Publications by authors named "Linda Higgins"

58 Publications

How Successful Are Residents and Fellows at Quality Improvement?

J Healthc Qual 2020 Jul/Aug;42(4):e50-e57

Background: Nationally, there is an expectation that residents and fellows participate in quality improvement (QI), preferably interprofessionally. Hospitals and educators invest time and resources in projects, but little is known about success rates or what fosters success.

Purpose: To understand what proportion of trainee QI projects were successful and whether there were predictors of success.

Methods: We examined resident and fellow QI projects in an integrated healthcare system that supports diverse training programs in multiple hospitals over 2 years. All projects were reviewed to determine whether they represented actual QI. Projects determined as QI were considered completed or successful based on QI project sponsor self-report. Multiple characteristics were compared between successful and unsuccessful projects.

Results: Trainees submitted 258 proposals, of which 106 (41.1%) represented actual QI. Non-QI projects predominantly represented needs assessments or retrospective data analyses. Seventy-six percent (81/106) of study sponsors completed surveys about their projects. Less than 25% of projects (59/258) represented actual QI and were successful. Project category was predictive of success, specifically those aimed at preventive care or education.

Conclusion: Less than a quarter of trainee QI projects represent successful QI.

Implications: Hospitals and training programs should identify interventions to improve trainee QI experience.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JHQ.0000000000000258DOI Listing
January 2021

Hospital Nurses' Work Activity in a Technology-Rich Environment: A Triangulated Quality Improvement Assessment.

J Nurs Care Qual 2017 Jul/Sep;32(3):208-217

Wolff Center at UPMC, Pittsburgh, Pennsylvania (Dr Higgins and Mss Shovel, Martin, Rogers, and Minnier and Mr Bilderback); and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Mss Lorenz and Minnier).

The aim of this project was to describe hospital nurses' work activity through observations, nurses' perceptions of time spent on tasks, and electronic health record time stamps. Nurses' attitudes toward technology and patients' perceptions and satisfaction with nurses' time at the bedside were also examined. Activities most frequently observed included documenting in and reviewing the electronic health record. Nurses' perceptions of time differed significantly from observations, and most patients rated their satisfaction with nursing time as excellent or good.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/NCQ.0000000000000237DOI Listing
August 2017

Can a selective PPARγ modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone?

Diabetes Care 2014 Jul 10;37(7):1918-23. Epub 2014 Apr 10.

Center for Human Nutrition, University of Texas Southwestern Medical Center and VA North Texas Healthcare System, Dallas, TX

Objective: INT131 besylate is a potent, nonthiazolidinedione, selective peroxisome proliferator-activated receptor γ (PPARγ) modulator (SPPARM) designed to improve glucose metabolism while minimizing the side effects of full PPARγ agonists. This placebo-controlled study compared the efficacy and side effects of INT131 besylate versus 45 mg pioglitazone HCl in subjects with type 2 diabetes (T2D).

Research Design And Methods: This was a 24-week randomized, double-blind, placebo- and active-controlled study of 0.5-3.0 mg INT131 versus 45 mg pioglitazone or placebo daily in 367 subjects with T2D on sulfonylurea or sulfonylurea plus metformin. The primary efficacy analysis was the comparison of change from baseline to week 24 in hemoglobin A1c (HbA1c) across treatment groups. Fluid status was assessed with a prospective scoring system for lower-extremity pitting edema.

Results: INT131 had a steep dose response for efficacy as measured by changes in HbA1c. After 24 weeks' treatment, the 0.5-mg dose demonstrated minimal efficacy (HbA1c -0.3 ± 0.12%) and the 2-mg dose demonstrated near-maximal efficacy (HbA1c -1.1 ± 0.12%), which was not statistically different from the efficacy of 45 mg pioglitazone (HbA1c -0.9 ± 0.12%; P < 0.01 for noninferiority). With the 1-mg dose, INT131 provided significant improvements in glycemic control (HbA1c 0.8 ± 0.12; P < 0.001 vs. placebo) but with less edema, weight gain, and hemodilution than observed with 45 mg pioglitazone.

Conclusions: INT131 demonstrated dose-dependent reductions in HbA1c, equivalent to 45 mg pioglitazone, but with less fluid accumulation and weight gain, consistent with its SPPARM design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc13-2480DOI Listing
July 2014

Parent and child perceptions of a self-regulated, home-based exercise program for children with cystic fibrosis.

Nurs Res 2013 Sep-Oct;62(5):305-14

College of Nursing, Ohio State University, Columbus, OH 43210, USA.

Background: Despite recognized benefits, many children with cystic fibrosis (CF) do not consistently participate in physical activities. There is little empirical literature regarding the feelings and attitudes of children with CF toward exercise programs, parental roles in exercise, or factors influencing exercise experiences during research participation.

Objectives: The aim of this study is to describe the exercise experiences of children with CF and their parents during participation in a 6-month program of self-regulated, home-based exercise.

