tbuckley/cabot-search huggingface dataset:
Inhibition of Melanoma Growth by Small Molecules That Promote the Mitochondrial Localization of ATF2
Authors: Tal Varsano, Eric Lau, Yongmei Feng, Marine Garrido, Loribelle Milan, Susanne Heynen-Genel, Christian A. Hassig, Ze'ev A. Ronai
Journal: Clinical Cancer Research (2013)

Effective therapy for malignant melanoma, the leading cause of death from skin cancer, remains an area of significant unmet need in oncology. The elevated expression of PKCε in advanced metastatic melanoma results in the increased phosphorylation of the transcription factor ATF2 on threonine 52, which causes its nuclear localization and confers its oncogenic activities. The nuclear-to-mitochondrial translocation of ATF2 following genotoxic stress promotes apoptosis, a function that is largely lost in melanoma cells, due to its confined nuclear localization. Therefore, promoting the nuclear export of ATF2, which sensitizes melanoma cells to apoptosis, represents a novel therapeutic modality.We conducted a pilot high-throughput screen of 3,800 compounds to identify small molecules that promote melanoma cell death by inducing the cytoplasmic localization of ATF2. The imaging-based ATF2 translocation assay was conducted using UACC903 melanoma cells that stably express doxycycline-inducible GFP-ATF2.We identified two compounds (SBI-0089410 and SBI-0087702) that promoted the cytoplasmic localization of ATF2, reduced cell viability, inhibited colony formation, cell motility, and anchorage-free growth, and increased mitochondrial membrane permeability. SBI-0089410 inhibited the 12-O-tetradecanoylphorbol-l3-acetate (TPA)-induced membrane translocation of protein kinase C (PKC) isoforms, whereas both compounds decreased ATF2 phosphorylation by PKCε and ATF2 transcriptional activity. Overexpression of either constitutively active PKCε or phosphomimic mutant ATF2(T52E) attenuated the cellular effects of the compounds.The imaging-based high-throughput screen provides a proof-of-concept for the identification of small molecules that block the oncogenic addiction to PKCε signaling by promoting ATF2 nuclear export, resulting in mitochondrial membrane leakage and melanoma cell death.
Downregulation of Endothelin-1 by Farnesoid X Receptor in Vascular Endothelial Cells
Authors: Fengtian He, Jiang Li, Ying Mu, Ramalinga Kuruba, Zheng Ma, Annette Wilson, Sean Alber, Yu Jiang, Troy Stevens, Simon Watkins, Bruce Pitt, Wen Xie, Song Li
Journal: Circulation Research (2005)

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenals, and intestine. FXR may play an important role in the pathogenesis of cardiovascular diseases via regulating the metabolism and transport of cholesterol. In this study, we report that FXR is also expressed in rat pulmonary artery endothelial cells (EC), a "nonclassical" bile acid target tissue. FXR is functional in EC, as demonstrated by induction of its target genes such as small heterodimer partner (SHP) after treatment with chenodeoxycholic acid, a FXR agonist. Interestingly, activation of FXR in EC led to downregulation of endothelin (ET)-1 expression. Reporter assays showed that activation of FXR inhibited transcriptional activation of the human ET-1 gene promoter and also repressed the activity of a heterologous promoter driven by activator protein (AP)-1 response elements. Electrophoretic mobility-shift and chromatin immunoprecipitation assays indicated that FXR reduced the binding activity of AP-1 transcriptional factors, suggesting that FXR may suppress ET-1 expression via negatively interfering with AP-1 signaling. These studies suggest that FXR may play a role in endothelial homeostasis and may serve as a novel molecular target for manipulating ET-1 expression in vascular EC.
MINIMALLY INVASIVE SURGERY
Authors: Mark Vierra, M.D
Journal: Annual Review of Medicine (1995)

▪ Abstract With the widespread introduction of laparoscopic cholecystectomy in late 1989, the practice and expectations of general surgery were changed forever. The techniques of laparoscopy were not new—they had been adopted by gynecologists and orthopedic surgeons at least a decade before—but it was laparoscopic cholecystectomy that captured the attention of the surgical profession and the public and spawned the tremendous growth in what has come to be called minimally invasive surgery. Although this surgery has tremendous appeal, offering quicker recovery, less pain, and possibly greater safety, it presents new challenges in the areas of training, credentialing, and quality assessment and raises serious questions about the real benefits of new technology at a time when the political and economic sensitivity of these issues is greater than ever. In this chapter I limit myself to a discussion of laparoscopy in general surgery, with a focus on what we have learned from laparoscopic cholecystectomy and on what this knowledge suggests for the future of other laparoscopic general surgical procedures.
Screening and Assessment of Coronary Heart Disease in HIV-Infected Patients
Authors: Priscilla Y. Hsue, Kathleen Squires, Ann F. Bolger, Bernadette Capili, George A. Mensah, Zelalem Temesgen, Christine A. Wanke, David A. Wohl
Journal: Circulation (2008)

