tbuckley/cabot-search huggingface dataset:
Oncogenic functions of hMDMX in in vitro transformation of primary human fibroblasts and embryonic retinoblasts
Authors: Kristiaan Lenos, Job de Lange, Amina FAS Teunisse, Kirsten Lodder, Matty Verlaan-de Vries, Eliza Wiercinska, Marja JM van der Burg, Karoly Szuhai, Aart G Jochemsen
Journal: Molecular Cancer (2011)

Abstract Background In around 50% of all human cancers the tumor suppressor p53 is mutated. It is generally assumed that in the remaining tumors the wild-type p53 protein is functionally impaired. The two main inhibitors of p53, hMDM2 (MDM2) and hMDMX (MDMX/MDM4) are frequently overexpressed in wild-type p53 tumors. Whereas the main activity of hMDM2 is to degrade p53 protein, its close homolog hMDMX does not degrade p53, but it represses its transcriptional activity. Here we study the role of hMDMX in the neoplastic transformation of human fibroblasts and embryonic retinoblasts, since a high number of retinoblastomas contain elevated hMDMX levels. Methods We made use of an in vitro transformation model using a retroviral system of RNA interference and gene overexpression in primary human fibroblasts and embryonic retinoblasts. Consecutive knockdown of RB and p53, overexpression of SV40-small t, oncogenic HRasV12 and HA-hMDMX resulted in a number of stable cell lines representing different stages of the transformation process, enabling a comparison between loss of p53 and hMDMX overexpression. The cell lines were tested in various assays to assess their oncogenic potential. Results Both p53-knockdown and hMDMX overexpression accelerated proliferation and prevented growth suppression induced by introduction of oncogenic Ras, which was required for anchorage-independent growth and the ability to form tumors in vivo . Furthermore, we found that hMDMX overexpression represses basal p53 activity to some extent. Transformed fibroblasts with very high levels of hMDMX became largely resistant to the p53 reactivating drug Nutlin-3. The Nutlin-3 response of hMDMX transformed retinoblasts was intact and resembled that of retinoblastoma cell lines. Conclusions Our studies show that hMDMX has the essential properties of an oncogene. Its constitutive expression contributes to the oncogenic phenotype of transformed human cells. Its main function appears to be p53 inactivation. Therefore, developing new drugs targeting hMDMX is a valid approach to obtain new treatments for a subset of human tumors expressing wild-type p53.
Antiretroviral Treatment of Adult HIV Infection
Authors: Scott M Hammer, Joseph J Eron, Peter Reiss, Robert T Schooley, Melanie A Thompson, Sharon Walmsley, Pedro Cahn, Margaret A Fischl, Jose M Gatell, Martin S Hirsch, Donna M Jacobsen, Julio S G Montaner, Douglas D Richman, Patrick G Yeni, Paul A Volberding
Journal: JAMA (2012)

<h3>Context</h3>New trial data and drug regimens that have become available in the last 2 years warrant an update to guidelines for antiretroviral therapy (ART) in human immunodeficiency virus (HIV)–infected adults in resource-rich settings.<h3>Objective</h3>To provide current recommendations for the treatment of adult HIV infection with ART and use of laboratory-monitoring tools. Guidelines include when to start therapy and with what drugs, monitoring for response and toxic effects, special considerations in therapy, and managing antiretroviral failure.<h3>Data Sources, Study Selection, and Data Extraction</h3>Data that had been published or presented in abstract form at scientific conferences in the past 2 years were systematically searched and reviewed by an International Antiviral Society–USA panel. The panel reviewed available evidence and formed recommendations by full panel consensus.<h3>Data Synthesis</h3>Treatment is recommended for all adults with HIV infection; the strength of the recommendation and the quality of the evidence increase with decreasing CD4 cell count and the presence of certain concurrent conditions. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine) plus a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir or darunavir), or an integrase strand transfer inhibitor (raltegravir). Alternatives in each class are recommended for patients with or at risk of certain concurrent conditions. CD4 cell count and HIV-1 RNA level should be monitored, as should engagement in care, ART adherence, HIV drug resistance, and quality-of-care indicators. Reasons for regimen switching include virologic, immunologic, or clinical failure and drug toxicity or intolerance. Confirmed treatment failure should be addressed promptly and multiple factors considered.<h3>Conclusion</h3>New recommendations for HIV patient care include offering ART to all patients regardless of CD4 cell count, changes in therapeutic options, and modifications in the timing and choice of ART in the setting of opportunistic illnesses such as cryptococcal disease and tuberculosis.
Impact of First-Line vs Second-Line Antibiotics for the Treatment of Acute Uncomplicated Sinusitis
Authors: Jay F. Piccirillo
Journal: JAMA (2001)