Methods: This qualitative descriptive study was nested within a randomized controlled trial of a self-regulated, home-based exercise program and used serial semistructured interviews conducted individually at 2 and 6 months with 11 purposively selected children with CF and their parent(s).

Results: Six boys and five girls, ages 10-16 years, and parents(nine mothers, four fathers) participated in a total of 44 interviews. Five major thematic categories describing child and parent perceptions and experience of the bicycle exercise program were identified in the transcripts: (a) motivators, (b) barriers, (c) effort/work, (d) exercise routine, and (e) sustaining exercise. Research participation, parent-family participation, health benefits, and the child's personality traits were the primary motivators. Competing activities, priorities, and responsibilities were the major barriers in implementing the exercise program as prescribed. Motivation waned, and the novelty wore off for several (approximately half) parent-child dyads, who planned to decrease or stop the exercise program after the study ended.

Discussion: We identified motivators and barriers to a self-regulated, home-based exercise program for children with CF that can be addressed in planning future exercise interventions to maximize the health benefits for children with CF and the feasibility and acceptability to the children and their families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/NNR.0b013e3182a03503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053557PMC
November 2013

Exercise intensity self-regulation using the OMNI scale in children with cystic fibrosis.

Pediatr Pulmonol 2013 May 19;48(5):497-505. Epub 2012 Sep 19.

Schools of Medicine and Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.

Prescribing exercise at intensities that improve fitness is difficult in children with cystic fibrosis (CF) due to ventilatory limitations and fluctuating health status. Our aim was to determine if children with CF could regulate the intensity of cycle ergometer and treadmill exercise using target ratings of perceived exertion (RPE) derived from the Children's OMNI Scale. We examined prescription congruence (similar oxygen consumption [VO₂] and heart rate [HR] for target RPE) and intensity discrimination (different VO₂ and HR for different RPEs), from cycle to cycle and cycle to treadmill. Subjects were 24 children (12 male, 12 female), aged 10-17 years with varying disease severity. Each child participated in one orientation, one estimation trial (graded maximal exercise test), and two production trials (cycle and treadmill, alternating between RPE 4 and 7). At RPE 4, congruence was evident for both VO₂ and HR on the treadmill. On the cycle at RPE 4, VO₂ was significantly higher only in the first production trial, although HRs tended to be higher in the production trials than the estimation trial. Prescription congruence was also supported at RPE 7, with no significant differences in VO₂ or HR between estimation and production trials on cycle or treadmill. Results fully supported intensity discrimination, with significant differences between VO₂ and HR at RPE 4 and 7 (P < 0.0001). Children with CF appear capable of using the OMNI Scale to regulate cycle and treadmill exercise intensity. Training using this methodology has the potential to promote fitness in children with CF of varying severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ppul.22639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541455PMC
May 2013

Selective modulation of PPARγ activity can lower plasma glucose without typical thiazolidinedione side-effects in patients with Type 2 diabetes.

J Diabetes Complications 2011 May-Jun;25(3):151-8. Epub 2010 Aug 23.

Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75230-9052, USA.

Objective: INT131 besylate is a potent non-thiazolidinedione selective peroxisome proliferator-activated receptor γ (PPARγ) modulator (SPPARM) designed to improve insulin sensitivity and glucose metabolism while minimizing the side effects of full agonist thiazolidinediones. This study was conducted to determine short-term efficacy and safety of INT131 besylate in patients with Type 2 diabetes mellitus (T2DM).

Research Design And Methods: This was a 4-week randomized, double-blind, placebo-controlled multi-center study with 1 or 10mg INT131 besylate or placebo daily in subjects with T2DM not receiving pharmacotherapy for their hyperglycemia. The primary efficacy analysis was the comparison of treatment groups with respect to least square mean change from baseline to Week 4 of fasting plasma glucose (FPG).

Results: Baseline mean (± S.D.) FPG for the study population was 171 ± 42 mg/dl. Change in FPG (± S.E., mg/dl) from baseline after 4 weeks was 8 ± 8 (P=NS) with placebo, -22 ± 8 with 1mg INT131 besylate (P=.0056) and -46 ± 7 with 10mg INT131 besylate (P<.0001). Modeling of available data from the literature of the effect of rosiglitazone under similar study conditions suggested that 1 mg of INT131 besylate had a similar reduction in FPG as expected with 8 mg of rosiglitazone. INT131 besylate was well tolerated, and the 1 mg dose demonstrated no evidence of fluid retention or weight gain.

Conclusions: INT131 besylate demonstrated a dose dependent reduction in FPG. The FPG reduction with 1mg INT131 besylate was comparable to the modeled 8 mg dose of rosiglitazone, and did not cause fluid retention or weight gain. These results are consistent with the INT131 SPPARM design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jdiacomp.2010.06.006DOI Listing
August 2011

P38alpha-selective mitogen-activated protein kinase inhibitor for improvement of cultured human islet recovery.

