tbuckley/cabot-search huggingface dataset:
Dynamics of Senescent Cell Formation and Retention Revealed by p14ARF Induction in the Epidermis
Authors: Ronit Tokarsky-Amiel, Narmen Azazmeh, Aharon Helman, Yan Stein, Alia Hassan, Alexander Maly, Ittai Ben-Porath
Journal: Cancer Research (2013)

Cellular senescence, a state of cell-cycle arrest accompanied by dramatic morphologic and metabolic changes, is a central means by which cells respond to physiologic stress and oncogene activity. Senescence is thought to play important roles in aging and in tumor suppression, yet the dynamics by which senescent cells are formed, their effects on tissue function and their eventual fate are poorly understood. To study cellular senescence within an adult tissue, we developed transgenic mice inducibly expressing p14(ARF) (human ortholog of murine p19(ARF)), a central activator of senescence. Induction of p14(ARF) in the epidermis rapidly led to widespread apoptosis and cell-cycle arrest, a stage that was transient, and was followed by p53-dependent cellular senescence. The endogenous Cdkn2a products p19(ARF) and p16(Ink4a) were activated by the transgenic p14(ARF) through p53, revealing a senescence-promoting feed-forward loop. Commitment of cells to senescence required continued p14(ARF) expression, indicating that entry into this state depends on a persistent signal. However, once formed, senescent cells were retained in the epidermis, often for weeks after transgene silencing, indicating an absence of an efficient rapidly acting mechanism for their removal. Stem cells in the hair follicle bulge were largely protected from apoptosis upon p14(ARF) induction, but irreversibly lost their ability to proliferate and initiate follicle growth. Interestingly, induction of epidermal hyperplasia prevented the appearance of senescent cells upon p14(ARF) induction. Our findings provide basic insights into the dynamics of cellular senescence, a central tumor- suppressive mechanism, and reveal the potential for prolonged retention of senescent cells within tissues.
Inhibition of MRP4 prevents and reverses pulmonary hypertension in mice
Authors: Yannis Hara, Yassine Sassi, Christelle Guibert, Natacha Gambaryan, Peter Dorfmüller, Saadia Eddahibi, Anne-Marie Lompré, Marc Humbert, Jean-Sébastien Hulot
Journal: Journal of Clinical Investigation (2011)

Multidrug resistance-associated protein 4 (MRP4, also known as Abcc4) regulates intracellular levels of cAMP and cGMP in arterial SMCs. Here, we report our studies of the role of MRP4 in the development and progression of pulmonary arterial hypertension (PAH), a severe vascular disease characterized by chronically elevated pulmonary artery pressure and accompanied by remodeling of the small pulmonary arteries as a prelude to right heart failure and premature death. MRP4 expression was increased in pulmonary arteries from patients with idiopathic PAH as well as in WT mice exposed to hypoxic conditions. Consistent with a pathogenic role for MRP4 in PAH, WT mice exposed to hypoxia for 3 weeks showed reversal of hypoxic pulmonary hypertension (PH) following oral administration of the MRP4 inhibitor MK571, and Mrp4-/- mice were protected from hypoxic PH. Inhibition of MRP4 in vitro was accompanied by increased intracellular cAMP and cGMP levels and PKA and PKG activities, implicating cyclic nucleotide-related signaling pathways in the mechanism underlying the protective effects of MRP4 inhibition. Our data suggest that MRP4 could represent a potential target for therapeutic intervention in PAH.
Six Months of Diazoxide Treatment at Bedtime in Newly Diagnosed Subjects With Type 1 Diabetes Does Not Influence Parameters of β-Cell Function and Autoimmunity but Improves Glycemic Control
Authors: Maria Anita Radtke, Ingrid Nermoen, Magnus Kollind, Svein Skeie, Jan Inge Sørheim, Johan Svartberg, Ingrid Hals, Torolf Moen, Gry Høst Dørflinger, Valdemar Grill
Journal: Diabetes Care (2009)

