-tissue sarcomas arising in the trunk and extremities, were analyzed. Immunoperoxidase procedure (avidin-biotin complex method) was done on paraffin-embedded sections with anti–phosphorylated AKT (Thr308), anti–phosphorylated p44/42 extracellular signal–regulated kinase 1 and 2 (ERK1/2) (Thr202/Tyr204), anti–phosphorylated forkhead in rhabdomyosarcoma (FKHR) (Ser256), and anti-Ki 67 antibodies. Expression levels of phosphorylated AKT (p-AKT), phosphorylated ERK1/2 (p-ERK1/2), and phosphorylated FKHR (p-FKHR) were categorized as either weaker (level 1) or equal to or stronger (level 2) compared with those in the endothelial cells of the same specimens. Percentage of cells showing intranuclear staining with Ki-67 was shown as the Ki-67 labeling index (LI). Cases were divided into two groups: level 1, Ki-67 LI &amp;lt; 20%; level 2, Ki-67 LI ≥ 20%. Results: Twenty-six (28.0%), 6 (6.5%), and 46 (44.1%) of the tumors showed level 2 expression for p-AKT, p-ERK1/2, and Ki-67 LI, respectively. Tumors with level 2 p-AKT expression showed a higher ratio of level 2 p-FKHR expression (P &amp;lt; 0.01). Multivariate analysis revealed p-AKT expression and Ki-67 LI to be independent prognosticators for overall survival, and p-AKT expression for disease-free survival. Conclusion: p-AKT expression level is a significant prognosticator in soft-tissue sarcoma.
Delivery of CCL21 to Metastatic Disease Improves the Efficacy of Adoptive T-Cell Therapy
Authors: Uma Thanarajasingam, Laura Sanz, Rosa Diaz, Jian Qiao, Luis Sanchez-Perez, Tim Kottke, Jill Thompson, John Chester, Richard G. Vile
Journal: Cancer Research (2007)

Abstract Adoptive T-cell transfer has achieved significant clinical success in advanced melanoma. However, therapeutic efficacy is limited by poor T-cell survival after adoptive transfer and by inefficient trafficking to tumor sites. Here, we report that intratumoral expression of the chemokine CCL21 enhances the efficacy of adoptive T-cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro and down-regulates expression of CD62L, we hypothesized that tumor cell–mediated expression of this chemokine might recruit, and retain, adoptively transferred T cells to the sites of tumor growth. Mice bearing metastatic tumors stably transduced with CCL21 survived significantly longer following adoptive T-cell transfer than mice bearing non–CCL21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors, tumor-expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells and led to the priming of antitumor immunity following T-cell transfer. To translate these observations into a protocol of real clinical usefulness, we showed that adsorption of a retrovirus encoding CCL21 to OT-1 T cells before adoptive transfer increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in cure of metastatic disease and the generation of immunologic memory in the majority of treated mice. These studies indicate a promising role for CCL21 in enhancing the therapeutic efficacy of adoptive T-cell therapy. [Cancer Res 2007;67(1):300–8]
Immunohistochemical Expression of DNA Repair Proteins in Familial Breast Cancer Differentiate<i>BRCA2</i>-Associated Tumors
Authors: Emiliano Honrado, Ana Osorio, José Palacios, Roger L. Milne, Lydia Sánchez, Orland Díez, Alicia Cazorla, Kirsi Syrjakoski, David Huntsman, Päivi Heikkilä, Enrique Lerma, Anne Kallioniemi, Carmen Rivas, William D. Foulkes, Heli Nevanlinna, Javier Benítez
Journal: Journal of Clinical Oncology (2005)

Morphologic and immunohistochemical studies of familial breast cancers have identified specific characteristics associated with BRCA1 mutation-associated tumors when compared with BRCA2 and non-BRCA1/2 tumors, but have not identified differences between BRCA2 and non-BRCA1/2 tumors. Because BRCA1 and BRCA2 genes participate in the DNA repair pathway, we have performed an immunohistochemical study with markers related to this pathway to establish the profile of the three groups.We have studied two tissue microarrays that include 103 familial and 104 sporadic breast tumors, with a panel of DNA repair markers including ATM, CHEK2, RAD51, RAD50, XRCC3, and proliferating cell nuclear antigen.We found more frequent expression of CHEK2 in BRCA1 and BRCA2 tumors than in non-BRCA1/2 and sporadic tumors. We found absence of nuclear expression and presence of cytoplasmic expression of RAD51 in BRCA2 tumors that differentiate them from other familial tumors. We validated these results with a new series of patient cases. The final study with 253 familial patient cases (74 BRCA1, 71 BRCA2, 108 non-BRCA1/2), and 288 sporadic patient cases, has allowed us to confirm our preliminary results. Because BRCA2 tumors present a specific immunohistochemical profile for RAD51 and CHEK2 markers that is different from non-BRCA1/2 tumors, we have built a multivariate model with these markers that distinguish both tumors with an estimated probability of at least 76%.Our results suggest that BRCA2 tumors demonstrate more cytoplasmic and less nuclear RAD51 staining, and increased CHEK2 staining. This pattern may distinguish BRCA2 from familial non-BRCA1/2 tumors.
Oxidized LDL and Malondialdehyde-Modified LDL in Patients With Acute Coronary Syndromes and Stable Coronary Artery Disease
Authors: Paul Holvoet, Johan Vanhaecke, Stefaan Janssens, Frans Van de Werf, Désiré Collen
Journal: Circulation (1998)