Pancreas 2010 May;39(4):436-43

Southern California Islet Cell Resources Center, Department of Diabetes, Endocrinology and Metabolism, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.

Objectives: We investigated whether the recovery of cultured human islets is improved through the addition of a p38alpha-selective mitogen-activated protein kinase inhibitor, SD-282, to clinically used serum-free culture medium.

Methods: Immediately after isolation, islets were cultured for 24 hours in medium alone (control) or medium containing dimethyl sulfoxide, 0.1 microM SD-282, or 0.3 microM SD-282. Cytokine expression, apoptotic beta-cell percentage, and islet function were assessed postculture.

Results: Expression of p38 and phosphorylated p38 in islets increased during culture. Interleukin 6 mRNA expression in cultured islets, as well as IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor released into the medium, was significantly reduced by adding SD-282. The apoptotic beta-cell percentage was significantly lower in islets cultured with 0.1 microM SD-282, but not 0.3 microM, as compared with the control. Stimulation indices measured in vitro were higher but without significance (P = 0.06); the function of transplanted islets in diabetic NOD-scid mice was also better in 0.1-microM SD-282 group as compared with control.

Conclusions: Better islet function was obtained by adding 0.1 microM SD-282 to the serum-free culture medium. This improvement was associated with suppression of cytokine production and prevention of beta-cell apoptosis. However, this beneficial effect was diminished at a higher concentration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPA.0b013e3181c0dd8fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860020PMC
May 2010

Topical alpha-selective p38 MAP kinase inhibition reduces acute skin inflammation in guinea pig.

J Inflamm Res 2010 18;3:9-16. Epub 2010 Feb 18.

Scios Inc, Fremont, CA, USA.

Certain skin pathologies, including psoriasis, are thought to be immune-mediated inflammatory diseases. Available literature clearly indicates the involvement of inflammatory cells (neutrophils, T cells, and macrophages), their cytokines, and the p38 mitogen-activated protein kinase (MAPK) signaling pathway in the pathophysiology of psoriasis. Neutrophils play an important role in the formation of acute inflammatory changes in psoriasis. Acute inflammation or acute flares in psoriasis remain poorly addressed in clinical medicine. In this communication, we first establish a simple and reproducible model for studying neutrophil-mediated acute skin inflammation. Using the hairless guinea pig, due to the similarity of skin architecture to that of human, acute inflammation was induced with an intradermal injection of 50 μg/mL lipopolysaccharide (LPS) in 50 μL solution. Myeloperoxidase (MPO) activity was measured by MPO-positive neutrophils and shown to increase for 24-hours post-injection. Simultaneously, the level of phosphorylated p38 MAPK was documented for 48-hours post-LPS injection in the skin. Next, we used this model to examine the therapeutic potential of an α-selective p38 MAPK inhibitor, SCIO-469. A comparison of topical application of SCIO-469 at 5 mg/mL or 15 mg/mL to vehicle revealed that SCIO-469 dose-dependently reduces acute skin inflammation and that this effect is statistically significant at the higher dose. Further examination of tissues that received this dose also revealed statistically significant reduction of MPO activity, phosphorylated p38 MAPK, interleukin-6, and cyclooxygenase-2. These data suggest that the α-selective p38 MAPK inhibitor, SCIO-469, acts as a topical anti-inflammatory agent via the p38 MAPK pathway to reduce neutrophil induced acute inflammation in the skin. These observations suggest that α-selective p38 MAPK inhibition may be an effective therapeutic strategy to manage acute skin inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218738PMC
http://dx.doi.org/10.2147/jir.s6718DOI Listing
November 2011

Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulation as a strategy for safer therapeutic PPARgamma activation.

Am J Clin Nutr 2010 Jan 11;91(1):267S-272S. Epub 2009 Nov 11.

InteKrin Therapeutics Inc., Los Altos, CA 94022, USA.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a clinically validated target for treatment of insulin resistance. PPARgamma activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients with type 2 diabetes without the concern for hypoglycemia or gastrointestinal toxicities associated with some other medications used to treat this disease. However, thiazolidinediones are linked to safety and tolerability issues such as weight gain, fluid retention, edema, congestive heart failure, and bone fracture. Distinctive properties of PPARgamma provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPARgamma is a nuclear receptor that forms a complex with coreceptor RXR and a cell type- and cell state-specific array of coregulators to control gene transcription. PPARgamma affinity for these components, and hence transcriptional response, is determined by the conformational changes induced by ligand binding within a complex pocket with multiple interaction points. This molecular mechanism thereby offers the opportunity for selective modulation. A desirable selective PPARgamma modulator profile would include high-affinity interaction with the PPARgamma-binding pocket in a manner that leads to retention of the insulin-sensitizing activity that is characteristic of full agonists as well as mitigation of the effects leading to increased adiposity, fluid retention, congestive heart failure, and bone fracture. Examples of endogenous and synthetic selective PPARgamma modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3945/ajcn.2009.28449EDOI Listing
January 2010

Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart.

