tbuckley/cabot-search huggingface dataset:
Development, Prevention, and Potential Reversal of Left Ventricular Hypertrophy in Chronic Kidney Disease
Authors: Lawrence P. McMahon, Simon D. Roger, Adeera Levin
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Although a high prevalence of left ventricular (LV) hypertrophy is recognized with increasing severity of chronic kidney disease (CKD), previously neither its progression nor its potential for prevention or reversal has been addressed adequately in this population group. A nested analysis of a 2-yr study involving 155 patients with stage 3/4 CKD, examining effects of hemoglobin change (range, 90 to 130 g/L) on LV mass in patients with (n = 46; 30%) and without (n = 105; 70%) initial LV hypertrophy, is reported. At baseline, the group with LV hypertrophy was older (P < 0.01), had higher BP (P < 0.01), had greater LV wall and cavity dimensions (P < 0.001), and had more prevalent use of antihypertensive agents (P < 0.001) but a lower hemoglobin concentration (P < 0.05) and GFR (P < 0.01). A total of 117 patients were available for assessment at 2 yr. Importantly, 57 (68%) with initial normal LV indices showed no appreciable change with time; however, 27 (32%) developed LV hypertrophy, with growth in both wall and cavity dimensions (P < 0.001). In contrast, 23 (50%) of those with initial LV hypertrophy maintained elevated LV indices, whereas 10 (22%) regressed, through wall but not cavity reduction, to within normal LV indices. Predisposing factors to maintaining or achieving normal LV mass dimensions included relative youth (P < 0.05), a lower pulse pressure (P < 0.05), and a higher GFR (P < 0.05) but not hemoglobin concentration or parathyroid hormone levels. These findings suggest that even at a relatively advanced stage of renal dysfunction, control of BP and volume, together with regulated metabolic and clinical indices, may contribute to the prevention or even reversal of LV hypertrophy in a substantial proportion of patients.
15-Lipoxygenase expression and 15(S)-hydroxyeicoisatetraenoic acid release and reincorporation in induced sputum of asthmatic subjects
Authors: Mirella Profita, Angelo Sala, Loredana Riccobono, Alessandra Paternò, Angela Mirabella, Anna Bonanno, Daniela Guerrera, Elisabetta Pace, Giovanni Bonsignore, Jean Bousquet, Antonio M. Vignola
Journal: Journal of Allergy and Clinical Immunology (2000)
Coupling of β <sub>2</sub> -Adrenoceptor to G <sub>i</sub> Proteins and Its Physiological Relevance in Murine Cardiac Myocytes
Authors: Rui-Ping Xiao, Pavel Avdonin, Ying-Ying Zhou, Heping Cheng, Shahab A. Akhter, Thomas Eschenhagen, Robert J. Lefkowitz, Walter J. Koch, Edward G. Lakatta
Journal: Circulation Research (1999)

Abstract —Transgenic mouse models have been developed to manipulate β-adrenergic receptor (βAR) signal transduction. Although several of these models have altered βAR subtypes, the specific functional sequelae of βAR stimulation in murine heart, particularly those of β 2 -adrenergic receptor (β 2 AR) stimulation, have not been characterized. In the present study, we investigated effects of β 2 AR stimulation on contraction, [Ca 2+ ] i transient, and L-type Ca 2+ currents ( I Ca ) in single ventricular myocytes isolated from transgenic mice overexpressing human β 2 AR (TG4 mice) and wild-type (WT) littermates. Baseline contractility of TG4 heart cells was increased by 3-fold relative to WT controls as a result of the presence of spontaneous β 2 AR activation. In contrast, β 2 AR stimulation by zinterol or isoproterenol plus a selective β 1 -adrenergic receptor (β 1 AR) antagonist CGP 20712A failed to enhance the contractility in TG4 myocytes, and more surprisingly, β 2 AR stimulation was also ineffective in increasing contractility in WT myocytes. Pertussis toxin (PTX) treatment fully rescued the I Ca , [Ca 2+ ] i , and contractile responses to β 2 AR agonists in both WT and TG4 cells. The PTX-rescued murine cardiac β 2 AR response is mediated by cAMP-dependent mechanisms, because it was totally blocked by the inhibitory cAMP analog Rp-cAMPS. These results suggest that PTX-sensitive G proteins are responsible for the unresponsiveness of mouse heart to agonist-induced β 2 AR stimulation. This was further corroborated by an increased incorporation of the photoreactive GTP analog [γ- 32 P]GTP azidoanilide into α subunits of G i2 and G i3 after β 2 AR stimulation by zinterol or isoproterenol plus the β 1 AR blocker CGP 20712A. This effect to activate G i proteins was abolished by a selective β 2 AR blocker ICI 118,551 or by PTX treatment. Thus, we conclude that (1) β 2 ARs in murine cardiac myocytes couple to concurrent G s and G i signaling, resulting in null inotropic response, unless the G i signaling is inhibited; (2) as a special case, the lack of cardiac contractile response to β 2 AR agonists in TG4 mice is not due to a saturation of cell contractility or of the cAMP signaling cascade but rather to an activation of β 2 AR-coupled G i proteins; and (3) spontaneous β 2 AR activation may differ from agonist-stimulated β 2 AR signaling.
Coexistence of beta 1- and beta 2-adrenoceptors in human right atrium. Direct identification by (+/-)-[125I]iodocyanopindolol binding.
Authors: O E Brodde, K Karad, H R Zerkowski, N Rohm, J C Reidemeister
Journal: Circulation Research (1983)

