tbuckley/cabot-search huggingface dataset:
6-Formylindolo (3,2-b)carbazole (FICZ) enhances retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells
Authors: Rodica P Bunaciu, Andrew Yen
Journal: Molecular Cancer (2013)

The aryl hydrocarbon receptor (AhR) ligand 6-Formylindolo(3,2-b)carbazole (FICZ) has received increasing attention since its identification as an endogenous AhR ligand and a photoproduct of tryptophan. FICZ and its metabolites have been detected in human fluids. We recently reported that AhR promotes retinoic acid (RA)-induced granulocytic differentiation of HL-60 myeloblastic leukemia cells by restricting the nuclear abundance of the stem cell associated transcription factor Oct4. The standard clinical management of acute promyelocytic leukemia (APL) is differentiation induction therapy using RA. But RA is not effective for other myeloid leukemias, making the mechanism of RA-induced differentiation observed in a non-APL myeloid leukemia of interest. To our knowledge, this is the first study regarding the influence of FICZ on RA-induced differentiation in any type of leukemic blasts. Using flow cytometry and Western blotting assays, we determined the effects of FICZ on RA-induced differentiation of HL-60 human leukemia cells. All experiments were performed in triplicate. The groups RA and FICZ + RA were compared using the Paired-Samples T-Test. Western blot figures present the typical blots. We demonstrate that FICZ enhances RA-induced differentiation, assessed by the expression of the membrane differentiation marker CD11b; cell cycle arrest; and the functional differentiation marker, inducible-oxidative metabolism. FICZ causes changes in signaling events that are known to drive differentiation, and notably augments the RA-induced sustained activation of the RAF/MEK/ERK axis of the mitogen-activated protein kinase (MAPK) cascade. FICZ also augments expression of the known MAPK signaling regulatory molecules c-Cbl, VAV1, pY458 p85 PI3K, Src-family kinases (SFKs), and IRF-1, a transcription factor associated with this putative signalsome that promotes RA-induced differentiation. Moreover, FICZ in combination with RA also increases expression of AhR and even more so of both Cyp1A2 and p47phox, which are known to be transcriptionally regulated by AhR. pY1021 PDGFRβ, a marker associated with retinoic acid syndrome was also increased. Our data suggest that FICZ modulates intracellular signaling pathways and enhances RA-induced differentiation.
<i>Yersinia</i> virulence factor YopJ acts as a deubiquitinase to inhibit NF-κB activation
Authors: Honglin Zhou, Denise M. Monack, Nobuhiko Kayagaki, Ingrid Wertz, Jianpin Yin, Beni Wolf, Vishva M. Dixit
Journal: The Journal of Experimental Medicine (2005)

The bacterial pathogens of the genus Yersinia, the causative agents of plague, septicemia, and gastrointestinal syndromes, use a type III secretion system to inject virulence factors into host target cells. One virulence factor, YopJ, is essential for the death of infected macrophages and can block host proinflammatory responses by inhibiting both the nuclear factor κB (NF-κB) and mitogen-activated protein kinase pathways, which might be important for evasion of the host immune response and aid in establishing a systemic infection. Here, we show that YopJ is a promiscuous deubiquitinating enzyme that negatively regulates signaling by removing ubiquitin moieties from critical proteins, such as TRAF2, TRAF6, and IκBα. In contrast to the cylindromatosis tumor suppressor CYLD, which attenuates NF-κB signaling by selectively removing K63-linked polyubiquitin chains that activate IκB kinase, YopJ also cleaves K48-linked chains and thereby inhibits proteasomal degradation of IκBα. YopJ, but not a catalytically inactive YopJ mutant, promoted deubiquitination of cellular proteins and cleaved both K48- and K63-linked polyubiquitin. Moreover, an in vitro assay was established to demonstrate directly the deubiquitinating activity of purified YopJ.
Physiological Studies with Somatocrinin, A Growth Hormone-Releasing Factor
Authors: W B Wehrenberg, A Baird, F Zeytin, F Esch, P Bohlen, N Ling, S Y Ying, R Guillemin
Journal: The Annual Review of Pharmacology and Toxicology (1985)

Physiological Studies with Somatocrinin, A Growth Hormone-Releasing Factor, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/pharmtox/25/1/annurev.pa.25.040185.002335-1.gif
Phase I Dose-Escalation Study of the Novel Antiandrogen BMS-641988 in Patients with Castration-Resistant Prostate Cancer
Authors: Dana Rathkopf, Glenn Liu, Michael A. Carducci, Mario A. Eisenberger, Aseem Anand, Michael J. Morris, Susan F. Slovin, Yasutsuna Sasaki, Shunji Takahashi, Seiichiro Ozono, Nga Kit Eliza Fung, Shinta Cheng, Jinping Gan, Marco Gottardis, Mary T. Obermeier, Jyotsna Reddy, Steven Zhang, Blisse J. Vakkalagadda, Leila Alland, George Wilding, Howard I. Scher
Journal: Clinical Cancer Research (2010)