J Clin Invest 2009 Apr 9;119(4):986-96. Epub 2009 Mar 9.

Division of Cardiovascular Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

Myocardial Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibition improves cardiac function following myocardial infarction (MI), but the CaMKII-dependent pathways that participate in myocardial stress responses are incompletely understood. To address this issue, we sought to determine the transcriptional consequences of myocardial CaMKII inhibition after MI. We performed gene expression profiling in mouse hearts with cardiomyocyte-delimited transgenic expression of either a CaMKII inhibitory peptide (AC3-I) or a scrambled control peptide (AC3-C) following MI. Of the 8,600 mRNAs examined, 156 were substantially modulated by MI, and nearly half of these showed markedly altered responses to MI with CaMKII inhibition. CaMKII inhibition substantially reduced the MI-triggered upregulation of a constellation of proinflammatory genes. We studied 1 of these proinflammatory genes, complement factor B (Cfb), in detail, because complement proteins secreted by cells other than cardiomyocytes can induce sarcolemmal injury during MI. CFB protein expression in cardiomyocytes was triggered by CaMKII activation of the NF-kappaB pathway during both MI and exposure to bacterial endotoxin. CaMKII inhibition suppressed NF-kappaB activity in vitro and in vivo and reduced Cfb expression and sarcolemmal injury. The Cfb-/- mice were partially protected from the adverse consequences of MI. Our findings demonstrate what we believe is a novel target for CaMKII in myocardial injury and suggest that CaMKII is broadly important for the genetic effects of MI in cardiomyocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI35814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662543PMC
April 2009

p38alpha-selective MAP kinase inhibitor reduces tumor growth in mouse xenograft models of multiple myeloma.

Anticancer Res 2008 Nov-Dec;28(6A):3827-33

Scios Inc, Fremont, CA 94555, USA.

Multiple myeloma (MM) is a clonal plasma cell malignancy, which is currently incurable. Therefore, new mono- or combined therapy treatment regimens in the early and advanced phases of MM are urgently needed to combat this disease. Recently, p38 mitogen-activated protein kinase (MAPK) has been implicated as playing an important role in MM. Therefore, the effect of a p38alpha-selective MAPK inhibitor, SCIO-469 (indole-5-carboxamide, ATP-competitive inhibitor), or its structural analog, SD-282 (indole-5-carboxamide, ATP-competitive inhibitor) was examined in mouse xenograft models of MM using human RPMI-8226 or H-929 plasmacytoma inocula. Oral treatment with SCIO-469 (10, 30, 90 mg/kg) twice daily was initiated in mice with palpable tumors of RPMI-8226 origin, a condition that mimics early human myeloma disease. In mice with palpable tumors, 14 days of SCIO-469 treatment significantly reduced RPMI-8226 tumor growth in a dose-dependent manner. A significant dose-dependent reduction in RPMI-8226 tumor growth was also observed when SCIO-469 oral treatment at doses of 10, 30 and 90 mg/kg twice daily was initiated in mice with tumors of pronounced size, a condition that mimics advanced human myeloma disease. In a similar set of studies employing the SCIO-469 analogue SD-282 at 90 mg/kg/bid orally, histological assessment at the end of the study demonstrated a significant reduction in RPMI-8226 tumor growth and angiogenesis. SD-282 treatment was additionally shown to significantly reduced expression of heat-shock protein-27 (HSP-27) and phospho-p38 in the tumor cells. Furthermore, co-administration of SCIO-469 with dexamethasone elicited antitumor properties in dexamethasone-sensitive H-929 tumors at much lower than the typically effective doses of dexamethasone, suggesting its potential for combined therapy. In conclusion, p38 inhibitors reduced human myeloma cell growth in vivo both at early and advanced phases of the disease. The current study also provides evidence of potential for co-therapy with dexamethasone.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2009

Analgesic effects of p38 kinase inhibitor treatment on bone fracture healing.

Pain 2009 Mar 23;142(1-2):116-26. Epub 2009 Jan 23.

Department of Biochemistry & Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School & Graduate School of Biomedical Sciences, MSB E659, 185 S. Orange Avenue, Newark, NJ, USA.