Working Group 4 H uman immunodeficiency virus (HIV)-infected individ- uals are living longer in the era of antiretroviral therapy.As a result, they are increasingly prone to the development of concomitant chronic disease.Coronary heart disease (CHD) is the leading cause of death in the United States and Europe.Recent studies suggest that CHD rates may be increasing among HIV-infected patients (see Epidemiological Evidence for Cardiovascular Disease in HIV-Infected Patients and Relationship to Highly Active Antiretroviral Therapy, Working Group 2), and thus appropriate screening strategies for CHD in this population are needed.Recently, approaches to screening and assessment of cardiovascular disease (CVD) in HIV-infected individuals were discussed at a State of the Science Conference.Although insufficient evidence now exists to recommend a screening strategy for CHD in HIV that differs from that recommended in the non-HIV population, emerging risk factors and surrogate markers for atherosclerosis unique to the HIV population suggest specific strategies that may be useful in this population.Two broad screening categories are discussed here.The first screening strategy seeks to define the pretest likelihood of disease by identifying the presence of predisposing risk factors such as hypertension, elevated serum cholesterol, cigarette smoking, and physical inactivity.The second screening strategy aims at the detection of established CHD, even in its earliest stages.The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel.Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.The opinions expressed in this manuscript are those of the authors
Mature Vascular Endothelium Can Give Rise to Smooth Muscle Cells via Endothelial-Mesenchymal Transdifferentiation
Authors: Maria G. Frid, Vishakha A. Kale, Kurt R. Stenmark
Journal: Circulation Research (2002)

Though in the past believed to be a rare phenomenon, endothelial-mesenchymal transdifferentiation has been described with increasing frequency in recent years. It is believed to be important in embryonic vascular development, yet less is known regarding its role in the adult vasculature. Using FACS and immunomagnetic (Dynabeads) purification techniques (based on uptake of DiI-acetylated low-density lipoproteins and/or PECAM-1 expression) and double-label indirect immunostaining (for endothelial and smooth muscle [SM] markers), we demonstrate that mature bovine vascular endothelium contains cells of an endothelial phenotype (defined by VE-cadherin, von Willebrand factor, PECAM-1, and elevated uptake of acetylated low-density lipoproteins) that can undergo endothelial-mesenchymal transdifferentiation and further differentiate into SM cells (as defined by expression of α-SM-actin, SM22α, calponin, and SM-myosin). “Transitional” cells, coexpressing both endothelial markers and α-SM-actin, were consistently observed. The percentage of cells capable of endothelial-mesenchymal transdifferentiation within primary endothelial cultures was estimated as 0.01% to 0.03%. Acquisition of a SM phenotype occurred even in the absence of proliferation, in γ-irradiated (30 Gy) and/or mitomycin C–treated primary cell cultures. Initiation of transdifferentiation correlated with disruption of cell-cell contacts (marked by loss of VE-cadherin expression) within endothelial monolayers, as well as with the action of transforming growth factor-β 1 . In conclusion, our in vitro data show that mature bovine systemic and pulmonary endothelium contains cells that can acquire a SM phenotype via a transdifferentiation process that is transforming growth factor-β 1 – and cell-cell contact–dependent, but proliferation-independent.
Imatinib and pegylated human recombinant interferon-α2b in early chronic-phase chronic myeloid leukemia
Authors: Michele Baccarani, Giovanni Martinelli, Gianantonio Rosti, Elena Trabacchi, Nicoletta Testoni, Simona Bassi, Marilina Amabile, Simona Soverini, Fausto Castagnetti, Daniela Cilloni, Barbara Izzo, Antonio de Vivo, Emanuela Messa, Francesca Bonifazi, Angela Poerio, Simona Luatti, Emilia Giugliano, Daniele Alberti, Gianluca Fincato, Domenico Russo, Fabrizio Pane, Giuseppe Saglio
Journal: Blood (2004)
Mapping the Active Site of CD59
Authors: Jinghua Yu, Ruben Abagyan, Shanghong Dong, Alexander Gilbert, Victor Nussenzweig, Stephen Tomlinson
Journal: The Journal of Experimental Medicine (1997)