BMS-641988 is an androgen receptor antagonist with increased potency relative to bicalutamide in both in vitro and in vivo prostate cancer models. A first-in-man phase I study was conducted to define the safety and tolerability of oral BMS-641988 in patients with castration-resistant prostate cancer (CRPC).Doses were escalated from 5 to 150 mg based on discrete pharmacokinetic parameters in cohorts of three to six subjects. After establishing safety with 20 mg of BMS-641988 in the United States, a companion study was opened in Japan to assess differences in drug metabolism between populations.Sixty-one men with CRPC were treated with daily BMS-641988. The pharmacokinetics (PK) of BMS-641988 and its active metabolites were proportional to dose. One patient experienced an epileptic seizure at a dose of 60 mg administered twice. Despite achieving target drug exposures, antitumor activity was limited to one partial response. Seventeen of 23 evaluable patients (74%) exhibited stable disease on imaging (median 15 weeks; range 8-32), and 10 of 61 patients (16%) achieved a ≥ 30% decline in levels of prostate-specific antigen (PSA). Partial agonism was seen within the context of this study upon removal of the drug as evidenced by a decrease in PSA.Although the clinical outcomes of predominantly stable disease and partial agonism were similar to what was observed in the preclinical evaluation of the compound, the limited antitumor activity of BMS-641988 at therapeutic dose levels coupled with an episode of seizure activity led to study closure.
Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells
Authors: Ying Wang, Chang Han, Lu Lu, Susan Magliato, Tong Wu
Journal: Hepatology (2013)

Hedgehog (Hh) signaling plays an important role in embryonic development and in the regulation of a variety of cellular functions. Aberrant activation of Hh signaling has been implicated in several human cancers including hepatocellular carcinoma (HCC). In this study we examined the pathobiological functions and molecular mechanisms of the Hh signaling pathway in HCC cells. Treatment of cultured human HCC cells (Huh7, Hep3B, and HepG2) with the Hh signaling ligand (recombinant Shh) or agonist, SAG and purmorphamine, prevented the induction of autophagy. In contrast, GANT61 (a small molecule inhibitor of Gli1 and Gli2) induced autophagy, as determined by immunoblotting for microtubule-associated protein light chain 3 (LC3) and p62, GFP-LC3 puncta, monodansylcadaverine (MDC) staining, and transmission electron microscopy. Hh inhibition-induced autophagy was associated with up-regulation of Bnip3, as determined by immunoblotting and real-time polymerase chain reaction (PCR) assay. Knockdown of Bnip3 by RNAi impaired GANT61-induced autophagy. Additionally, Hh inhibition-induced autophagy was associated with Bnip3-mediated displacement of Bcl-2 from Beclin-1, as determined by immunoblotting and immunoprecipitation assays. Furthermore, inhibition of Hh signaling increased HCC cell apoptosis and decreased cell viability, as determined by caspase and WST-1 assays. Pharmacological or genetic inhibition of autophagy by 3-methyladenine (3-MA) or Beclin-1 small interfering RNA (siRNA) partially suppressed GANT61-induced cell apoptosis and cytotoxicity. In a tumor xenograft model using SCID mice inoculated with Huh7 cells, administration of GANT61 inhibited tumor formation and decreased tumor volume; this effect was partially blocked by the autophagy inhibitor, 3-MA. Conclusion: These findings provide novel evidence that Hh inhibition induces autophagy through up-regulation of Bnip3 and that this mechanism contributes to apoptosis. Therefore, the status of autophagy is a key factor that determines the therapeutic response to Hh-targeted therapies. (Hepatology 2013;53:995–1010)
Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography
Authors: Jorma Wartiovaara, Lars-Göran Öfverstedt, Jamshid Khoshnoodi, Jingjing Zhang, Eetu Mäkelä, Sara Sandin, Vesa Ruotsalainen, R. Holland Cheng, Hannu Jalanko, Ulf Skoglund, Karl Tryggvason
Journal: Journal of Clinical Investigation (2004)