WITHsignificant morbidity, anxiety, reduced quality of life, lost time from work, and treatment expense.It is estimated that approximately 35 million US residents have some form of sinusitis, and in 1996 the direct cost of this disorder in the United States was more than $3.3 billion. 1 McCaig and Hughes 2 analyzed National Ambulatory Medical Care Surveys (NAMCS) data and found that acute and chronic sinusitis was the fifth most common diagnosis for which antibiotics were prescribed and also found an increasing trend of office visits between the years 1980 and 1992.In 1992 alone, sinusitis accounted for 12% of all recorded antibiotic prescriptions.There was a trend over time toward increased use of more expensive broad-spectrum antibiotics and decreased use of less expensive narrow-spectrum antibiotics.Ironically, this trend to prescribe more expensive antibiotics with a broader spectrum of action occurs despite evidence that about two thirds of patients with acute sinusitis improve or are cured without any antibiotics. 3,47][8] Recommendations for antibiotics for initial treatment of acute sinusitis vary between older less expensive antibiotics (eg, amoxicillin and trimethoprim-sulfamethoxazole) 9,10 and newer more expensive drugs with a broader antimicrobial spectrum (eg, clarithromycin, amoxicillin and clavula-
Differential Modulation of L-type Ca <sup>2+</sup> Current by SR Ca <sup>2+</sup> Release at the T-Tubules and Surface Membrane of Rat Ventricular Myocytes
Authors: Fabien Brette, Laurent Sallé, Clive H. Orchard
Journal: Circulation Research (2004)

We have characterized modulation of I Ca by Ca 2+ at the t-tubules (ie, in control cells) and surface sarcolemma (ie, in detubulated cells) of cardiac ventricular myocytes, using the whole-cell patch clamp technique to record I Ca . I Ca inactivation was significantly slower in detubulated cells than in control cells (27.1±7.8 ms, n=22, versus 16.4±7.9 ms, n=22; P &lt;0.05). In atrial myocytes, which lack t-tubules, I Ca inactivation was not changed by the treatment used to produce detubulation. In the presence of ryanodine or BAPTA, or when Ba 2+ was used as the charge carrier, the rate of inactivation was not significantly different in control and detubulated cells. Frequency-dependent facilitation occurred in control cells but not in detubulated cells, and was abolished by ryanodine. These results suggest that Ca 2+ released from the SR has a greater effect on I Ca in the t-tubules than at the surface sarcolemma. This does not appear to be due to differences in local Ca 2+ release from the SR, because the gain of Ca 2+ release was not significantly different in control and detubulated cells. These data suggest that the t-tubules are a key site for the regulation of transsarcolemmal Ca 2+ flux by Ca 2+ release from the SR; this could play a role in altered Ca 2+ homeostasis in pathological conditions. The full text of this article is available online at http://circres.ahajournals.org.
Wnt5a Is Required for Endothelial Differentiation of Embryonic Stem Cells and Vascularization via Pathways Involving Both Wnt/β-Catenin and Protein Kinase Cα
Authors: Dong-Hwa Yang, Ju-Young Yoon, Soung-Hoon Lee, Vitezslav Bryja, Emma R. Andersson, Ernest Arenas, Young-Guen Kwon, Kang-Yell Choi
Journal: Circulation Research (2008)

