tbuckley/cabot-search huggingface dataset:
Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53
Authors: Megan J. Bywater, Gretchen Poortinga, Elaine Sanij, Nadine Hein, Abigail Peck, Carleen Cullinane, Meaghan Wall, Leonie Cluse, Denis Drygin, Kenna Anderes, Nanni Huser, Chris Proffitt, Joshua Bliesath, Mustapha Haddach, Michael K. Schwaebe, David M. Ryckman, William G. Rice, Clemens Schmitt, Scott W. Lowe, Ricky W. Johnstone, Richard B. Pearson, Grant A. McArthur, Ross D. Hannan
Journal: Cancer Cell (2012)

SummaryIncreased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies.Highlights•Hematologic cancer cell survival is dependent on activated Pol I transcription•CX-5461, a selective inhibitor of Pol I, treats hematologic cancers in mice•CX-5461 selectively kills tumor cells by activating p53-dependent apoptosis•CX-5461 shows potent antiproliferative capacity in human hematologic tumor cells
Signal Transduction Pathways Regulating Hematopoietic Differentiation
Authors: Thomas E. Smithgall
Journal: Pharmacological Reviews (1998)

Hematopoiesis, the process by which pluripotent stem cells give rise to functionally diverse mature blood cells, involves a complex array of hematopoietic growth factors. These factors regulate the survival and proliferation of early progenitors, influence differentiation commitment, and modulate
Contribution of CXCR4+/PDGFRβ+ progenitor cells in hypoxic alveolar arterioles muscularization: role of myocardin
Authors: Wei Jie, Xiaoyan Wang, Lei Huang, Junli Guo, Dong Kuang, Pengcheng Zhu, Mei Li, Xia Zhao, Yaqi Duan, Guoping Wang, Qilin Ao
Journal: Cardiovascular Research (2010)

Bone marrow (BM) progenitor cells may contribute to vascular remodelling. The present study aimed to investigate the contribution of BM-derived CXCR4(+) (a CXC chemokine receptor) and PDGFRbeta(+) (platelet-derived growth factor receptor beta) progenitor cells in hypoxia-induced muscularization of alveolar arterioles.Accumulation of GFP(+) (green fluorescent protein) cells was markedly increased in the pulmonary vasculature by the hypoxic (10% O(2,) 4 weeks) chimeric mice with transgenic GFP-tagged BM. After injection of BM-derived CXCR4(+)/PDGFRbeta(+) progenitor cells into C57BL/6J mice, followed by 6-week hypoxia, the cells were found to home to the alveolar arterioles and readily differentiated into smooth muscle cells (SMCs). Under the same hypoxic conditions, mice infused with myocardin lentiviral RNAi vector-transduced progenitor cells displayed lower myocardin expression in the muscularized alveolar arterioles, correlating with decreased pulmonary artery pressure and arteriole muscularization. In vitro experiments further confirmed that the differentiation of the progenitor cells into SMCs occurred under hypoxia (1% O(2)), and SMC differentiation could be suppressed when myocardin RNAi was administered.Theses results suggest that myocardin may contribute to the differentiation of CXCR4(+)/PDGFRbeta(+) progenitor cells into SMCs induced by hypoxia, which leads to the muscularization of alveolar arterioles.
Prostacyclin Induces Apoptosis of Vascular Smooth Muscle Cells by a cAMP-Mediated Inhibition of Extracellular Signal-Regulated Kinase Activity and Can Counteract the Mitogenic Activity of Endothelin-1 or Basic Fibroblast Growth Factor
Authors: Rung-chi Li, Tereza Cindrova-Davies, Jeremy N. Skepper, Lynda A. Sellers
Journal: Circulation Research (2004)