Nephrin is a key functional component of the slit diaphragm, the structurally unresolved molecular filter in renal glomerular capillaries. Abnormal nephrin or its absence results in severe proteinuria and loss of the slit diaphragm. The diaphragm is a thin extracellular membrane spanning the approximately 40-nm-wide filtration slit between podocyte foot processes covering the capillary surface. Using electron tomography, we show that the slit diaphragm comprises a network of winding molecular strands with pores the same size as or smaller than albumin molecules, as demonstrated in humans, rats, and mice. In the network, which is occasionally stratified, immunogold-nephrin antibodies labeled individually detectable globular cross strands, about 35 nm in length, lining the lateral elongated pores. The cross strands, emanating from both sides of the slit, contacted at the slit center but had free distal endings. Shorter strands associated with the cross strands were observed at their base. Immunolabeling of recombinant nephrin molecules on transfected cells and in vitrified solution corroborated the findings in kidney. Nephrin-deficient proteinuric patients with Finnish-type congenital nephrosis and nephrin-knockout mice had only narrow filtration slits that lacked the slit diaphragm network and the 35-nm-long strands but contained shorter molecular structures. The results suggest the direct involvement of nephrin molecules in constituting the macromolecule-retaining slit diaphragm and its pores.
Systemic Administration of a Conditionally Replicating Adenovirus, Targeted to Angiogenesis, Reduced Lung Metastases Burden in Cotton Rats
Authors: Michael Peled, Aviv Shaish, Avi Katav, Shoshana Greenberger, Iris Barshack, Reshef Tal, Livnat Bangio, Eyal Breitbart, Dror Harats
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Angiogenesis is an essential process for solid tumor development. To interfere with angiogenesis, AdPPE3x-E1, an adenovirus that is transcriptionally targeted to replicate in angiogenic endothelial cells, was constructed, by replacing the E1 promoter with the modified preproendothelin-1 promoter, PPE-1-3x, previously shown to induce specific transcription in angiogenic endothelial cells. Experimental Design: The specificity of AdPPE3x-E1 to endothelial cells was shown by quantitative PCR and immunostaining, and its antiangiogenic effect was evaluated in Matrigel models. The in vivo efficacy of AdPPE3x-E1 was also tested in a cotton rat lung metastases model. Results: The replication rate of AdPPE3x-E1 in endothelial cells was similar to that of AdCMV-E1, a nonselective replicating adenovector, but the replication rate was reduced up to 60-fold in nonendothelial cells. Moreover, AdPPE3x-E1 reduced endothelial cell viability by 90% whereas nonendothelial cells were not affected. In in vitro and in vivo Matrigel models, endothelial cells infected with AdPPE3x-E1 did not develop capillary-like structures. The systemic administration of AdPPE3x-E1 reduced the lung metastases burden in a cotton rat model by 55%, compared with saline-treated rats, without significant evidence of toxicity. Quantitative PCR analysis showed that the viral copy number of AdPPE3x-E1 was increased 3-fold in the lung metastases but not in the liver, compared with a nonreplicating adenovector control. Conclusions: We have shown here for the first time an antimetastatic effect induced by an angiogenesis-transcriptionally targeted adenovirus following systemic administration. Because adenovirus replication is more efficient in humans than in cotton rats, we assume a significant effect for AdPPE3x-E1 treatment in fighting human solid tumors and metastases.
Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial
Authors: Connie Celum, Anna Wald, James Hughes, Jorge Sanchez, Stewart Reid, Sinead Delany-Moretlwe, Frances Cowan, Martin Casapia, Abner Ortiz, Jonathan Fuchs, Susan Buchbinder, Beryl Koblin, Sheryl Zwerski, Scott Rose, Jing Wang, Lawrence Corey
Journal: The Lancet (2008)
Hospital Volume and Outcomes of Mechanical Ventilation
Authors: Onyebuchi A. Arah
Journal: New England Journal of Medicine (2006)

To the Editor: In the article by Kahn et al. (July 6 issue),1 the number of patients receiving mechanical ventilation per hospital bed was about 0.7 per year in hospitals in the lowest quartile of hospital volume (≥150 patients per year), as compared with 1.6 per year in hospitals in the highest quartile of volume (>400 patients per year). The decision to initiate mechanical ventilation in a given patient rests on the course of the disease, the quality of nursing, and the availability of ventilators. Thus, among patients with identical Acute Physiology and Chronic Health Evaluation (APACHE) scores, the proportion admitted to an intensive care unit (ICU) may vary among hospitals. In equally good units, the number of deaths will be the same, given a low threshold and good clinical judgment. However, mortality will fall as the number of patients who undergo mechanical ventilation rises, as suggested by Figure 2 in the article.
Antigen-induced B lymphocyte activation involves the p21ras and ras.GAP signaling pathway.
Authors: A H Lazarus, K Kawauchi, M J Rapoport, T L Delovitch
Journal: The Journal of Experimental Medicine (1993)