In this study, we examined the signaling pathways activated by Wnt5a in endothelial differentiation of embryonic stem (ES) cells and the function of Wnt5a during vascular development. We first found that Wnt5a(-/-) mouse embryonic stem (mES) cells exhibited a defect in endothelial differentiation, which was rescued by addition of Wnt5a, suggesting that Wnt5a is required for endothelial differentiation of ES cells. Involvement of both beta-catenin and protein kinase (PK)Calpha pathways in endothelial differentiation of mES cells requiring Wnt5a was indicated by activation of both beta-catenin and PKCalpha in Wnt5a(+/-) but not in Wnt5a(-/-) mES cells. We also found that beta-catenin or PKCalpha knockdowns inhibited the Wnt5a-induced endothelial differentiation of ES cells. Moreover, the lack of endothelial differentiation of Wnt5a(-/-) mES cells was rescued only by transfection of both beta-catenin and PKCalpha, indicating that both genes are required for Wnt5a-mediated endothelial differentiation. Wnt5a was also found to be essential for the differentiation of mES cells into immature endothelial progenitor cells, which are known to play a role in repair of damaged endothelium. Furthermore, a defect in the vascularization of the neural tissue was detected at embryonic day 14.5 in Wnt5a(-/-) mice, implicating Wnt5a in vascular development in vivo. Thus, we conclude that Wnt5a is involved in the endothelial differentiation of ES cells via both Wnt/beta-catenin and PKC signaling pathways and regulates embryonic vascular development.
fMRI Correlates of White Matter Hyperintensities in Late-Life Depression
Authors: Howard J. Aizenstein, Carmen Andreescu, Kathryn L. Edelman, Jennifer L. Cochran, Julie Price, Meryl A. Butters, Jordan Karp, Meenal Patel, Charles F. Reynolds
Journal: American Journal of Psychiatry (2011)

This study tests whether or not the structural white matter lesions that are characteristic of late-life depression are associated with alterations in the functional affective circuits of late-life depression. This study used an emotional faces paradigm that has been shown to engage the affective limbic brain regions.Thirty-three elderly depressed patients and 27 nondepressed comparison subjects participated in this study. The patients were recruited through the NIMH-sponsored Advanced Center for Interventions and Services Research for the Study of Late-Life Mood Disorders at the University of Pittsburgh Center for Bioethics and Health Law. Structural and functional MRI was used to assess white matter hyperintensity (WMH) burden and functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) response on a facial expression affective-reactivity task in both elderly participants with nonpsychotic and nonbipolar major depression (unmedicated) and nondepressed elderly comparison subjects.As expected, greater subgenual cingulate activity was observed in the depressed patients relative to the nondepressed comparison subjects. This same region showed greater task-related activity associated with a greater burden of cerebrovascular white matter change in the depressed group. Moreover, the depressed group showed a significantly greater interaction of WMH by fMRI activity effect than the nondepressed group.The observation that high WMH burden in late-life depression is associated with greater BOLD response on the affective-reactivity task supports the model that white matter ischemia in elderly depressed patients disrupts brain mechanisms of affective regulation and leads to limbic hyperactivation.
Ankle-Brachial Blood Pressure Index Predicts All-Cause and Cardiovascular Mortality in Hemodialysis Patients
Authors: Kumeo Ono, Akiyasu Tsuchida, Hironobu Kawai, Hidenori Matsuo, Ryouji Wakamatsu, Akira Maezawa, Shintarou Yano, Tomoyuki Kawada, Yoshihisa Nojima
Journal: Journal of the American Society of Nephrology (2003)

A reduction in ankle-brachial BP index (ABPI) is associated with generalized atherosclerotic diseases and predicts cardiovascular mortality and morbidity in several patient populations. However, a large-scale analysis of ABPI is lacking for hemodialysis (HD) patients, and its use in this population is not fully validated. A cohort of 1010 Japanese patients undergoing chronic hemodialysis was studied between November 1999 and May 2002. Mean age at entry was 60.6 +/- 12.5 yr, and duration of follow-up was 22.3 +/- 5.6 mo. Patients were stratified into five groups (< 0.9, > or = 0.9 to < 1.0, > or = 1.0 to < 1.1, > or = 1.1 to < 1.3, and > or = 1.3) by ABPI measured at entry by an oscillometric method. The frequency distribution of ABPI was 16.5% of patients < 0.9, 8.6% of patients > or = 0.9 to < 1.0, 16.9% of patients 1.0 > or = to < 1.1, and 47.0% of patients > or 1.1 to < 1.3, whereas 10.9% of patients had an abnormally high ABPI (> or = 1.3). The relative risk of a history of diabetes mellitus (DM), cardiovascular, and cerebrovascular disease was significantly higher in patients with lower ABPI than those with ABPI > or = 1.1 to <1.3. During the study period, 77 cardiovascular and 41 noncardiovascular fatal events occurred. On the basis of Cox proportional hazards regression analysis, ABPI emerged as a strong independent predictor of all-cause and cardiovascular mortality. After adjustment for confounding variables, the hazard ratio (HR) for ABPI < 0.9 was 4.04 (95% confidence interval, 2.38 to 6.95) for all-cause mortality and 5.90 (2.83 to 12.29) for cardiovascular mortality. Even those with modest reductions in the ABPI (> or = 0.9 to <1.1) appeared to be at increased risk. Patients having abnormally high ABPI (> or = 1.3) also had poor prognosis (HR, 2.33 [1.11 to 4.89] and 3.04 [1.14 to 8.12] for all-cause and cardiovascular mortality, respectively). Thus, the present findings validate ABPI as a powerful and independent predictor for all-cause and cardiovascular mortality among hemodialysis patients.
Homicides and the Lunar Cycle: Toward a Theory of Lunar Influence on Human Emotional Disturbance
Authors: ARNOLD L. LIEBER, CAROLYN R. SHERIN
Journal: American Journal of Psychiatry (1972)