CD59 is a widely distributed membrane-bound inhibitor of the cytolytic membrane attack complex (MAC) of complement. This small (77 amino acid) glycoprotein is a member of the Ly6 superfamily of proteins and is important in protecting host cells from the lytic and proinflammatory activity of the MAC. CD59 functions by binding to C8 and/or C9 in the nascent MAC and interfering with C9 membrane insertion and polymerization. We present data obtained from a combination of molecular modeling and mutagenesis techniques, which together indicate that the active site of CD59 is located in the vicinity of a hydrophobic groove on the face of the molecule opposite to a “hydrophobic strip” suggested earlier. In addition, removal of the single N-linked glycosylation site at Asn18 of CD59 resulted in an enhancement of complement inhibitory activity.
Result of two randomized trials comparing nolatrexed (Thymitaq™) versus methotrexate in patients with recurrent head and neck cancer
Authors: X. Pivot, S. Wadler, C. Kelly, R. Ruxer, J. Tortochaux, J. Stern, D. Belpomme, Y. Humblet, C. Domenge, N. Clendeninn, A. Johnston, C. Penning, M. Schneider
Journal: Annals of Oncology (2001)
Possible role of V beta T cell receptor genes in susceptibility to collagen-induced arthritis in mice.
Authors: S Banerjee, T M Haqqi, H S Luthra, J M Stuart, C S David
Journal: The Journal of Experimental Medicine (1988)

Arthritis was induced by immunization of type II collagen in adjuvant in mice from H-2q-bearing crosses between SWR (H-2q/q) and B10 (H-2b/b mice), two strains known to be resistant to collagen-induced arthritis (CIA). The resistance of B10 is known to be due to its MHC haplotype, but it was postulated that the resistance of SWR mice which expresses the susceptible MHC haplotype could be due to the deletion of close to 50% of the V beta genes of the T cell receptor (TCR) in them. 17% of the F1 hybrids, 33% of the SWR backcrosses, 68% of the B10 backcrosses, and 52% of the F2 hybrids developed arthritis on follow-up to 5 mo after primary immunization with collagen. There was no significant difference in anti-type II collagen antibody titers between the arthritic and nonarthritic mice in each of these crosses. The segregation of the TCR genes with arthritis was determined in the F2 population by typing with F23.1 mAb that reacts with T cells using V beta 8 subfamily genes in their TCRs. SWR mice are F23.1- as V beta 8 genes are deleted in them. All six of arthritic mice homozygous for H-2q, and thus with an H-2 haplotype similar to SWR mice, expressed the F23.1 marker. These studies indicate that for complete susceptibility to collagen-induced arthritis, not only is a susceptible MHC haplotype (H-2q) important, but possibly also the presence of a subset of T cells using certain specific V beta genes in their TCRs. Other background genes may, however, modulate the severity of arthritis.
Low plasma concentrations of VIP and elevated levels of other neuropeptides during exacerbations of asthma
Authors: LO Cardell, R Uddman, L Edvinsson
Journal: European Respiratory Journal (1994)

Neuropeptides in the lung occur in neurons, neuroendocrine and inflammatory cells. Their widespread distribution and physiological effects suggest that they may play important roles in asthma. We investigated whether, during an exacerbation of asthma, patients displayed changes in plasma levels of the neuropeptides vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP), and neuropeptide Y (NPY). Venous blood from 25 adult patients attending the emergency ward with an exacerbation of asthma was sampled before and after treatment. Plasma levels of VIP-, SP-, CGRP- and NPY-like immunoreactivity (-LI) were determined by immunoassay, and the results obtained were compared with findings in 21 healthy controls. The mean plasma levels of VIP-LI were lower in patients (3.4 +/- 0.4 pmol.l-1) than in controls (10.4 +/- 0.7 pmol.l-1), whereas the levels of CGRP-LI (43.7 +/- 3.4 pmol.l-1), SP-LI (4.6 +/- 0.4 pmol.l-1) and NPY-LI levels (159 +/- 6 pmol.l-1) were higher in patients than in controls (21.1 +/- 3.4; 2.2 +/- 0.2 and 105 +/- 8 pmol.l-1, respectively). A relationship was seen between the reversibility of obstruction, expressed as improvement of peak expiratory flow upon treatment, and the neuropeptide levels, such that lower VIP-LI levels and higher CGRP-LI levels correlated with less reversibility. Plasma levels of neuropeptides, VIP-LI and CGRP-LI in particular, may therefore be employed as predictors of responsiveness to bronchodilatory therapy.
Thymic Stromal Lymphopoietin, a Novel Proinflammatory Mediator in Rheumatoid Arthritis That Potently Activates CD1c+ Myeloid Dendritic Cells to Attract and Stimulate T Cells
Authors: Frederique M. Moret, Cornelis E. Hack, Kim M. G. van der Wurff‐Jacobs, Timothy R. D. J. Radstake, Floris P. J. G. Lafeber, Joel A. G. van Roon
Journal: Arthritis & Rheumatology (2014)