Ligation of a B lymphocyte surface immunoglobulin (sIg) antigen receptor (AgR) by its specific Ag ligand initiates a signaling pathway that culminates in B cell activation. However, many events of this pathway have not been elucidated. Here we present three novel findings that demonstrate directly that AgR-mediated signaling in B cells functions by the p21ras/ras.GAP-dependent pathway. First, stimulation of TA3 7.9 Ag-specific murine B lymphoma cells for 2 min with either Ag or F(ab')2 anti-IgM induces p21ras activation as measured by an increase in the GTP/GDP ratio of its bound nucleotides. This activation of p21ras does not occur via a change in its guanine nucleotide exchange rate. Second, Ag stimulation results in the inhibition of activity of p120 ras.GAP, a protein that regulates p21ras activation. Tyrosine phosphorylation of ras.GAP occurs within 1 min after Ag stimulation but is no longer detectable at 20 min after stimulation, at which time ras.GAP activity remains inhibited. Thus, tyrosine phosphorylation of ras.GAP is not required for the inhibition of its activity. Third, despite the role proposed for a ras.GAP-associated p190 protein in the control of ras.GAP activity in B cells, p190 was not detectable either in anti-ras.GAP immunoprecipitates of [35S]methionine labeled lysates of Ag-stimulated or -unstimulated 7.9 cells or as a tyrosine phosphoprotein in Western blots of anti-ras.GAP immunoprecipitates of Ag-stimulated 7.9 cell lysates. Inasmuch as the TA3 7.9 B lymphoma is representative of a mature, sIgM-bearing B cell, our observations raise the intriguing possibility that the capacity of p190 to associate with ras.GAP and regulate the activities of ras.GAP and p21ras in a B cell is dependent on the stage of differentiation of the B cell.
Geographical variation and incidence of inflammatory bowel disease among US women
Authors: Hamed Khalili, Edward S Huang, Ashwin N Ananthakrishnan, Leslie Higuchi, James M Richter, Charles S Fuchs, Andrew T Chan
Journal: Gut (2012)

Geographical variation in the incidence of Crohn's disease (CD) and ulcerative colitis (UC) according to the latitude of residence has been reported in Europe. However, there are no comparable data in the USA. The incidence of CD and UC in relation to latitude was assessed in a geographically diverse population of women enrolled in two large prospective studies in the USA.A prospective study was undertaken of women enrolled in the Nurses' Health Study I (NHS) in 1976 and in the NHS II in 1989. Information on state of residence at the time of birth, at age 15 years and age 30 years was collected in 1992 in NHS I and in 1993 in NHS II. Reported diagnoses of incident CD or UC to the end of 2003 were confirmed by medical record review. Cox proportional hazards models were used to calculate HRs and 95% CIs for risk of CD and UC.In both cohorts, among 175,912 women reporting their residence in 1992, 257 cases of CD and 313 cases of UC were documented over 3,428,376 person-years of follow-up. The incidence of CD and UC increased significantly with increasing latitude (p(trend)<0.01), with residence at age 30 years more strongly associated with risk. Compared with women residing in northern latitudes at age 30, the multivariate-adjusted HR for women residing in southern latitudes was 0.48 (95% CI 0.30 to 0.77) for CD and 0.62 (95% CI 0.42 to 0.90) for UC. The effect of latitude of residence on risk of CD and UC did not vary according to smoking history (p(interaction)=0.26 for CD and 0.99 for UC).In a population of US women, increasing latitude of residence was associated with a higher incidence of CD and UC.
CHEMOKINES, SPHINGOSINE-1-PHOSPHATE, AND CELL MIGRATION IN SECONDARY LYMPHOID ORGANS
Authors: Jason G. Cyster
Journal: Annual Review of Immunology (2004)

Secondary lymphoid organs serve as hubs for the adaptive immune system, bringing together antigen, antigen-presenting cells, and lymphocytes. Two families of G protein-coupled receptors play essential roles in lymphocyte migration through these organs: chemokine receptors and sphingosine-1-phosphate (S1P) receptors. Chemokines expressed by lymphoid stromal cells guide lymphocyte and dendritic cell movements during antigen surveillance and the initiation of adaptive immune responses. S1P receptor-1 is required for lymphocyte egress from thymus and secondary lymphoid organs and is downregulated by the immunosuppressive drug FTY720. Here, we review the steps associated with the initiation of adaptive immune responses in secondary lymphoid organs, highlighting the roles of chemokines and S1P.
The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis
Authors: Kevin L Winthrop, Joel Silverfield, Arthur Racewicz, Jeffrey Neal, Eun Bong Lee, Pawel Hrycaj, Juan Gomez-Reino, Koshika Soma, Charles Mebus, Bethanie Wilkinson, Jennifer Hodge, Haiyun Fan, Tao Wang, Clifton O Bingham
Journal: Annals of the Rheumatic Diseases (2015)