Traditional and COX-2 selective non-steroidal anti-inflammatory drug (NSAID) treatment inhibits fracture healing in animal models. This indicates that either the inflammatory phase following a bone fracture is necessary for efficient or sufficient bone regeneration to heal the fracture or COX-2 may have a specific function during bone regeneration unrelated to inflammation. These observations also indicate that NSAID use during fracture healing may be contra-indicated. Thus, identification of different analgesics for fracture pain or other orthopaedic surgical procedures would be of significant clinical benefit. Inhibitors of p38 kinase also have significant analgesic properties. However, p38 kinase is a critical regulator of inflammation. To assess the potential use of p38 kinase inhibition as a therapeutic strategy to manage fracture pain, the analgesic properties of SCIO-469, a p38alpha kinase inhibitor, were assessed in a rat fracture model and compared to other common analgesics. In addition, the effects of SCIO-469 treatment on ultimate fracture healing outcomes were measured by radiography and torsional mechanical testing. The data indicate that SCIO-469 was an effective analgesic. No adverse events related to fracture healing were observed in rats treated with SCIO-469. Immunohistochemistry showed that p38 kinase is activated primarily in the first days following a fracture. These observations suggest that p38alpha kinase inhibition may be an effective therapeutic strategy to manage orthopaedic-related pain. These observations also indicate that COX-2 has a specific function during bone regeneration other than promoting inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pain.2008.12.019DOI Listing
March 2009

p38 MAPK inhibition reduces diabetes-induced impairment of wound healing.

Diabetes Metab Syndr Obes 2009 Jun 23;2:91-100. Epub 2009 Jun 23.

Scios Inc., Fremont, CA, USA.

In healthy tissue, a wound initiates an inflammatory response characterized by the presence of a hematoma, infiltration of inflammatory cells into the wound and, eventually, wound healing. In pathological conditions like diabetes mellitus, wound healing is impaired by the presence of chronic nonresolving inflammation. p38 mitogen-activated protein kinase (MAPK) inhibitors have demonstrated anti-inflammatory effects, primarily by inhibiting the expression of inflammatory cytokines and regulating cellular traffic into wounds. The db/db mouse model of type 2 diabetes was used to characterize the time course of expression of activated p38 during impaired wound healing. The p38α-selective inhibitor, SCIO-469, was applied topically and effects on p38 activation and on wound healing were evaluated. A topical dressing used clinically, Promogran™, was used as a comparator. In this study, we established that p38 is phosphorylated on Days 1 to 7 post-wounding in db/db mice. Further, we demonstrated that SCIO-469, at a dose of 10 μg/wound, had a positive effect on wound contraction, granulation tissue formation, and re-epithelialization, and also increased wound maturity during healing. These effects were similar to or greater than those observed with Promogran™. These results suggest a novel approach to prophylactic and therapeutic management of chronic wounds associated with diabetes or other conditions in which healing is impaired.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048002PMC
June 2009

Inhibition of p38alpha MAPK disrupts the pathological loop of proinflammatory factor production in the myelodysplastic syndrome bone marrow microenvironment.

Leuk Lymphoma 2008 Oct;49(10):1963-75

Scios Inc, Fremont, CA, USA.

Myelodysplastic syndromes (MDS) are common causes of ineffective hematopoiesis and cytopenias in the elderly. Various myelosuppressive and proinflammatory cytokines have been implicated in the high rates of apoptosis and hematopoietic suppression seen in MDS. We have previously shown that p38 MAPK is overactivated in MDS hematopoietic progenitors, which led to current clinical studies of the selective p38alpha inhibitor, SCIO-469, in this disease. We now demonstrate that the myelosuppressive cytokines TNFalpha and IL-1beta are secreted by bone marrow (BM) cells in a p38 MAPK-dependent manner. Their secretion is stimulated by paracrine interactions between BM stromal and mononuclear cells and cytokine induction correlates with CD34+ stem cell apoptosis in an inflammation-simulated in vitro bone marrow microenvironment. Treatment with SCIO-469 inhibits TNF secretion in primary MDS bone marrow cells and protects cytogenetically normal progenitors from apoptosis ex vivo. Furthermore, p38 inhibition diminishes the expression of TNFalpha or IL-1beta-induced proinflammatory chemokines in BM stromal cells. These data indicate that p38 inhibition has anti-inflammatory effects on the bone marrow microenvironment that complements its cytoprotective effect on progenitor survival. These findings support clinical investigation of p38alpha as a potential therapeutic target in MDS and other related diseases characterised by inflammatory bone marrow failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428190802322919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735641PMC
October 2008

Role of p38 mitogen-activated protein kinase in ozone-induced airway hyperresponsiveness and inflammation.

Eur J Pharmacol 2008 Dec 30;600(1-3):117-22. Epub 2008 Sep 30.

Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.