OBJECTIVE Continuous β-cell rest with diazoxide preserves residual endogenous insulin production in type 1 diabetes. However, side effects have hampered therapeutic usefulness. In a double-blind study, we tested whether lower, intermittent dosing of diazoxide had beneficial effects on insulin production, metabolic control, and autoimmunity markers in the absence of side effects. RESEARCH DESIGN AND METHODS Forty-one newly diagnosed type 1 diabetic patients were randomized to 6 months of treatment with placebo or 100 mg diazoxide at bedtime. A1C, C-peptide (fasting and glucagon stimulated), and FoxP3+ regulatory T-cells (Tregs) were measured. Patients were followed for 6 months after intervention. RESULTS Of six dropouts, three were due to perceived side effects; one subject in the diazoxide group experienced rash, another dizziness, and one in the placebo group sleep disturbance. Adverse effects in others were absent. Diazoxide treatment reduced A1C from 8.6% at baseline to 6.0% at 6 months and 6.5% at 12 months. Corresponding A1C value in the placebo arm were 8.3, 7.3, and 7.5% (P &amp;lt; 0.05 for stronger reduction in the diazoxide group). Fasting and stimulated C-peptide decreased during 12 months similarly in both arms (mean −0.30 and −0.18 nmol/l in the diazoxide arm and −0.08 and −0.09 nmol/l in the placebo arm). The proportion of Tregs was similar in both arms and remained stable during intervention but was significantly lower compared with nondiabetic subjects. CONCLUSIONS Six months of low-dose diazoxide was without side effects and did not measurably affect insulin production but was associated with improved metabolic control.
Therapeutic Embolization With Detachable Silicone Balloons
Authors: Robert I. White
Journal: JAMA (1979)

A recently developed percutaneous transcatheter technique for selectively occluding arteries with detachable silicone balloons was applied in four patients. Uncontrollable hemorrhage from carcinoma of the cervix was controlled by selective uterine artery occlusion in one patient. Life-threatening hemorrhage from cystic fibrosis in another patient was controlled by balloon occlusion of a bronchial artery. A patient with hypernephroma and another with right ischial fibrous histiocytoma each had preoperative occlusion of the arteries supplying the neoplasms to reduce operative blood loss and to obviate the need for surgical ligation of the internal iliac artery in the latter patient. Detachable balloon embolization techniques represent a nonoperative method for permanently occluding arteries without the risks of inadvertent embolization.
Effect of a twelve week exercise programme on cardio-respiratory and body composition variables in non-obese young and middle-aged females
Authors: Gail M. White, R. J. Young
Journal: British Journal of Sports Medicine (1978)

This study investigated the effect of a 12-week exercise programme consisting of jogging, calistnenics, and recreational activities on the cardiorespiratory function and body composition of 15 young and 15 middle-aged nonobese women 21-32 and 34-57 years, respectively. The exercise programme was 3 days per week for an average of 45 minutes each session. Pre- and post-programme data were obtained on: age, height, total body weight, resting heart rate, systolic and diastolic blood pressure, vital capacity, submaximal heart rate, supra-iliac skinfold, thigh skinfold, waist girth, cup size, body density, and percent fat. The t-test was used to test the difference between the young and middle-aged groups before and after the exercise programme and to test the pre- and post-programme mean values of each group. No differences between the groups or changes due to the exercise programme were observed on total body weight. No significant cardiorespiratory differences were found between the two groups at either test period, however, the young group decreased significantly (p &lt; .01) in submaximal HR and the middle-aged group decreased significantly in resting (p &lt; .01) and submaximal (p &lt; .001) HR illustrating the positive effect of the programme. No significant body composition differences were found between the two groups at the pre-test. At the post-test the middle-aged group had a significantly (p &lt; .10) larger thigh skinfold thickness than the young group. The young group did not change significantly on body composition measures from pre- to post-test. In contrast, the middle-aged group increased significantly in body density (p &lt; .01) and decreased in percent body fat (p &lt; .01) due to a significant (p &lt; .01) reduction in supra-iliac skinfold thickness from 21.67 ± 2.35 to 18.13 ± 2.08 mm. The data were compared with data from other studies using similar age groups. The pre-test percent fat of the young group (25.07 ± .74) was similar to values reported in other studies. The middle-aged group had a relatively lower fat percentage (27.46 ± 1.58) compared with other middle-aged groups.
Prostate cancer cell–stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases
Authors: Xinhai Wan, Paul G. Corn, Jun Yang, Nallasivam Palanisamy, Michael W. Starbuck, Eleni Efstathiou, Elsa M. Li Ning Tapia, Amado J. Zurita, Ana Aparicio, Murali K. Ravoori, Elba S. Vazquez, Dan R. Robinson, Yi-Mi Wu, Xuhong Cao, Matthew K. Iyer, Wallace McKeehan, Vikas Kundra, Fen Wang, Patricia Troncoso, Arul M. Chinnaiyan, Christopher J. Logothetis, Nora M. Navone
Journal: Science Translational Medicine (2014)