Objective To evaluate tofacitinib's effect upon pneumococcal and influenza vaccine immunogenicity. Methods We conducted two studies in patients with rheumatoid arthritis using the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and the 2011–2012 trivalent influenza vaccine. In study A, tofacitinib-naive patients were randomised to tofacitinib 10 mg twice daily or placebo, stratified by background methotrexate and vaccinated 4 weeks later. In study B, patients already receiving tofacitinib 10 mg twice daily (with or without methotrexate) were randomised into two groups: those continuing (‘continuous’) or interrupting (‘withdrawn’) tofacitinib for 2 weeks, and then vaccinated 1 week after randomisation. In both studies, titres were measured 35 days after vaccination. Primary endpoints were the proportion of patients achieving a satisfactory response to pneumococcus (twofold or more titre increase against six or more of 12 pneumococcal serotypes) and influenza (fourfold or more titre increase against two or more of three influenza antigens). Results In study A (N=200), fewer tofacitinib patients (45.1%) developed satisfactory pneumococcal responses versus placebo (68.4%), and pneumococcal titres were lower with tofacitinib (particularly with methotrexate). Similar proportions of tofacitinib-treated and placebo-treated patients developed satisfactory influenza responses (56.9% and 62.2%, respectively), although fewer tofacitinib patients (76.5%) developed protective influenza titres (≥1:40 in two or more of three antigens) versus placebo (91.8%). In study B (N=183), similar proportions of continuous and withdrawn patients had satisfactory responses to PPSV-23 (75.0% and 84.6%, respectively) and influenza (66.3% and 63.7%, respectively). Conclusions Among patients starting tofacitinib, diminished responsiveness to PPSV-23, but not influenza, was observed, particularly in those taking concomitant methotrexate. Among existing tofacitinib users, temporary drug discontinuation had limited effect upon influenza or PPSV-23 vaccine responses. Trial registration numbers NCT01359150, NCT00413699 .
One-Night Mandibular Advancement Titration for Obstructive Sleep Apnea Syndrome
Authors: Boris Pételle, Gerard Vincent, Frédéric Gagnadoux, Dominique Rakotonanahary, Bernard Meyer, Bernard Fleury
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

The effect of a dental appliance (DA) is usually evaluated in a single mandibular position reached after several weeks and corresponding to either improvement of symptoms or intolerance to any further advancement. The purpose of this study was to test the feasibility of one-night evaluation of the efficacy of a DA. The study population consisted of seven patients (six men) with obstructive sleep apnea syndrome (66.9 ± 32.4 apneas and/or hypopneas per hour). Patients underwent two consecutive polysomnographies; first with a temporary DA (two arches connected by a hydraulic system) progressively adjusted during the night to correct sleep disordered breathing and second with a permanent DA (two arches connected by Herbst attachments) set to the effective degree of advancement during the titration night. All patients completed the protocol. The mean mandibular advancement reached during the titration night was 12.6 ± 2.7 mm. Arousal was never observed during or for 60 seconds following advancement. The apnea–hypopnea index (AHI) was significantly reduced from 66.9 ± 32.4 to 26.1 ± 20.7 per hour during the titration night from the diagnostic night (p < 0.01). During the second night, the AHI was 19.6 ± 20.2 per hour and was less than 20 per hour in 71.4% of patients and less than 10 per hour in 42.9% of patients. The efficacy of a DA can be evaluated during a single night of polysomnography.
Delayed skin test reactivity to Propionibacterium acnes correlates with severity of inflammation in acne vulgaris
Authors: P. KERSEY, M. SUSSMAN, M. DAHL
Journal: British Journal of Dermatology (1980)

Propionibacterium acnes is the bacterial species most consistently isolated from acne lesions. Intradermal injection of a heat-killed suspension of P. acnes induced a delayed erythematous and often popular inflammatory reaction which was maximal after 24-48 h. This response was dose related and was probably mediated at least partly by immune mechanisms. In eighty-one subjects with acne of varying severity of the acne. These findings indicate that the host response to P. acnes is an important variable in determining the severity of inflammatory acne.