Prostanoids can suppress vascular smooth muscle cell (VSMC) proliferation, but the mechanism through which this is mediated has not been identified. In this study, we show rat aortic VSMCs to express the EP1, EP2, EP3, EP4, and IP receptors. The EP4 receptor-specific agonist, 11-deoxy-PGE1, induced a time-dependent phosphorylation of protein kinase C and extracellular signal-regulated kinase (ERK) 1/2 in serum-depleted (0.1%) VSMCs, whereas the EP2 receptor agonist, butaprost, was without effect. PGI2 or iloprost at the IP receptor inhibited basal ERK phosphorylation with IC50 values of 10 nmol/L. Iloprost also attenuated the sustained activation of ERK induced by endothelin-1 or basic fibroblast growth factor (bFGF). Endothelin-1 or bFGF significantly increased the number of VSMCs counted 24 hours later compared with basal, and both responses were blocked by the MEK inhibitor, U0126, or iloprost. Under basal conditions, U0126 or iloprost reduced the number of viable cells and increased caspase-3 activity, which could be reversed by coapplication with endothelin-1, bFGF, or the adenylate cyclase inhibitor, SQ22536. Endothelin-1, bFGF, or SQ22536 prevented the depression to below basal levels of ERK phosphorylation induced by iloprost. Forskolin activated caspase-3 and attenuated basal ERK phosphorylation, which were prevented by SQ22536, endothelin-1, or bFGF. These data suggest that iloprost induces apoptosis via a cAMP-mediated suppression of ERK activity. In turn, this apoptotic response can be blocked by a mitogenic stimulus that re-establishes ERK activity back to basal levels, but at the expense of any concomitant proliferative activity. However, ERK stimulation by a selective EP4 receptor agonist, suggests that prostanoids may have diverse and complex roles in VSMC physiology.
A targeted functional RNA interference screen uncovers glypican 5 as an entry factor for hepatitis B and D viruses
Authors: Eloi R. Verrier, Che C. Colpitts, Charlotte Bach, Laura Heydmann, Amélie Weiss, Mickaël Renaud, Sarah C. Durand, François Habersetzer, David Durantel, Georges Abou‐Jaoudé, Maria M. López Ledesma, Daniel J. Felmlee, Magali Soumillon, Tom Croonenborghs, Nathalie Pochet, Michael Nassal, Catherine Schuster, Laurent Brino, Camille Sureau, Mirjam B. Zeisel, Thomas F. Baumert
Journal: Hepatology (2015)

Chronic hepatitis B and D infections are major causes of liver disease and hepatocellular carcinoma worldwide. Efficient therapeutic approaches for cure are absent. Sharing the same envelope proteins, hepatitis B virus and hepatitis delta virus use the sodium/taurocholate cotransporting polypeptide (a bile acid transporter) as a receptor to enter hepatocytes. However, the detailed mechanisms of the viral entry process are still poorly understood. Here, we established a high-throughput infectious cell culture model enabling functional genomics of hepatitis delta virus entry and infection. Using a targeted RNA interference entry screen, we identified glypican 5 as a common host cell entry factor for hepatitis B and delta viruses.These findings advance our understanding of virus cell entry and open new avenues for curative therapies. As glypicans have been shown to play a role in the control of cell division and growth regulation, virus-glypican 5 interactions may also play a role in the pathogenesis of virus-induced liver disease and cancer.
Lithium Carbonate and Isocarboxazid—An Effective Drug Approach in Severe Depressions
Authors: HARRY ZALL
Journal: American Journal of Psychiatry (1971)

The author presents three case reports that emphasize the difficulties in finding an effective antidepressant drug program for regularly recurring depressions. All three patients responded well to the combination of lithium carbonate and isocarboxazid. The author concludes that lithium and at least one monoamine oxidase inhibitor may act synergistically in relieving certain severe depressions in manic-depressive illness.
How big is the problem with MDR-TB cases in Macedonia?
Authors: Biljana Ilievska Poposka, Maja Zakoska, Cveta Vragoterova, Stefan Talevski
Journal: European Respiratory Journal (2012)

Background: Multi-drug resistance tuberculosis (MDR-TB) is one of the most challenging problems in the National Strategy for control tuberculosis in Macedonia. The aim of this study was to present all patients with MDR-TB who were registered in the National MDR-TB Register in Macedonia from 2001 till 2011.  Material: 32 patients who were treated with individualized therapeutic regimes were enrolled in the study. Patients follow-up ended when an outcome was recorded or, in December 2011 for those still on treatment.  Results: 29 patients were with bacteriological confirmation, and 3 cases were suspected for MDR-TB. MDR-TB cases participate with 0,5-4,6 % in the total resistant strain obtained from positive culture during the last six year. 30 patients (93, 75%) had acquired resistance and only 2 patients (6, 25 %) had primary MDR resistance. Time to culture conversion was two months or less in the most of patients. The results of treatment outcome are: 9 patients were cured (28, 12 %), 13 patients (40, 62%) died, 5 patients interrupted the treatment (15,62%) and 5 patients (15,62 %) are still on treatment. No one patient had XDR-TB initially, but only one cases emerged XDR-TB during the treatment.  Conclusion: To improve management and treatment results of MDR-TB patients in Macedonia, we need more efforts in providing necessary medications, clinical conditions and treatment under direct control.
Molecular network of cartilage homeostasis and osteoarthritis
Authors: Megumi Hashimoto, Tomoyuki Nakasa, Tomohiro Hikata, Hiroshi Asahara
Journal: Medicinal Research Reviews (2007)