Dovitinib is therapeutically active in a subset of patients with prostate cancer bone metastases, partly due to blockade of FGFR-mediated stromal-epithelial interactions in the bone microenvironment.
TRIFLUOPERAZINE IN CHILDREN AND ADOLESCENTS WITH MARKED BEHAVIOR PROBLEMS
Authors: S. WAYNE SMITH
Journal: American Journal of Psychiatry (1965)

In the treatment of 38 emotionally disturbed children and adolescents, one-fifth had Marked Improvement, over half had Moderate Improvement, and one-fifth had Unsatisfactory Improvement. Side effect of slight sleepiness or dizziness occurred in 24%. Trifluoperazine provided the means of reducing hyperactivity, anxiety, and aggressiveness. The drug helped these children become receptive to counseling and other supportive measures, to schooling, to work therapies and to interpersonal relationships.
advances for treating in-hospital cardiac arrest: safety and effectiveness of a new automatic external cardioverter-defibrillator
Authors: Antoni Martínez-Rubio, Nabil Kanaan, Martin Borggrefe, Michael Block, Markku Mäkijärvi, Francesco Fedele, Carlo Pappone, Wilhelm Haverkamp, José Luis Merino, Gonzalo Barón Esquivias, Juan Cinca
Journal: Journal of the American College of Cardiology (2003)
The System of Group-Centered Psychotherapy for Neurotics in Czechoslovakia
Authors: FERDINAND KNOBLOCH
Journal: American Journal of Psychiatry (1968)

The provision of adequate psychotherapeutic help to all who can benefit from it is perhaps a major problem in all civilized countries. The author reports on a system for the treatment of the neuroses established in Prague as part of the Czechoslovak Health Services, which he recommends as a model for community-based mental health services. A mong the advantages of the system, he feels, are its efficiency in the use of both professional and nonprofessional manpower and an emphasis upon interpersonal circuits of behavior, overcoming the one-person model of mental life.
Multiple venous thrombosis in SAPHO syndrome
Authors: T Kawabata
Journal: Annals of the Rheumatic Diseases (2004)

A 42 year old Japanese woman presented to our clinic complaining of severe pain in her neck, both shoulders, and lumbar spine. She had had pustulosis palmaris and plantaris from age 16 and recurrent painful swelling of the clavicles, the sternoclavicular joints, and the sternum from age 25. She reported multiple visits to the doctor for similar symptoms, and she was treated with non-steroidal anti-inflammatory drugs.

On initial examination at our clinic, her lumbar and cervical spine mobility was limited considerably. She had an oedematous face and subcutaneous collateral circulation on chest and abdomen. Laboratory testing showed a white cell count of 13.5×109/l and a C reactive protein of 142 mg/l (normal <5). Antinuclear antibodies, antineutrophil cytoplasmic antibodies, anticardiolipin antibodies, lupus anticoagulants, and rheumatoid factors were all negative. Prothrombin time and …
Suppression of Signal Transducer and Activator of Transcription 3–Dependent B Lymphocyte Terminal Differentiation by Bcl-6
Authors: Rajko Reljic, Simon D. Wagner, Luke J. Peakman, Douglas T. Fearon
Journal: The Journal of Experimental Medicine (2000)

Lymphocytes usually differentiate into effector cells within days after antigen exposure, except in germinal centers where terminal differentiation is delayed while somatic hypermutation creates high-affinity antibody mutants. Here we investigate whether arrest of terminal differentiation can be mediated by BCL-6, a transcriptional repressor that is expressed by germinal center B cells and is required for this phase of B cell development. We find that BCL-6 suppresses the differentiation of transformed and primary B cells to plasma cells by inhibiting the signal transducer and activator of transcription 3–dependent expression of the major regulator of plasma cell development, the B lymphocyte–induced maturation protein (Blimp-1). This function of BCL-6 as a repressor of B lymphocyte differentiation may also underlie the association between chromosomal translocations of its gene and B cell lymphomas.
Plasma Proneurotensin as a Novel Biomarker for the Prediction of Incident Breast Cancer
Authors: O. Melander, A.S. Maisel, P. Almgren, M. Belting, U. Kilger, J. Struck, P. Nilsson, J. Manjer, A. Bergmann, M. Orho-Melander
Journal: Annals of Oncology (2013)
Autoantibodies in Patients with Chronic Obstructive Pulmonary Disease
Authors: Carol A. Feghali-Bostwick, Aneal S. Gadgil, Leo E. Otterbein, Joseph M. Pilewski, Michael W. Stoner, Eva Csizmadia, Yingze Zhang, Frank C. Sciurba, Steven R. Duncan
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Adaptive immune responses are present in patients with chronic obstructive pulmonary disease (COPD), and it has been postulated that these processes could be autoreactive.
Implication of Metastasis Suppressor <i>NM23-H1</i> in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells
Authors: Mathieu Boissan, Olivier De Wever, Floria Lizarraga, Dominique Wendum, Renaud Poincloux, Nicolas Chignard, Christèle Desbois-Mouthon, Sylvie Dufour, Béatrice Nawrocki-Raby, Philippe Birembaut, Marc Bracke, Philippe Chavrier, Christian Gespach, Marie-Lise Lacombe
Journal: Cancer Research (2010)