Background —The association between oxidative modifications of LDL and coronary artery disease (CAD) is suspected but not established. Therefore, the association between plasma levels of oxidized LDL and malondialdehyde (MDA)-modified LDL and acute coronary syndromes and stable CAD was investigated. Methods and Results —The study population contained 63 patients with acute coronary syndromes (45 with acute myocardial infarction and 18 with unstable angina pectoris), 35 nontransplanted patients with angiographically confirmed stable angina, 28 heart transplant patients with posttransplant CAD, 79 heart transplant patients without CAD, and 65 control subjects. After correction for age, sex, and LDL and HDL cholesterol, plasma levels of oxidized LDL and MDA-modified LDL were significantly higher in patients with CAD than in individuals without CAD ( r 2 =0.57 and r 2 =0.26, respectively; both P =0.0001). Plasma levels of MDA-modified LDL were significantly higher in patients with acute coronary syndromes than in individuals with stable CAD ( r 2 =0.65; P =0.0001) and were associated with increased levels of troponin I and C-reactive protein ( r 2 =0.39 and r 2 =0.34, respectively; both P =0.0001). Plasma levels of oxidized LDL were not associated with increased levels of troponin I and C-reactive protein ( r 2 =0.089 and r 2 =0.063, respectively). Conclusions —Elevated plasma levels of oxidized LDL are associated with CAD. Elevated plasma levels of MDA-modified LDL suggest plaque instability and may be useful for the identification of patients with acute coronary syndromes.
Effects of Repetitive Transcranial Magnetic Stimulation on Motor Symptoms in Parkinson Disease
Authors: Ying-hui Chou, Patrick T. Hickey, Mark Sundman, Allen W. Song, Nan-kuei Chen
Journal: JAMA Neurology (2015)

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has been closely examined as a possible treatment for Parkinson disease (PD). However, results evaluating the effectiveness of rTMS in PD are mixed, mostly owing to low statistical power or variety in individual rTMS protocols.To determine the rTMS effects on motor dysfunction in patients with PD and to examine potential factors that modulate the rTMS effects.Databases searched included PubMed, EMBASE, Web of Knowledge, Scopus, and the Cochrane Library from inception to June 30, 2014.Eligible studies included sham-controlled, randomized clinical trials of rTMS intervention for motor dysfunction in patients with PD.Relevant measures were extracted independently by 2 investigators. Standardized mean differences (SMDs) were calculated with random-effects models.Motor examination of the Unified Parkinson's Disease Rating Scale.Twenty studies with a total of 470 patients were included. Random-effects analysis revealed a pooled SMD of 0.46 (95% CI, 0.29-0.64), indicating an overall medium effect size favoring active rTMS over sham rTMS in the reduction of motor symptoms (P<.001). Subgroup analysis showed that the effect sizes estimated from high-frequency rTMS targeting the primary motor cortex (SMD, 0.77; 95% CI, 0.46-1.08; P<.001) and low-frequency rTMS applied over other frontal regions (SMD, 0.50; 95% CI, 0.13-0.87; P=.008) were significant. The effect sizes obtained from the other 2 combinations of rTMS frequency and rTMS site (ie, high-frequency rTMS at other frontal regions: SMD, 0.23; 95% CI, -0.02 to 0.48, and low primary motor cortex: SMD, 0.28; 95% CI, -0.23 to 0.78) were not significant. Meta-regression revealed that a greater number of pulses per session or across sessions is associated with larger rTMS effects. Using the Grading of Recommendations, Assessment, Development, and Evaluation criteria, we characterized the quality of evidence presented in this meta-analysis as moderate quality.The pooled evidence suggests that rTMS improves motor symptoms for patients with PD. Combinations of rTMS site and frequency as well as the number of rTMS pulses are key modulators of rTMS effects. The findings of our meta-analysis may guide treatment decisions and inform future research.
Improved turn around time for molecular genetic analysis for cystic fibrosis: The Irish experience
Authors: Frances Flanagan, Louisa Glackin, Dubhfeasa Slattery
Journal: European Respiratory Journal (2011)