Abstract This review article presents the current understanding of the molecular basis of articular cartilaginous homeostasis, and outlines potential areas to focus on within the developing field of therapeutics for cartilage disorders. Articular cartilage, an integral component of joints in extremities and the vertebral column, is essential for locomotion. Disturbance of joint development or cartilage homeostasis causes congenital osteocartilaginous dysplasia or osteoarthritic diseases, respectively. Symptomatic treatments and surgical replacement of joints are effective but can also be problematic in terms of quality of life over time. Recently, new insights into the molecular biological basis of chondrocyte differentiation and cartilage homeostasis have been reported. While joint formation is regulated by several growth factors such as Wnts (wingless‐related MMTV integration site) and Gdfs (growth and differentiation factors), the pathology of osteoarthritis is now interpreted as the disruption of balance between anabolic and catabolic signals. Current findings in molecular biology on joint development are reviewed concisely to aid in the understanding of the molecular network that governs articular cartilage development and homeostasis. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 3, 464–481, 2008
Recurrent lupus nephritis after kidney transplantation: a surveillance biopsy study
Authors: G. E. Norby, E. H. Strom, K. Midtvedt, A. Hartmann, I.-M. Gilboe, T. Leivestad, J. Stenstrom, H. Holdaas
Journal: Annals of the Rheumatic Diseases (2010)

To determine the incidence of recurrent lupus nephritis (LN) in renal transplant recipients with systemic lupus erythematosus (SLE).All patients with SLE that had undergone transplant with a functioning graft were asked in 2008 to participate in a cross-sectional study. The study included a standardised clinical examination, laboratory tests and a biopsy of the transplanted kidney.A total of 41 (93%) of a cohort of 44 patients with SLE with renal transplants participated. Of the biopsies, 3 were indication biopsies and 38 were surveillance biopsies. In all, 22 patients (54%) had biopsy-proven recurrence of LN. The majority of the cases were subclinical and characterised as class I/class II LN. Proteinuria (mg protein/mmol creatinine) was significantly increased in patients with recurrence, 70.6 (104.9) mg/mmol versus 11.9 (6.7) mg/mmol in patients without recurrence (p=0.038). Lupus anticoagulant was found more frequently in the patients with recurrence, nine versus two patients (p=0.033). Recurrence of LN was associated with receiving a kidney from a living donor (p=0.049). In all, 83% (34 of 41) had chronic allograft nephropathy in the transplanted kidneys with no difference between patients with recurrence or without.Subclinical recurrence of LN is common in patients with renal transplants with SLE. The majority of the patients have chronic allograft nephropathy.
Remission in Major Depressive Disorder: A Comparison of Pharmacotherapy, Psychotherapy, and Control Conditions
Authors: Nicola Casacalenda, J. Christopher Perry, Karl Looper
Journal: American Journal of Psychiatry (2002)

The aim of this study was to assess the percentages of full remission in studies of patients with major depressive disorder in which pharmacotherapy, psychotherapy, and control conditions were directly compared.Computerized searches of the MEDLINE and PsychINFO databases up to November 2000 were used to identify six multiple-cell randomized, controlled, double-blind trials for well-defined major depressive disorder in which medications, psychotherapy, and control conditions were directly compared and for which remission percentages were reported.The studies included a total of 883 outpatients with mild to moderate, primarily nonmelancholic, nonpsychotic major depressive disorder. Treatment duration ranged from 10 to 34 weeks (median=16 weeks). An intent-to-treat analysis indicated that, according to measurements by independent blind raters, antidepressant medication (tricyclic antidepressants and phenelzine) and psychotherapy (primarily cognitive behavior and interpersonal therapies) were more efficacious than control conditions, but there were no differences between active treatments. The percentages of remission for all patients randomly assigned to medication, psychotherapy, and control conditions were 46.4%, 46.3%, and 24.4%, respectively. Furthermore, significantly more patients dropped out of control conditions (54.4%) than either treatment with medication (37.1%) or psychotherapy (22.2%).Both antidepressant medication and psychotherapy may be considered first-line treatments for mildly to moderately depressed outpatients.
Factor V Leiden mutation, prothrombin gene mutation and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis : results of a case-control study
Authors: Harry L. A. Janssen, Johan R. Meinardi, Frank P. Vleggaar, Stan H. M. van Uum, Elizabeth B. Haagsma, Felix J. M. van der Meer, Jan van Hattum, Robert A. F. M. Chamuleau, Rob P. Adang, Jan P. Vandenbroucke, Bart van Hoek, Frits R. Rosendaal
Journal: Blood (2000)
Sulforaphane: from chemoprevention to pancreatic cancer treatment?
Authors: J. W Lampe
Journal: Gut (2009)