Loss of NM23-H1 expression correlates with the degree of metastasis and with unfavorable clinical prognosis in several types of human carcinoma. However, the mechanistic basis for the metastasis suppressor function of NM23-H1 is obscure. We silenced NM23-H1 expression in human hepatoma and colon carcinoma cells and methodologically investigated effects on cell-cell adhesion, migration, invasion, and signaling linked to cancer progression. NM23-H1 silencing disrupted cell-cell adhesion mediated by E-cadherin, resulting in β-catenin nuclear translocation and T-cell factor/lymphoid-enhancing factor-1 transactivation. Further, NM23-H1 silencing promoted cellular scattering, motility, and extracellular matrix invasion by promoting invadopodia formation and upregulating several matrix metalloproteinases (MMP), including membrane type 1 MMP. In contrast, silencing the related NM23-H2 gene was ineffective at promoting invasion. NM23-H1 silencing activated proinvasive signaling pathways involving Rac1, mitogen-activated protein kinases, phosphatidylinositol 3-kinase (PI3K)/Akt, and src kinase. Conversely, NM23-H1 was dispensable for cancer cell proliferation in vitro and liver regeneration in NM23-M1 null mice, instead inducing cellular resistance to chemotherapeutic drugs in vitro. Analysis of NM23-H1 expression in clinical specimens revealed high expression in premalignant lesions (liver cirrhosis and colon adenoma) and the central body of primary liver or colon tumors, but downregulation at the invasive front of tumors. Our findings reveal that NM23-H1 is critical for control of cell-cell adhesion and cell migration at early stages of the invasive program in epithelial cancers, orchestrating a barrier against conversion of in situ carcinoma into invasive malignancy.
Effects of Angiotensin I and Angiotensin II on Canine Hepatic Vascular Resistance
Authors: JOSEPH DI SALVO, STEVEN BRITTON, PATRICK GALVAS, THOMAS W. SANDERS
Journal: Circulation Research (1973)

The effects of angiotensin I (0.2-3.2 µg) and angiotensin II (0.1-1.6 µg) injections into the pump-perfused arterial supply of the liver were studied in dogs anesthetized with sodium pentobarbital. Marked increases in hepatic artery perfusion pressure (10-50%), reflecting directionally similar changes in resistance to blood flow, were caused by either angiotensin I or angiotensin II. Resistance increases produced by angiotensin I were significantly attenuated by the synthetic nonapeptide SQ 20881 (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro, 50 µg/kg, iv) that inhibits enzymatic conversion of angiotensin I to angiotensin II. In contrast, responses caused by angiotensin II were unaltered by SQ 20881. However, resistance increases caused by either angiotensin I or angiotensin II were blocked by 1-Sar-8-Ala-angiotensin II (100 µg/kg min -1 , ia), a specific angiotensin II antagonist. These findings parallel the finding that responses to angiotensin I in the vasculature supplied by the hepatic artery are largely caused by local enzymatic conversion of angiotensin I to angiotensin II. Such conversion appears to occur to the extent of about 46%.
Right pelvic mass in a patient with a radically resected carcinoid of the appendix
Authors: N Fazio, F Luca, L Monfardini, G Pelosi, L Bodei, K Lorizzo, G Di Meglio, B Gibelli, D Ravizza, G Bonomo, C M Grana, S Baio, M Squadroni, G Paganelli, F de Braud
Journal: Gut (2009)

A 22-year-old male patient with a radiologically detected right pelvic mass presented without any symptoms. Two years before he underwent appendectomy due to acute appendicitis elsewhere, and a carcinoid was incidentally diagnosed. Our revised histological report confirmed a conventional carcinoid of the appendix, excluding a goblet cell carcinoid (adenocarcinoid). The tumour infiltrated the whole wall thickness without serosal invasion; margins were negative; the macroscopic size of the tumour had been omitted in the original pathology report.