Introduction: Ireland's Cystic Fibrosis (CF) newborn screening programme is due to commence later in 2011 using immune reactive trypsinogen & genetic analysis for the detection of cystic fibrosis transmembrane regulator protein (CFTR) mutations. The National Centre for Medical Genetics screens for 11 CFTR mutations & further analysis for rarer mutations is currently performed in Manchester (using gene sequencing & multiplex ligation-dependant probe amplification (MLPA) testing). Prior to 2008 this further analysis was performed in Exeter & subsequently in Brest.

Aim: To identify the turn-around time for genetic analysis results for children with suspected CF

Methods: A 16 year retrospective study of genetic analysis results for CFTR mutations was performed. The turn-around time was defined as the number of days from sending DNA until reports were received. Descriptive statistics were used.

Results: Overall, the median time to receive genetic analysis results was 23 days, range 1-2434 days (n=91). The median turn-around time for the identification of 2 positive CFTR mutations was 21 days, range 1-1973 days. The most common identified mutation, Phe508del/Phe508del, had the shortest median turn around time of 18 days, range 1-107 days. Three patients initially suspected of having CF & with 2 positive sweat tests, did not have any CFTR mutations identified (median time 2252 days, range 229-2434 days).

Conclusion: Recent technological advancements allow for more detailed genetic analysis to be performed, identifying newer CFTR mutations over a shorter time period. The introduction of newborn screening & extended CFTR genetic analysis will ensure that the time to CF diagnosis is greatly improved.
Obesity in psoriasis: leptin and resistin as mediators of cutaneous inflammation
Authors: A. Johnston, S. Arnadottir, J.E. Gudjonsson, A. Aphale, A.A. Sigmarsdottir, S.I. Gunnarsson, J.T. Steinsson, J.T. Elder, H. Valdimarsson
Journal: British Journal of Dermatology (2008)

Obesity is a significant risk factor for psoriasis and body mass index (BMI) correlates with disease severity. Objectives To investigate the relationship between obesity and psoriasis, focusing on the role of adipokines such as leptin and resistin.Patients with psoriasis (n = 30) were recruited and their BMI, waist circumference and disease severity [Psoriasis Area and Severity Index (PASI)] were recorded. Fasting serum samples were obtained on enrolment and after a course of ultraviolet (UV) B treatment. Age-, sex- and BMI-matched healthy controls were also recruited.On enrolment, serum leptin and soluble leptin receptor levels were not raised compared with the controls. However, resistin, interleukin (IL)-1beta, IL-6, and chemokines CCL2, CXCL8 and CXCL9 were all significantly elevated in the patient group and serum resistin correlated with disease severity (r = 0.372, P = 0.043). Improvement after UVB treatment was accompanied by decreased serum CXCL8. In vitro, both leptin and resistin could induce CXCL8 and tumour necrosis factor-alpha production by blood monocytes, and leptin could additionally induce IL-1beta and IL-1 receptor antagonist production. Leptin also dose dependently increased secretion of the growth factor amphiregulin by ex vivo-cultured lesional psoriasis skin.These data support the view that leptin and resistin may be involved in the pathogenesis of psoriasis in overweight individuals, possibly by augmenting the cytokine expression by the inflammatory infiltrate.
Symptoms of anxiety and depression in childhood and use of MDMA: prospective, population based study
Authors: Anja C Huizink, Robert F Ferdinand, Jan van der Ende, Frank C Verhulst
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To investigate whether using ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is preceded by symptoms of behavioural and emotional problems in childhood and early adolescence. <b>Design</b> Prospective, longitudinal, population based study. <b>Setting The Dutch province of Zuid-Holland. Participants</b> A sample of 1580 individuals, followed up across a 14 year period, from childhood into adulthood. <b>Main outcome measures</b> The first assessment took place in 1983 before MDMA appeared as a recreational drug in the Netherlands and included the child behaviour checklist to obtain standardised parents9 reports of their children9s behavioural and emotional problems. Use of the drug was assessed with the composite international diagnostic interview 14 years later. <b>Results</b> Eight syndrome scales of childhood behaviour were examined. Scores in the deviant range for the scales designated as anxious or depressed in childhood were significantly related to use of MDMA in adolescents and adults, resulting in an increased risk (hazard ratio 2.22, 95% confidence interval 1.20 to 4.11, P = 0.01). <b>Conclusions</b> Individuals with childhood symptoms of anxiety and depression may have an increased tendency to use MDMA in adolescence or young adulthood. Its effects are supposed to include enhanced feelings of bonding with other people, euphoria, or relaxation. Especially individuals with symptoms of anxiety or depression may be susceptible to these positive effects.
Plasma Adiponectin and Endogenous Glucose Production in Humans
Authors: Norbert Stefan, Michael Stumvoll, Barbora Vozarova, Christian Weyer, Tohru Funahashi, Yuji Matsuzawa, Clifton Bogardus, P. Antonio Tataranni
Journal: Diabetes Care (2003)