Over the past several decades, research on the action of bioactive constituents of plants (ie, phytochemicals) has focused predominantly on their cancer-preventive properties. Evidence for a protective role for vegetables is strongest and most consistent for vegetables in the Cruciferae (Brassicaceae) plant family, such as broccoli, cabbage, Brussels sprouts and cauliflower.1–4 Cruciferous vegetables are characterised by a unique phytochemistry: their high content of the sulfur-containing glucosinolates or β-thioglucoside N -hydroxysulfates with a side chain and sulfur-linked β-d-glucopyranose moiety.5 Hydrolysis of glucosinolates by a β-thioglucosidase (myrosinase), either in the plant or by gut bacteria, results in the formation of biologically active compounds such as isothiocyanates and indoles.6 These bioactive compounds are hypothesised to be responsible for the chemoprotective effects conferred by a high cruciferous vegetable intake.

Isothiocyanates may exert their protective effects through several distinct mechanisms. Of the isothiocyanates, sulforaphane, which is found in broccoli and broccoli sprouts at particularly high levels, has been the most extensively studied. Considerable attention has focused on sulforaphane as a “blocking” agent—that is, its ability to modulate the nuclear factor-erythroid-2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway.7 Sulforaphane reacts with specific thiol groups on Keap1, promoting Nrf2 dissociation from Keap1, and allowing subsequent activation of antioxidant response element (ARE)-driven gene expression of phase II biotransformation enzymes (glutathione S -transferases, UDP-glucuronosyltransferases, etc.).7 However, sulforaphane acts by other mechanisms too. It induces cell cycle arrest and apoptosis in cancer cells, …
Reply: The Association between Obstructive Sleep Apnea Severity and N-Terminal Pro–B-Type Natriuretic Peptide Levels in Women
Authors: Gabriela Querejeta Roca, Susan Redline, Naresh Punjabi, Brian Claggett, Christie M. Ballantyne, Scott D. Solomon, Amil M. Shah
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

From the Authors:

We appreciate Dr. Mirrakhimov’s and Dr. Lin’s comments regarding our article in the Journal (1) studying the association between obstructive sleep apnea (OSA) and serum high-sensitivity troponin (hs-TnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) in 1,645 community-dwelling subjects free of coronary heart disease and heart failure from the intersection between the Atherosclerosis Risk in the Communities (ARIC) and the Sleep Heart Health Study (SHHS). We agree with Dr. Mirrakhimov that our study’s finding may not be generalizable to persons of nonwhite race/ethnicity. As with most previous studies evaluating the relationship between OSA and biomarkers of myocardial injury, the population participating in both ARIC and SHHS was predominantly white. To the best of our knowledge, despite findings of significant race-related differences in the sleep architecture and OSA symptoms (2), there is a lack of robust data on the cardiovascular implications of OSA in several ethnic populations, in particular Hispanics (3). Further studies will be necessary to elucidate whether the association between hs-TnT and OSA severity is also applicable to other ethnic populations and to clarify the cardiovascular implications of OSA more generally in these understudied populations. In this respect, several ongoing NHLBI cohort studies, including the Jackson Heart Study in African Americans (4) and the Study of Latinos (5), offer a unique potential opportunity.