Ozone is a potent oxidant and causes airway hyperresponsiveness and neutrophilia. To determine the role of p38 mitogen-activated protein kinase (MAPK) activation, we studied the effect of a p38alpha inhibitor SD-282 (Scios Inc, Fremont, CA USA) on ozone-induced airway hyperresponsiveness and neutrophilia. Balb/c mice received SD-282 (30 or 90 mg/kg i.p) or vehicle 1 h before exposure to either ozone (3 ppm, 3 h) or air. Three hours after exposure, lungs were analysed for cytokine levels and bronchoalveolar lavage was performed. Another set of mice were dosed 6 h after exposure and 1 h before assessing airway hyperresponsiveness. SD-282 (90 mg/kg) significantly inhibited ozone-induced airway hyperresponsiveness (-LogPC(150): SD-282: -1.73+/-0.14 vs. vehicle: -0.99+/-0.15, P<0.05). Bronchoalveolar lavage neutrophil numbers were time-dependently increased in vehicle-dosed, ozone-exposed mice, greatest at 20-24 h after exposure. SD-282 (30 and 90 mg/kg) significantly inhibited ozone induced neutrophil numbers at 3 h and 20-24 h after ozone SD-282 significantly inhibited ozone-induced increases in phosphorylated p38 MAPK expression, and in cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and IL-1beta but not MIP-1alpha gene expression. We conclude that p38 MAPK is involved in ozone-induced airway hyperresponsiveness and lung neutrophilia. Inhibition of p38 MAPK with small molecule kinase inhibitors may be a means of reducing ozone-induced inflammation and airway hyperresponsiveness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2008.09.031DOI Listing
December 2008

The Development of INT131 as a Selective PPARgamma Modulator: Approach to a Safer Insulin Sensitizer.

PPAR Res 2008 ;2008:936906

InteKrin Therapeutics, Inc., 4300 El Camino Real, Suite 201, Los Altos, CA 94022, USA.

INT131 (formerly T0903131, T131, AMG131) is a potent non-thiazolidinedione (TZD) selective peroxisome proliferator-activated receptor gamma modulator (SPPARM) currently in Phase 2 clinical trials for treatment of type-2 diabetes mellitus (T2DM). This new chemical entity represents a second generation SPPARM approach developed after the first generation PPARgamma full agonists to address their inherent limitations. INT131 was specifically and carefully designed using preclinical models to exhibit a biological profile of strong efficacy with de minimis side effects compared to PPARgamma full agonists. As a potent PPARgamma modulator, INT131 binds to PPARgamma with high affinity. In pharmacology models of diabetes and in early clinical studies, it achieved a high level of efficacy in terms of antidiabetic actions such as insulin sensitization and glucose and insulin lowering, but had little activity in terms of other, undesired, effects associated with TZD PPARgamma full agonists such as edema and adipogenesis. Ongoing clinical development is directed at translating these findings into establishing a novel and effective treatment for T2DM patients with an improved safety profile in relation to that currently available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2008/936906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2522386PMC
July 2011

Role of p38 mitogen activated protein kinase in a model of osteosarcoma-induced pain.

Pharmacol Biochem Behav 2008 Oct;90(4):664-75

Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0818, USA.

The focus of this work was to examine the potential role of p38 mitogen activated protein kinase (p38) in a mouse model of bone cancer (osteosarcoma) pain. To generate osteosarcoma and sham animals, osteosarcoma cells or medium were injected into the medullary canal of the femur. Initially, ipsilateral tactile allodynia was observed in both groups, but by 12 days post-surgery, thresholds in the sham group returned towards baseline while hypersensitivity in the osteosarcoma group lasted throughout the study. An increase in phosphorylated p38 was detected by western blotting in dorsal root ganglia (DRG) and spinal cord day 14 after surgery. Immunohistochemistry showed that p38 was phosphorylated in DRG and spinal dorsal horn neurons at this time point. Two doses of a selective p38 inhibitor, SCIO-469, were administered in the chow starting 5 days post-surgery and continued throughout the study. Treatment with SCIO-469 led to a decrease in osteosarcoma-induced clinical score but had no effect on the allodynia. Bone erosion and tumor growth were also examined but no significant reduction of bone erosion or tumor growth was observed in the SCIO-469 treated mice. These data suggest that the p38 signaling pathway does not play a major role in bone cancer-mediated pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pbb.2008.05.016DOI Listing
October 2008

Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS.

Blood 2008 Oct 12;112(8):3434-43. Epub 2008 May 12.

Albert Einstein College of Medicine, Bronx, NY, USA.

MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. We demonstrate that smad2, a downstream mediator of transforming growth factor-beta (TGF-beta) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34(+) cells, providing direct evidence of overactivation of TGF-beta pathway in this disease. Suppression of the TGF-beta signaling by lentiviral shRNA-mediated down-regulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-beta-mediated gene activation in BM stromal cells, and reverses TGF-beta-mediated cell-cycle arrest in BM CD34(+) cells. Furthermore, SD-208 treatment alleviates anemia and stimulates hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-beta1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-beta signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2008-02-139824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569182PMC
October 2008

Prevention of trabecular bone loss induced by estrogen deficiency by a selective p38alpha inhibitor.

J Bone Miner Res 2008 Sep;23(9):1389-97

Department of Rehabilitation and Geriatrics, Service of Bone Diseases, University Hospital of Geneva, Geneva, Switzerland.