To determine the levels of thymic stromal lymphopoietin (TSLP) and the numbers of TSLP receptor (TSLPR)-expressing CD1c+ (blood dendritic cell antigen 1-positive) myeloid dendritic cells (MDCs) in the joints as compared with the peripheral blood (PB) of patients with rheumatoid arthritis (RA), as well as to determine the capacity of TSLP to induce MDC-dependent T cell activation.TSLP levels were measured in synovial fluid (SF) samples from patients with RA and those with osteoarthritis (OA). MDC numbers in PB and SF samples from RA patients and TSLPR expression on these cells were assessed by fluorescence-activated cell sorter analysis. PB and SF MDCs from RA patients were stimulated with TSLP, and cytokine production was measured by multiplex immunoassay. TSLP-primed MDCs were cocultured with autologous CD4+ T cells in the absence of additional stimuli, and subsequently, cell proliferation and cytokine production were measured.TSLP levels were significantly increased in SF samples from RA versus OA patients. The numbers of TSLPR-expressing MDCs in the SF of RA patients were significantly increased as compared to those in the PB, and SF MDCs displayed increased levels of TSLPR. TSLP selectively stimulated the production of thymus and activation-regulated chemokine and macrophage inflammatory protein 1α by CD1c+ MDCs. TSLP-primed MDCs from PB and SF potently stimulated the proliferation of autologous CD4+ T cells as compared to unstimulated MDCs. Enhanced proliferation was associated with increased production of interferon-γ, interleukin-17 (IL-17), and IL-4.These data support an inflammatory mechanism by which increased intraarticular TSLP in RA potently activates TSLPR-expressing CD1c+ MDCs in the joints to secrete chemokines, causing chemotaxis and subsequent activation of CD4+ T cells. In addition to the demonstrated inflammatory potential of TSLP in experimental arthritis, this suggests that TSLP and TSLPR-expressing MDCs could both play a pivotal role in the immunopathology of RA.
Implications of the U.S. Food and Drug Administration Warning against the Use of Sildenafil for the Treatment of Pediatric Pulmonary Hypertension
Authors: Steven H. Abman, John P. Kinsella, Erika B. Rosenzweig, Usha Krishnan, Thomas Kulik, Mary Mullen, David L. Wessel, Robin Steinhorn, Ian Adatia, Brian Hanna, Jeffrey Feinstein, Jeffrey Fineman, Usha Raj, Tilman Humpl
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Pulmonary arterial hypertension (PAH) contributes to disability and death in children with diverse cardiac, pulmonary, or systemic diseases, and therapeutic options are currently limited. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. Although currently approved for use in adult PAH, sildenafil is used extensively off-label for the treatment of neonates, infants, and children with PAH. Past studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations, except for one single-center trial for persistent pulmonary hypertension of the newborn. Despite extensive clinical experience with sildenafil therapy in children and approval by the European Medicines Agency for its pediatric use in Europe, the U.S. Food and Drug Administration recently issued a warning against the use of sildenafil for pediatric PAH between 1 and 17 years of age due to an apparent increase in mortality during long-term therapy. Although these data are extremely limited, this U.S. Food and Drug Administration review challenges the pediatric PAH community to further assess the efficacy and safety of sildenafil, especially with chronic treatment. Although low doses of sildenafil are likely safe in pediatric PAH, further studies should carefully examine its role in the long-term therapy of children, especially with diverse causes of PAH. Pediatric patients with PAH require close surveillance and frequent monitoring, and persistent sildenafil monotherapy is likely insufficient with disease progression.
A1C Cut Points to Define Various Glucose Intolerance Groups in Asian Indians
Authors: Viswanathan Mohan, Venkataraman Vijayachandrika, Kuppan Gokulakrishnan, Ranjit Mohan Anjana, Anbazhagan Ganesan, Mary Beth Weber, K.M. Venkat Narayan
Journal: Diabetes Care (2009)