Dr. Lin’s letter raises the possibility that the negative association between NT-proBNP and OSA severity noted in our unadjusted analysis may be confounded by the differential distribution of sex by OSA severity. We agree with Dr. Lin that there are important sex-based differences in both the pathophysiology of OSA (6) and the cardiac response to insult and altered loading conditions (7). In our study, the association between OSA and NT-proBNP remained negative and strongly significant (P = 0.007), even after adjusting for sex and age. After further adjusting for body mass index, this association was no longer significant (P = 0.05). Similarly, in our dataset, sex did not modify the association between respiratory disturbance index and NT-proBNP level (P for interaction = 0.21). An exploratory sex-stratified analysis found a negative association in women of marginal significance (P = 0.05) and a null association in men. Our findings indicate a need for further research to address potential sex differences in cardiovascular biomarker responses to OSA-related stresses.
Temporal Trends in Presentation and Survival for HIV-Associated Lymphoma in the Antiretroviral Therapy Era
Authors: S. Gopal, M. R. Patel, E. L. Yanik, S. R. Cole, C. J. Achenbach, S. Napravnik, G. A. Burkholder, E. G. Reid, B. Rodriguez, S. G. Deeks, K. H. Mayer, R. D. Moore, M. M. Kitahata, J. J. Eron, K. L. Richards
Journal: JNCI Journal of the National Cancer Institute (2013)

Lymphoma is the leading cause of cancer-related death among HIV-infected patients in the antiretroviral therapy (ART) era. We studied lymphoma patients in the Centers for AIDS Research Network of Integrated Clinical Systems from 1996 until 2010. We examined differences stratified by histology and diagnosis year. Mortality and predictors of death were analyzed using Kaplan–Meier curves and Cox proportional hazards. Of 23 050 HIV-infected individuals, 476 (2.1%) developed lymphoma (79 [16.6%] Hodgkin lymphoma [HL]; 201 [42.2%] diffuse large B-cell lymphoma [DLBCL]; 56 [11.8%] Burkitt lymphoma [BL]; 54 [11.3%] primary central nervous system lymphoma [PCNSL]; and 86 [18.1%] other non-Hodgkin lymphoma [NHL]). At diagnosis, HL patients had higher CD4 counts and lower HIV RNA than NHL patients. PCNSL patients had the lowest and BL patients had the highest CD4 counts among NHL categories. During the study period, CD4 count at lymphoma diagnosis progressively increased and HIV RNA decreased. Five-year survival was 61.6% for HL, 50.0% for BL, 44.1% for DLBCL, 43.3% for other NHL, and 22.8% for PCNSL. Mortality was associated with age (adjusted hazard ratio [AHR] = 1.28 per decade increase, 95% confidence interval [CI] = 1.06 to 1.54), lymphoma occurrence on ART (AHR = 2.21, 95% CI = 1.53 to 3.20), CD4 count (AHR = 0.81 per 100 cell/µL increase, 95% CI = 0.72 to 0.90), HIV RNA (AHR = 1.13 per log 10 copies/mL, 95% CI = 1.00 to 1.27), and histology but not earlier diagnosis year. HIV-associated lymphoma is heterogeneous and changing, with less immunosuppression and greater HIV control at diagnosis. Stable survival and increased mortality for lymphoma occurring on ART call for greater biologic insights to improve outcomes.
Cloned Glutamate Receptors
Authors: Michael Hollmann, Stephen Heinemann
Journal: Annual Review of Neuroscience (1994)

The application of molecular cloning technology to the study of the glutamate receptor system has led to an explosion of knowledge about the structure, expression, and function of this most important fast excitatory transmitter system in the mammalian brain. The first functional ionotropic glutamate receptor was cloned in 1989 (Hollmann et al 1989) , and the results of this molecular-based approach over the past three years are the focus of this review. We discuss the implications of and the new questions raised by this work-which is probably only a glance at this fascinating and complex signaling system found in brains from the snails to man. Glutamate receptors are found throughout the mammalian brain, where they constitute the major excitatory transmitter system. The longest-known and best-studied glutamate receptors are ligand-gated ion channels, also called ionotropic glutamate receptors , which are permeable to cations. They have traditionally been classified into three broad subtypes based upon pharmaco­ logical and electrophysiological data: a-amino-3-hydroxy-5-methyl-4isoxazole propionate (AMPA) receptors, kainate (KA) receptors , and N-methyl-D-aspartate (NMDA) receptors. Recently, however, a family of G protein-coupled glutamate receptors , which are also called metabotropic glutamate or transl -aminocyclopentanel ,3-dicarboxylate (tACPD) recep­ tors, was identified (Sugiyama et al 1987) . (For reviews of the classification and the pharmacological and electrophysiological properties of glutamate receptors see Mayer & Westbrook 1987, Collingridge & Lester 1989, Honore 1989, Monaghan et al 1989, Wroblewski & Danysz 1 989, Hansen &