The highly specific beta-adrenoceptor radioligand, (+/-)-[125I]iodocyanopindolol, has been used to subclassify beta-adrenoceptors in membranes from human right atrial appendage obtained during open heart surgery. Binding of (+/-)-[125I]iodocyanopindolol was saturable (Bmax = 86.4 +/- 7.4 fmol (+/-)-[125I]iodocyanopindolol bound/mg protein, n = 4), of high affinity (KD = 53 +/- 6 pM, n = 4), rapid, reversible, and stereospecific. The relative potencies of isoprenaline, adrenaline, and noradrenaline for inhibition of (+/-)-[125I]iodocyanopindolol binding and activation of adenylate cyclase were 1:10:10, indicating a population composed mainly of beta 1-adrenoceptors. Inhibition of (+/-)-[125I]iodocyanopindolol binding by beta 1- (practolol, metoprolol, betaxolol) and beta 2- (IPS 339, ICI 118,551, zinterol, procaterol) selective drugs, however, resulted in biphasic displacement curves with slope factors (nH, pseudo Hill coefficients) significantly less than 1.0. Nonlinear regression analysis of these curves revealed a beta 1: beta 2 ratio of 80:20 in human right atrial appendage. Nonselective beta-adrenergic drugs (propranolol, isoprenaline, and adrenaline), on the contrary, inhibited binding with monophasic displacement curves and nH = 1.0. Binding of agonists to the beta-adrenoceptors in human right atrial appendage seems to be regulated by guanyl nucleotides. In the absence of GTP, isoprenaline binds to high and low affinity state of the beta-adrenoceptors. GTP (10(-4) M) converts this heterogeneous binding into a homogeneous one of low affinity. It is concluded that, in human right atria, beta 1- and beta 2-adrenoceptors coexist; however, beta 1-adrenoceptors predominate. The physiological function of beta 2-adrenoceptors in human right atrium remains to be elucidated.
A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors
Authors: S. Sharma, V. Abhyankar, R.E. Burgess, J. Infante, R.C. Trowbridge, J. Tarazi, S. Kim, M. Tortorici, Y. Chen, R.L. Robles
Journal: Annals of Oncology (2009)
Video. Micromanipulation of gametes and embryos: biopsy of a blastomere from an 8-cell human embryo
Authors: S Munne
Journal: Human Reproduction Update (1997)

The preimplantation diagnosis of genetic disease in preimplantation human embryos was introduced several years ago. It involves removing one or more cells from a cleaving embryo or a blastocyst, and then assessing the isolated cells for evidence of chromosomal anomalies or genetic disease, usually by means of fluorescence in-situ hybridization (FISH), the polymerase chain reaction (PCR) and variants of it. The whole diagnostic procedure can be completed within one day, and correctly diagnosed embryos then replaced in the mother’s uterus. The number of correctly-diagnosed children is now accumulating as more clinics introduce this procedure into their practice. Details of PCR and FISH can be found in various publications (e.g. Delhanty and Handyside,1995). One form of operation is to remove a single blastomere from an 8-cell embryo, and this is the procedure shown in this video. This procedure is demonstrated on two approximately 8-cell human embryos growing in vitro. A series of steps are involved in the process. The initial step is to make a hole in the zona pellucida, and so permit the passage of pipettes through this investment. Access is thus gained to the enclosed embryo. Two examples are shown on this video. The first example illustrates a standard operation, from the drilling of the zona pellucida to the gentle loosening and withdrawal of a single blastomere. The second example is concerned with the problems arising when the first blastomere is damaged during the procedure, and it becomes essential to biopsy a second blastomere.
Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor α by inhibiting NF-κB signaling pathway
Authors: Chenghai Li, Zhengfeng Yang, Chunyan Zhai, Wenwei Qiu, Dali Li, Zhengfang Yi, Lei Wang, Jie Tang, Min Qian, Jian Luo, Mingyao Liu
Journal: Molecular Cancer (2010)