Data on homicides were analyzed by computer to determine whether a relationship exists between the lunar synodic cycle and human emotional disturbance. A statistically significant lunar periodicity was demonstrated for homicides committed in Dade County, Fla., over a 15-year period. A similar, but nonsignificant, periodicity was found for homicides occurring over a 13-year period in Cuyahoga County, Ohio.
Reduced GM-CSF autoantibody in improved lung of autoimmune pulmonary alveolar proteinosis
Authors: K. Ohashi, A. Sato, T. Takada, T. Arai, Y. Kasahara, M. Hojo, T. Nei, H. Nakayama, N. Motoi, S. Urano, R. Eda, M. Yokoba, Y. Tsuchihashi, Y. Nasuhara, H. Ishii, M. Ebina, E. Yamaguchi, Y. Inoue, K. Nakata, R. Tazawa
Journal: European Respiratory Journal (2012)

We believe that our study is the first to identify different proportions of obstructive and restrictive airway disease between the main ethnic groups in sarcoidosis, and also the first to report an association of functional impairment with age.Despite a weak evidence base, sarcoidosis patients are often prescribed inhaled corticosteroids and b-agonists for respiratory symptoms regardless of their pattern of lung function at presentation [12].Large airway obstruction in sarcoidosis is associated with increased mortality [13] and our data suggest that these patients may represent an under-diagnosed group.Further studies are needed to confirm these demographic associations, as well as to assess disease progression and response to inhaled therapies in this particular clinical phenotype of sarcoidosis.
IMPACT OF PREOPERATIVE MODERATE/SEVERE MITRAL REGURGITATION ON PATIENTS UNDERGOING PERCUTANEOUS AND SURGICAL AORTIC VALVE REPLACEMENT: INSIGHTS FROM THE PARTNER TRIAL
Authors: Marco Barbanti, John Webb, Rebecca Hahn, Christopher Thompson, Ted Feldman, Susheel Kodali, Philip Green, Irene Hueter, Craig Smith, Alan Zajarias, Vasilis Babaliaros, Raj Makkar, Wilson Szeto, Maria Alu, D. Craig Miller, Martin Leon
Journal: Journal of the American College of Cardiology (2013)
BCR/ABL Stimulates WRN to Promote Survival and Genomic Instability
Authors: Artur Slupianek, Tomasz Poplawski, Stanislaw K. Jozwiakowski, Kimberly Cramer, Dariusz Pytel, Ewelina Stoczynska, Michal O. Nowicki, Janusz Blasiak, Tomasz Skorski
Journal: Cancer Research (2010)