OBJECTIVE To determine A1C cut points for glucose intolerance in Asian Indians. RESEARCH DESIGN AND METHODS A total of 2,188 participants without known diabetes were randomly selected from the Chennai Urban Rural Epidemiology Study. All had fasting plasma glucose (FPG) and 2-h postload plasma glucose measurements after a 75-g load and were classified as having impaired fasting glucose (IFG) (American Diabetes Association [ADA] criteria, FPG ≥5.5 and &amp;lt;7 mmol/l, and World Health Organization [WHO] criteria, FPG ≥6.1 and &amp;lt;7 mmol/l), impaired glucose tolerance (IGT) (2-h postload plasma glucose ≥7.8 and &amp;lt;11.1 mmol/l), or diabetes (FPG ≥7 mmol/l and/or 2-h postload plasma glucose ≥11.1 mmol/l). A1C was measured using the Bio-Rad Variant machine. Based on receiver operating characteristic curves, optimum sensitivity and specificity were derived for defining A1C cut points for diabetes, IGT, and IFG. RESULTS Mean ± SD values of A1C among subjects with normal glucose tolerance, IGT, and diabetes were 5.5 ± 0.4, 5.9 ± 0.6, and 8.3 ± 2.0%, respectively (Ptrend &amp;lt; 0.001) with considerable overlap. To identify diabetes based on 2-h postload plasma glucose, the A1C cut point of 6.1% had an area under the curve (AUC) of 0.941 with 88.0% sensitivity and 87.9% specificity. When diabetes was defined as FPG ≥7.0 mmol/l, the A1C cut point was 6.4% (AUC = 0.966, sensitivity 93.3%, and specificity 92.3%). For IGT, AUC = 0.708; for IFG, AUC = 0.632 (WHO criteria) and 0.708 (ADA criteria), and the A1C cut point was 5.6%. CONCLUSIONS In Asian Indians, A1C cut points of 6.1 and 6.4% defined diabetes by 2-h postload plasma glucose or FPG criteria, respectively. A value of 5.6% optimally identified IGT or IFG but was &amp;lt;70% accurate.
Tumor suppressor gene, PTEN, regulates activity of phospholipase C (PLC) and phospholipase D (PLD)
Authors: Christopher A. Alvarez-Breckenridge, Kristin Waite, Charis Eng
Journal: Cancer Research (2005)

5473  PTEN is an ubiquitously expressed tumor suppressor which plays a prominent role in the pathogenesis of many types of sporadic solid tumors, including breast cancer, and hematologic malignancies. Additionally, germline PTEN mutations cause Cowden syndrome which is characterized by a high risk of breast and thyroid cancers. PTEN is unique by being a dual specificity phosphatase, which is consequently linked to multiple growth related signaling pathways. The lipid phosphatase activity of PTEN decreases phosphatidylinositol-(3,4,5)-P3 which antagonizes the proliferative PI3K/Akt pathway. Beyond the Akt pathway, however, there has been minimal examination of the role PTEN may play in lipid derived cellular signaling. To explore this, we examined the ability of PTEN to regulate phospholipase C (PLC) and phospholipase D (PLD). Using an inducible PTEN expression vector in MCF-7 breast cancer cells, we observed that PLD appeared to regulate PTEN. In the MCF-7 cells, overexpression of PTEN results in 2 fold decrease in phosphatidylcholine levels and, concomitantly, a 50% increase in phosphatidic acid. Further, there was a 30% increase in PLD activity in unstimulated cells, and approximately 1.5 fold decrease in both lipid phosphatase-dead and pan-phosphatase dead lines suggest that the lipid phosphatase domain of PTEN was responsible for this increase. In the presence of estrogen, PTEN activity was also found to be necessary for PLD activation as a 1.45 fold increase in PLD activity was observed in wild type cells compared to control MCF-7 cells. With the seeming link between PTEN and PLD, we decided to examine PTEN’s possible upstream role by examining PLC subcellular translocation: upon PTEN overexpression, PLC moved from the cytosol to the membrane where it is functionally active. Corroborating this observation, in cells that overexpressed functionally inactive PTEN (pan phosphatase dead or lipid phosphatase dead), this translocation was not observed. Our data demonstrate that PTEN may regulate lipid-signaling events mediated by both PLC and PLD, thus suggesting that PTEN is involved in lipid signaling beyond the scope of the PI3K/Akt pathway with implications for cellular signaling, growth, and proliferation. The fact that PTEN signals through lipid transduction pathways beyond PI3K/Akt could also lead to the creation of novel targets for cancer therapy and prevention.