Tumor necrosis factor alpha (TNFalpha) has been used to treat certain tumors in clinic trials. However, the curative effect of TNFalpha has been undermined by the induced-NF-kappaB activation in many types of tumor. Maslinic acid (MA), a pharmacological safe natural product, has been known for its important effects as anti-oxidant, anti-inflammatory, and anti-viral activities. The aim of this study was to determine whether MA potentiates the anti-tumor activity of TNFalpha though the regulation of NF-kappaB activation.In this study, we demonstrate that MA significantly enhanced TNFalpha-induced inhibition of pancreatic cancer cell proliferation, invasion, and potentiated TNFalpha-induced cell apoptosis by suppressing TNFalpha-induced NF-kappaB activation in a dose- and time-dependent manner. Addition of MA inhibited TNFalpha-induced IkappaBalpha degradation, p65 phosphorylation, and nuclear translocation. Furthermore, MA decreased the expression levels of NF-kappaB-regulated genes, including genes involved in tumor cell proliferation (Cyclin D1, COX-2 and c-Myc), apoptosis (Survivin, Bcl-2, Bcl-xl, XIAP, IAP-1), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). In athymic nu/nu mouse model, we further demonstrated that MA significantly suppressed pancreatic tumor growth, induced tumor apoptosis, and inhibited NF-kappaB-regulated anti-apoptotic gene expression, such as Survivin and Bcl-xl.Our data demonstrate that MA can potentiate the anti-tumor activities of TNFalpha and inhibit pancreatic tumor growth and invasion by activating caspase-dependent apoptotic pathway and by suppressing NF-kappaB activation and its downstream gene expression. Therefore, MA together with TNFalpha could be new promising agents in the treatment of pancreatic cancer.
Low-grade astrocytoma: a decade of experience at St. Jude Children's Research Hospital.
Authors: A Gajjar, R A Sanford, R Heideman, J J Jenkins, A Walter, Y Li, J W Langston, M Muhlbauer, J M Boyett, L E Kun
Journal: Journal of Clinical Oncology (1997)

PURPOSE To evaluate the impact of primary tumor site, age at diagnosis, extent of resection, and histology on progression-free survival (PFS) in pediatric low-grade astrocytoma. PATIENTS AND METHODS Medical, pathologic, and imaging information were reviewed for 142 children (ages 2 months to 19 years) with low-grade astrocytoma treated between January 1984 and July 1994. Gross total resection (GTR) was attempted for cerebellar and cerebral hemisphere tumors, with biopsy or less aggressive resection used predominantly for tumors in other sites. Surgery was followed by observation in 107 cases, radiation therapy in 31, and chemotherapy in four. RESULTS The overall survival rate was 90% +/- 3% (SE) at 4 years. PFS was significantly better for patients with cerebellar and cerebral hemisphere tumors (n = 75) than those with tumors in all other sites (P = .0006). Within the former group, there was no significant difference in PFS for patients in whom GTR was achieved versus those with incomplete resections (4-year estimates, 89% and 77%, respectively). Histology (juvenile pilocytic v astrocytoma not otherwise specified [NOS]) was not related to PFS in an analysis that controlled for tumor site and patient age. Patients younger than 5 years at diagnosis had a significantly poorer PFS than older children, regardless of histology (P &lt; .03) or tumor site (P &lt; .002). Treatment for progressive/recurrent disease was effective in a majority of patients, but appeared more successful in patients with hemispheric than thalamic or hypothalamic tumors. CONCLUSION The overall survival in this series of pediatric low-grade astrocytomas is excellent. Age at diagnosis and tumor location, but not histology, had a significant impact on PFS. Efforts to improve treatment outcome should focus on young patients (&lt; 5 years) and on those with central midline tumors. The majority of patients with completely resected hemispheric tumors were monitored without further therapy, which supports attempted GTR of cerebral and cerebellar hemisphere low-grade astrocytoma.
Wide-field computational imaging of pathology slides using lens-free on-chip microscopy
Authors: Alon Greenbaum, Yibo Zhang, Alborz Feizi, Ping-Luen Chung, Wei Luo, Shivani R. Kandukuri, Aydogan Ozcan
Journal: Science Translational Medicine (2014)