Increased bone remodeling with estrogen deficiency is mediated by the production of cytokines such as TNFalpha and interleukin (IL)-1. Recent data have indicated that the p38 pathway mediates cytokines effects on enhanced bone turnover in postmenopausal osteoporosis. Thus, in this study, we investigated the effect of a selective p38alpha inhibitor, SD-282, on the prevention of bone loss induced by estrogen deficiency in an adult ovariectomized (OVX) rat model. Results indicate that oral administration of SD-282 for 8 wk dose-dependently blunted the increase in the bone resorption marker DPD/Cr induced by OVX in adult rats. Associated with this effect, SD-282 did not reduce but significantly enhanced by 2-fold the rise in the bone formation marker serum osteocalcin observed in OVX animals. In addition, SD-282 completely blocked vertebral bone loss associated with estrogen deficiency. Furthermore, a partial preventive effect was observed in long bones with reduction of trabecular bone loss and enhancement of cross-sectional area of the diaphysis. Prevention of trabecular bone loss and increased in cortical bone area were associated with improvement of biomechanical resistances. In conclusion, chronic administration of a selective p38alpha inhibitor effectively prevented trabecular bone loss and alteration of bone microarchitecture induced by estrogen deficiency. Prevention of bone loss was associated with inhibition of bone resorption with uncoupled changes in bone formation. These data strongly suggest that the p38 pathway is important for regulation of bone resorption induced by estrogen deficiency, and selective inhibitors of this pathway have potential for prevention of bone loss in postmenopausal osteoporosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1359/jbmr.080410DOI Listing
September 2008

Pyrimidine-based inhibitors of CaMKIIdelta.

Bioorg Med Chem Lett 2008 Apr 4;18(7):2404-8. Epub 2008 Mar 4.

Scios, Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA.

Non-ATP competitive pyrimidine-based inhibitors of CaMKIIdelta were identified. Computational studies were enlisted to predict the probable mode of binding. The results of the computational studies led to the design of ATP competitive inhibitors with optimized hinge interactions. Inhibitors of this class possessed improved enzyme and cellular activity compared to early leads.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2008.02.056DOI Listing
April 2008

Antitumor activity of TGF-beta inhibitor is dependent on the microenvironment.

Anticancer Res 2007 Nov-Dec;27(6B):4149-57

Scios Inc., Fremont, CA 94555, USA.

Pancreatic cancer is one of the deadliest forms of cancer and effective treatment remains a clinical challenge. Transforming growth factor-beta (TGF-beta) has important roles in primary tumor progression and in promoting metastasis, and has become an attractive target for therapy. Previously, we reported that treatment of pancreatic cancer cells in vitro with SD-208, a small molecule inhibitor of the TGF-beta receptor I kinase (TGF-betaRI), inhibited expression of genes associated with tumor progression and inhibited invasiveness in a cell-based assay. In a demonstration of efficacy of TGF-beta signaling inhibition in an in vivo model of pancreatic cancer, we showed significantly reduced primary tumor weight and decreased incidence of metastasis in the Panc-1 orthotopic xenograft model of established pancreatic cancer. In this report, we extend these in vivo findings to examine the mechanistic consequences of TGF-betaRI inhibition on Panc-1 primary tumors and their microenvironment in situ. In a longitudinal study of TGF-betaRI inhibition in the Panc-1 orthotopic model, we show that SD-208 treatment significantly reduced tumor growth measured as bioluminescence intensity throughout the study. Histological evaluation revealed that SD-208 treatment reduced proliferation and induced apoptosis in the primary tumors, and reduced fibrosis in the tumor microenvironment. An immune contribution (greater B-cell infiltration in SD-208-treated tumors) was also suggested by the histological analyses. SD-208 not only blocked direct TGF-beta signaling in Panc-1 primary tumors (reduced phospho SMAD2/3), but also down-regulated the expression of TGF-beta-regulated genes (PAI-1 and COL7A1). Taken together, our results indicate that a TGF-betaRI kinase inhibitor has a potential therapeutic benefit for pancreatic cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
February 2008

Role of the TGF-beta/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension.

Am J Respir Crit Care Med 2008 Apr 17;177(8):896-905. Epub 2008 Jan 17.

Johns Hopkins School of Medicine, Division of Pulmonary and Critical Care Medicine, 1830 East Monument Street, 5th Floor, Baltimore, MD 21205, USA.

Rationale: Pulmonary arterial hypertension is a progressive disease characterized by an elevation in the mean pulmonary artery pressure leading to right heart failure and a significant risk of death. Alterations in two transforming growth factor (TGF) signaling pathways, bone morphogenetic protein receptor II and the TGF-beta receptor I, Alk1, have been implicated in the pathogenesis of pulmonary hypertension (PH). However, the role of TGF-beta family signaling in PH and pulmonary vascular remodeling remains unclear.

Objectives: To determine whether inhibition of TGF-beta signaling will attenuate and reverse monocrotaline-induced PH (MCT-PH).

Methods: We have used an orally active small-molecule TGF-beta receptor I inhibitor, SD-208, to determine the functional role of this pathway in MCT-PH.