Immunohistochemical chromogranin-A, neuron specific enolase, and synaptophysin were positive. Follow-up was negative over the two subsequent …
Narcotics and Cancer Pain Control
Authors: C. S. Hill
Journal: CA A Cancer Journal for Clinicians (1988)

In the past two decades, improved cancer treatment has caused more patients to be cured and brought longer survival to those not cured.Nevertheless, a significant num ber remain ill, troubled by a wide variety of symptoms as the disease progresses.Pain, nausea and vomiting, anorexia, weakness, insomnia, and failure to thrive are the most important; of this group, pain is probably the outstanding symptom, the one patients dread most.As the tumor grows and spreads, the pain becomes dif fuse.Most likely, the pain originates from several sources, and removing the cause is impossible, making systemic analgesics the mainstay of treatment for this type of pain.At the same time, however, our under standing of pain has grown.We have found the opiate-(narcotic-) binding sites in the central nervous system and the naturally occurring ligands for these binding sites.We know the mechanisms of spinal cord modulation of pain, and we have a better understanding of neuropathic and deaffer entation pains and central pain states.We know that some pains are partially or totally unresponsive to opiates, and we are devel oping drugs for binding at specific opiate
Comparison of Antiplatelet Effects of Aspirin, Ticlopidine, or Their Combination After Stent Implantation
Authors: Hans J. Rupprecht, Harald Darius, Ulrike Borkowski, Thomas Voigtländer, Bernd Nowak, Sabine Genth, Jürgen Meyer
Journal: Circulation (1998)

Background —This study was performed to analyze the influence of either aspirin, ticlopidine, or their combination on platelet activation and aggregation parameters after stent implantation. Methods and Results —Sixty-one patients with successful implantation of a single Palmaz-Schatz stent in a native coronary artery were randomly assigned to either group A (aspirin 300 mg/d+ticlopidine 2×250 mg/d), group B (ticlopidine 2×250 mg/d), or group C (aspirin 300 mg/d). Platelet activation was evaluated on days 1, 7, and 14 by flow cytometry measurement of expression of CD62p (p-selectin) and the binding of fibrinogen to the platelet surface glycoprotein IIb/IIIa receptor. Platelet aggregation was induced by addition of ADP or collagen. Differences between treatment groups were compared by ANOVA. Between days 1 and 14, we observed a significant decrease in collagen-induced platelet aggregation in group A (62.2±2.5% versus 36.9±3.1%), whereas an increase was seen in group B (58.3±2.5% versus 67.7±3.2%) and no change was seen in group C ( P &lt;.0001). The ADP-induced aggregation declined significantly in group A (74.7±1.4% versus 55.3±2.6%), whereas a delayed reduction was seen in group B (72.0±3.0% versus 52.6±4.2%) and no change was seen in group C ( P =.0017). The CD62p expression declined significantly in groups A (68.2±2.7% versus 41.3±2.7%) and B (64.8±2.9% versus 39.3±3.5%) but not in group C ( P &lt;.0001). Moreover, the fibrinogen binding decreased significantly in group A (61.0±4.3% versus 36.3±4.2%) and with delay in group B (58.3±2.2% versus 39.4±3.0%), whereas no alterations were seen in group C ( P =.012). Conclusions —Our results demonstrate synergistic and accelerated platelet inhibitory effects of ticlopidine plus aspirin in patients after stent implantation compared with a monotherapy with either ticlopidine or aspirin alone.
Medication errors and confusion over labelling
Authors: R. J Hillier, S. P Kelly
Journal: Journal of the Royal Society of Medicine (2004)

Dr Wheeler and his colleagues (August 2004 JRSM1) make a strong case for standardized labelling to avoid confusion over ratios and percentages in drug solutions. May we draw attention to another potential source of confusion in relation to drug labelling. The unlabelled ampoule in Figure 1, which we presume to have contained Betnesol (betamethasone), was taken out of its packaging during routine cataract surgery for planned periocular injection. Theatre staff reacted appropriately by discarding it, and we reported the incident to the Medicines and Healthcare products Regulatory Agency. We also advised the manufacturers. The absence of a label was due to a manufacturing error, fortunately not coupled with the loss of coloured bands which do help to distinguish it from other products. However, this picture illustrates another potent source of error. Even when intravenous medications are correctly labelled, the similarity between their appearances is an example of a latent or potential systems failure.



Figure 1

An assortment of ampoules, including one accidentally unlabelled. Colour version available on [www.jrsm.org]
Clinical Outcomes of Catheter Substrate Ablation for High-Risk Patients With Atrial Fibrillation
Authors: Koonlawee Nademanee, Mark C. Schwab, Erol M. Kosar, Margaret Karwecki, Michael D. Moran, Nithi Visessook, Anthony Don Michael, Tachapong Ngarmukos
Journal: Journal of the American College of Cardiology (2008)