Lens-free holographic microscopy provides wide-field images with 3D focus adjustment of pathology slides for high-throughput and cost-effective human disease diagnostics.
Letter: Sequelae of virus infection in pregnancy.
Authors: J Donovan, A M Adelstein, P Leighton
Journal: BMJ (1974)

virtues of establish.edsimple treatment" (my italics).Bed rest is certainly effective,'0 but when carbenoxolone has been preposed as the "drug of choice" it would be prudent to mention that the drug actually confers no benefit on patients in bed."1As regards smoking, I agree that patients should be advised to stop."When this was done the reduction in ulcer crater size was 83 20/% in patients who stopped smoking and 71 8% in those who did not; it was only 56-6% in those not so advised.Interestingly, the reduotion was 61-3% in non-smokers.-Iam, etc.,
The HRCT scan pursuing real life pathology
Authors: R A Stockley
Journal: Thorax (2004)

HRCT scanning brings a new dimension to studies of COPD

The pathogenesis of chronic obstructive pulmonary disease (COPD) is widely considered to be the result of uncontrolled pulmonary inflammation. This is based on the original concept of a protease/antiprotease imbalance leading to peripheral tissue destruction and the development of emphysema. The premature development of emphysema in α1-antitrypsin deficiency gave rise to this hypothesis and led to an increasing field of research in the 1970s investigating the inflammation in emphysema using bronchoalveolar lavage. In addition, a series of in vitro experiments investigated the ability of enzymes to produce emphysema-like lesions and its prevention by proteinase inhibitors.1 More recently the smoking mouse and a series of gene knock-out and transgenic animals has explored not only the role of proteinases and inflammatory cells, but also proinflammatory cytokines, adhesion molecules, and growth factors in the development of emphysema.2

The study of upper airway secretions has indicated that inflammation is also present at this site, and several studies have demonstrated a proteinase/antiproteinase imbalance3,4 that is likely to influence the nature of airways disease, including development of bronchiectasis, mucus hypersecretion, and disturbances of mucociliary clearance.5 However, many patients do not expectorate spontaneously, and hence the process of sputum induction was applied to obtain samples from the upper airways in patients with COPD , as defined by the presence of airways obstruction. These studies have led to a change in direction concerning the important cellular and inflammatory proteins that are key to the pathogenesis of …
Telescoping and Gender Differences in Alcohol Dependence: New Evidence From Two National Surveys
Authors: Katherine M. Keyes, Silvia S. Martins, Carlos Blanco, Deborah S. Hasin
Journal: American Journal of Psychiatry (2010)

The course of alcohol disorders in women is often described as "telescoped" compared to that in men, with a later age at initiation of alcohol use but shorter times from use to dependence and treatment. This study examined evidence for such a telescoping effect in the general population and tested birth cohort effects for gender differences.Data from two U.S. national surveys conducted 10 years apart (1991-1992 and 2001-2002) using the same diagnostic instrument (the Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV) were used to analyze five birth cohorts. Age at initiation of alcohol use, time from first use to dependence, and time from dependence to first treatment were analyzed. Interaction terms (cohort by gender; cohort by gender by time) were tested in Cox proportional hazards models.Little evidence was found for a telescoping effect in women. For alcohol use and dependence, cohort and gender interacted, which suggests that gender differences are diminished in more recent cohorts. A three-way interaction of cohort, gender, and time was significant for time from first use to dependence, suggesting that men have a shorter time to dependence, especially in younger cohorts.A telescoping effect is not evident in the general population. Gender differences in the overall hazard of alcohol use and dependence are decreasing in more recent cohorts, while gender differences in time from first use to dependence are increasing. These findings challenge the commonly held notion of a gender-specific course of alcohol disorders and suggest the need for a greater clinical focus on problem drinking in women and further research on accelerated time to dependence in men.
Loss of PTEN Binding Adapter Protein NHERF1 from Plasma Membrane in Glioblastoma Contributes to PTEN Inactivation
Authors: Jennifer R. Molina, Fabiana C. Morales, Yuho Hayashi, Kenneth D. Aldape, Maria-Magdalena Georgescu
Journal: Cancer Research (2010)

Abstract Glioblastoma multiforme (GBM) is a severe brain malignancy with limited treatment and dismal prognosis. The tumor suppressor PTEN, a major inhibitor of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway, is frequently deleted in GBM tumors. PTEN antagonizes PI3K by dephosphorylating PI3K phosphoinositide substrates at the plasma membrane. The PTEN binding adapter protein NHERF1/EBP50 is overexpressed in GBM but its effects on tumorigenesis have yet to be determined. Here, we show that NHERF1 is localized to the plasma membrane in normal astrocytes and to the cytoplasm of GBM tumor cells. This cytoplasmic shift paralleled an altered membrane distribution of wild-type PTEN with consecutive Akt activation. Membrane re-targeting of NHERF1 in GBM cells recruited PTEN to the membrane and suppressed Akt activation and cell proliferation. Conversely, NHERF1 depletion in GBM cells with membrane-localized NHERF1 increased cell proliferation and Akt activation. Our findings define a tumor suppressor role for NHERF1 at the plasma membrane, and reveal a novel mechanism for PI3K/Akt activation through PTEN inactivation caused by a loss of membrane-localized NHERF1. Cancer Res; 70(17); 6697–703. ©2010 AACR.
Pancreatic cancer regression by intratumoural injection of live Streptococcus pyogenes in a syngeneic mouse model
Authors: C Maletzki, M Linnebacher, B Kreikemeyer, J Emmrich
Journal: Gut (2007)