OBJECTIVE—High plasma adiponectin is associated with reduced risk of type 2 diabetes, probably a consequence of its insulin-sensitizing properties. In vivo data in rodents suggest that the insulin-sensitization responsible for improvement of glycemia occurs in muscle and liver. Whereas associations of plasma adiponectin with muscle insulin sensitivity in humans have been examined, this has not been done for the liver. RESEARCH DESIGN AND METHODS—We therefore analyzed the relationship between fasting plasma adiponectin and basal endogenous glucose production [EGP]-basal) and insulin-suppressed EGP (EGP-insulin, isotope dilution technique) in 143 Pima Indians (94 with normal glucose tolerance, 36 with impaired glucose tolerance, and 16 with type 2 diabetes). RESULTS—Fasting plasma adiponectin concentrations were negatively correlated with EGP-basal and EGP-insulin before (P = 0.006 and P &amp;lt; 0.0001, respectively) as well as after adjustment for age, sex, percent body fat, and insulin-stimulated whole-body glucose uptake (P = 0.007 and P = 0.0005, respectively). CONCLUSIONS—These findings are compatible with the hypothesis that adiponectin increases hepatic insulin sensitivity. Consistent with data in animals, adiponectin may have generalized insulin-sensitizing effects in humans.
Profound atrophy of the bone marrow reflecting major histocompatibility complex class II-restricted destruction of stem cells by CD4+ cells.
Authors: J Sprent, C D Surh, D Agus, M Hurd, S Sutton, W R Heath
Journal: The Journal of Experimental Medicine (1994)

The effector functions of CD4+ cells in vivo are presumed to reflect a combination of lymphokine-mediated bystander reactions and direct cytotoxic T lymphocyte activity. To assess the relative importance of these two mechanisms, we studied the effects of transferring small doses of purified unprimed CD4+ cells to lightly irradiated (600 cGy) recipients expressing major histocompatibility complex class II (Ia) differences. Within the first week after transfer, the host marrow was rapidly repopulated with hemopoietic cells. Thereafter, however, the donor CD4+ cells caused massive destruction of hemopoietic cells, both in marrow and spleen. Marrow aplasia did not affect stromal cells and was prevented by coinjecting donor but not host bone marrow. The use of allotypic markers and fluorescence-activated cell sorter analysis indicated that the destructive effects of CD4+ cells were directed selectively to host Ia+ hemopoietic cells, including stem cells; donor hemopoietic cells and Ia- host T cells were spared. No evidence could be found that the ongoing destruction of host cells impaired the capacity of donor stem cells to repopulate marrow, spleen, or thymus. Moreover, CD4+ cells failed to destroy host-type hemopoietic cells from Ia-deficient mice. Tissue destruction by CD4+ cells thus did not seem to reflect a bystander reaction. We conclude that, under defined conditions, CD4+ cells can manifest extremely potent Ia-restricted CTL activity in vivo, probably through recognition of covert Ia expression on stem cells and/or their immediate progeny.
<i>Pi3kcb</i> Links Hippo-YAP and PI3K-AKT Signaling Pathways to Promote Cardiomyocyte Proliferation and Survival
Authors: Zhiqiang Lin, Pingzhu Zhou, Alexander von Gise, Fei Gu, Qing Ma, Jinghai Chen, Haidong Guo, Pim R.R. van Gorp, Da-Zhi Wang, William T. Pu
Journal: Circulation Research (2014)

Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence-specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined.To identify direct YAP targets that mediate its mitogenic and antiapoptotic effects in the heart.We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP-bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase, as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEA-domain occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the phosphoinositol-3-kinase-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by adeno-associated virus-mediated Pik3cb expression.Pik3cb is a crucial direct target of YAP, through which the YAP activates phosphoinositol-3-kinase-AKT pathway and regulates cardiomyocyte proliferation and survival.