BCR/ABL-transformed chronic myeloid leukemia (CML) cells accumulate numerous DNA double-strand breaks (DSB) induced by reactive oxygen species (ROS) and genotoxic agents. To repair these lesions BCR/ABL stimulate unfaithful DSB repair pathways, homologous recombination repair (HRR), nonhomologous end-joining (NHEJ), and single-strand annealing (SSA). Here, we show that BCR/ABL enhances the expression and increase nuclear localization of WRN (mutated in Werner syndrome), which is required for processing DSB ends during the repair. Other fusion tyrosine kinases (FTK), such as TEL/ABL, TEL/JAK2, TEL/PDGFβR, and NPM/ALK also elevate WRN. BCR/ABL induces WRN mRNA and protein expression in part by c-MYC-mediated activation of transcription and Bcl-xL-dependent inhibition of caspase-dependent cleavage, respectively. WRN is in complex with BCR/ABL resulting in WRN tyrosine phosphorylation and stimulation of its helicase and exonuclease activities. Activated WRN protects BCR/ABL-positive cells from the lethal effect of oxidative and genotoxic stresses, which causes DSBs. In addition, WRN promotes unfaithful recombination-dependent repair mechanisms HRR and SSA, and enhances the loss of DNA bases during NHEJ in leukemia cells. In summary, we postulate that BCR/ABL-mediated stimulation of WRN modulates the efficiency and fidelity of major DSB repair mechanisms to protect leukemia cells from apoptosis and to facilitate genomic instability.
Transplant Coronary Artery Disease
Authors: Bernard Cantin, Peizhong Wen, Dening Zhu, Michelle Dai, Shyam N. Panchal, Margaret E. Billingham, Judith K. Gwathmey, Hannah A. Valantine
Journal: Circulation (2001)

Background Allograft coronary atherosclerosis (TxCAD) is the leading cause of death after the first year after transplantation. TxCAD is believed to be a form of chronic rejection of the cardiac allografts. This study was undertaken to determine whether TxCAD could develop in the absence of a cellular alloimmune response. Methods and Results Inbred lean Zucker rats (&gt;26 generations) served as donors and recipients of the cardiac grafts. Donor hearts were explanted at 60 or 90 days. Explanted hearts were processed for coronary artery histological analysis. Cytokine expression was determined by reverse transcription–polymerase chain reaction, and the presence of T cells within the explanted hearts was evaluated by immunohistochemistry. Forty-six transplantations were made, and TxCAD developed in all but one of the transplanted hearts. Overall, one third of the vessels examined were affected by TxCAD, and in roughly half of these vessels, the disease was severe. Native hearts were free of atherosclerosis. Interleukin-2 was absent from the transplanted hearts, and T cells were present in minimal amounts (&lt;1 per low-power field). Conclusions TxCAD developed in the absence of a cellular alloimmune response in these genetically similar donors and recipients. The observed TxCAD was significant and comparable to what is found in rat allografting models.
Role of ROS in Aβ42 mediated cell surface P-selectin expression and actin polymerization
Authors: Andrey Tsoy, Sholpan Askarova, Tamara Shalakhmetova, Bauyrzhan Umbayev, Shalkar Adambekov, Zhaksybay Zhumadilov
Journal: Molecular Neurodegeneration (2013)

P-selectin and actin cytoskeleton reorganization play an important role in vascular inflammation. In turn, there is increasing evidence that cerebrovascular factors contribute significantly to the development and progression of Alzhemer’s disease. In this study we have evaluated the effects of Aβ42 oligomers on P-selectin expression and actin polymerization in mouse endothelial cells (bEnd3). Our results indicated that Aβ42 induced plasma membrane accumulation of P-selectin and promoted actin polymerization, and these events were correlated with increased reactive oxygen species (ROS) generation. The rapid, posttranslational cell signaling response mediated by ROS may well represent an important physiological trigger of the microvascular inflammation in Alzheimer disease.
How the public is being misled about complementary/alternative medicine
Authors: Edzard Ernst
Journal: Journal of the Royal Society of Medicine (2008)

Complementary/alternative medicine (CAM) is a hugely popular subject. Hardly a day goes by that the popular press does not report about one aspect of CAM or another. Currently there are approximately 41 million (!) web sites bombarding the public with information on this topic. Numerous studies have shown how unreliable, and indeed dangerously misleading, this information often is.1,2 To make matters worse, patients cannot rely either on conventional healthcare professionals, who tend to be ill-informed about this subject,3 or on CAM practitioners, who often over-estimate the value of their treatments.4 They cannot even trust the UK ‘official’ patient guide5 (sponsored by the Department of Health), which is promotional, uninformative and inaccurate.6 It is hardly surprising, therefore, that despite the plethora of information, 77% of patients feel ‘insufficiently informed about CAM’.7 In this article, I will try to outline how the public is being misled about CAM.