This study addressed the potential of bacteriolytic therapy using Streptococcus pyogenes in a syngeneic pancreatic carcinoma mouse model.Panc02 tumours were either infected with S pyogenes or were treated with the equivalent volume of vehicle. In addition to assessment of tumour histology and immunohistochemistry, isolated splenocytes were analysed by flow cytometry. Interferon (IFN) gamma secretion as a reaction of splenocytes against tumour cells was shown through the ELISpot technique. A cytotoxic effect of lymphocytes against tumour targets was detected by lactate dehydrogenase (LDH) release. Cytokine levels in serum were measured.A single application of live bacteria into established Panc02 tumours resulted in complete tumour regression. This antitumoral effect was accompanied by massive leucocyte infiltration into the tumours as well as a significant and sustained elevation of systemic levels of the proinflammatory cytokines IFN gamma, tumour necrosis factor alpha and interleukin 6. Lymphocytes obtained from treated mice specifically recognised syngeneic tumour cells in IFN gamma-ELISpot, and most importantly in cellular cytotoxicity assays, indicating a tumour-specific immune response.We provide data that both the direct lytic activity of S pyogenes towards tumour cells and the infection-driven infiltration of tumours by cells of the innate immune system lead to damage of tumour cells followed by a dissemination of tumour components. This last outcome allows for the activation of tumour-specific effector cells, most probably in draining lymph nodes, promoted by the proinflammatory context. Taken together, these data indicate that the application of live S pyogenes may be a promising new treatment strategy for advanced pancreatic cancer patients that warrants further investigation.
Ten-Year Multi-Institutional Results of Breast-Conserving Surgery and Radiotherapy in <i>BRCA1/2</i>-Associated Stage I/II Breast Cancer
Authors: Lori J. Pierce, Albert M. Levin, Timothy R. Rebbeck, Merav A. Ben-David, Eitan Friedman, Lawrence J. Solin, Eleanor E. Harris, David K. Gaffney, Bruce G. Haffty, Laura A. Dawson, Steven A. Narod, Ivo A. Olivotto, Andrea Eisen, Timothy J. Whelan, Olufunmilayo I. Olopade, Claudine Isaacs, Sofia D. Merajver, Julia S. Wong, Judy E. Garber, Barbara L. Weber
Journal: Journal of Clinical Oncology (2006)

We compared the outcome of breast-conserving surgery and radiotherapy in BRCA1/2 mutation carriers with breast cancer versus that of matched sporadic controls.A total of 160 BRCA1/2 mutation carriers with breast cancer were matched with 445 controls with sporadic breast cancer. Primary end points were rates of in-breast tumor recurrence (IBTR) and contralateral breast cancers (CBCs). Median follow-up was 7.9 years for mutation carriers and 6.7 years for controls.There was no significant difference in IBTR overall between carriers and controls; 10- and 15-year estimates were 12% and 24% for carriers and 9% and 17% for controls, respectively (hazard ratio [HR], 1.37; P = .19). Multivariate analyses for IBTR found BRCA1/2 mutation status to be an independent predictor of IBTR when carriers who had undergone oophorectomy were removed from analysis (HR, 1.99; P = .04); the incidence of IBTR in carriers who had undergone oophorectomy was not significantly different from that in sporadic controls (P = .37). CBCs were significantly greater in carriers versus controls, with 10- and 15-year estimates of 26% and 39% for carriers and 3% and 7% for controls, respectively (HR, 10.43; P < .0001). Tamoxifen use significantly reduced risk of CBCs in mutation carriers (HR, 0.31; P = .05).IBTR risk at 10 years is similar in BRCA1/2 carriers treated with breast conservation surgery who undergo oophorectomy versus sporadic controls. As expected, CBCs are significantly increased in carriers. Although the incidence of CBCs was significantly reduced in mutation carriers who received tamoxifen, this rate remained significantly greater than in controls. Additional strategies are needed to reduce contralateral cancers in these high-risk women.