Measurements And Main Results: The development of MCT-PH was associated with increased vascular cell apoptosis, which paralleled TGF-beta signaling as documented by psmad2 expression. Inhibition of TGF-beta signaling with SD-208 significantly attenuated the development of the PH and reduced pulmonary vascular remodeling. These effects were associated with decreased early vascular cell apoptosis, adventitial cell proliferation, and matrix metalloproteinase expression. Inhibition of TGF-beta signaling with SD-208 in established MCT-PH resulted in a small but significant improvement in hemodynamic parameters and medial remodeling.

Conclusions: These findings provide evidence that increased TGF-beta signaling participates in the pathogenesis of experimental severe PH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.200707-1083OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292828PMC
April 2008

Pharmacological properties of SD-282 - an alpha-isoform selective inhibitor for p38 MAP kinase.

Pharmacology 2008 7;81(3):204-20. Epub 2008 Jan 7.

Scios, Inc., Fremont, Calif., USA.

The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component. SD-282 represents a valuable tool to elucidate the role of p38 MAP kinase in multiple models of inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000112865DOI Listing
April 2008

Unicompartmental knee arthroplasty with the oxford prosthesis in patients with medial compartment arthritis.

J Bone Joint Surg Am 2008 Jan;90(1):118-22

Texas Center for Joint Replacement, 5940 West Parker, Suite 100, Plano, TX 75093, USA.

Background: The mobile-bearing feature of the Oxford unicompartmental knee replacement has the potential to optimize polyethylene wear, thereby leading to longer-term function of the implant. The function of the bearing requires intact soft tissues, with the ligaments being balanced throughout the range of motion intraoperatively through bone resection only. Final limb alignment is determined by the restored soft-tissue tension. The purposes of this study were to determine the limb alignment achieved in the absence of ligament release and to investigate the interplay of failure mode, survivorship, and limb alignment.

Methods: Fifty-five knees in fifty-one patients with medial compartment osteoarthritis had a unicompartmental replacement with an Oxford prosthesis. Evaluation included Knee Society clinical scores, radiographic evaluation, survivorship analysis, and modes of failure. The average duration of clinical follow-up was 11.8 years. Only two patients (three knees) were lost to follow-up.

Results: The mean postoperative Knee Society knee score and function score at the latest follow-up evaluation were 75 and 90 points, respectively. The overall alignment of the knee was restored to neutral, averaging 5.6 degrees of valgus alignment. Forty-seven of the fifty-five knees had the mechanical axis crossing the central 50% of the tibial plateau. Seven knees had revision surgery, and six of them required conversion to a total knee prosthesis. The main reason for revision was the progression of arthritis in the lateral compartment, which occurred in four knees at an average of 10.2 years postoperatively. These four knees had not been overcorrected into excessive valgus at the time of the original surgery, and we found no correlation, with the numbers studied, between alignment and bearing size. Survivorship analysis showed that the rate of survival at ten years was 85% with failure for any reason as the end point, 90% with progression of lateral compartment arthritis as the end point, and 96.3% with component loosening as the end point.

Conclusions: With this unicompartmental knee arthroplasty, the mechanical limb alignment resulting from balancing the knee ligaments, accomplished without releasing them, was consistently through the center of the knee. Progression of arthritis in the lateral compartment was the most common reason for late failure in this series and was not related to the initial postoperative alignment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2106/JBJS.F.00739DOI Listing
January 2008

Selective p38α mitogen-activated protein kinase inhibitor attenuates lung inflammation and fibrosis in IL-13 transgenic mouse model of asthma.

J Asthma Allergy 2008 Nov 16;1:31-44. Epub 2008 Nov 16.

Scios Inc, Fremont, CA, USA.

p38 Mitogen-activated protein kinase (MAPK) plays a critical role in the activation of inflammatory cells. We investigated the anti-inflammatory effects of a p38α-selective MAPK inhibitor (SD-282) in a mouse transgenic (CC10:IL-13) asthma model. The CC-10-driven over-expression of IL-13 in the mouse lung/airway has been shown to result in a remarkable phenotype recatitulating many features of asthma and characterized by eosinophilic and mononuclear inflammation, with airway epithelial cell hypertrophy, mucus cell metaplasia, the hyperproduction of neutral and acidic mucus, the deposition of Charcot-Leyden-like crystal, and airway sub-epitheilial fibrosis. Here we show how activated p38 MAPK can be observed in the lungs at the onset of asthma ie, around 8 weeks of age in both female and male mice. We also show that administration of a p38α MAPK selective inhibitor, SD-282 at 30 or 90 mg/kg, twice a day for a period of four weeks beginning at the onset of asthma, significantly reduced the inflammation (p < 0.001); hyperplasia of airway epithelium (p < 0.05); goblet cell metaplasia and mucus hypersecretion (p < 0.001) and reduced lung remodeling and fibrosis (p < 0.01), alleviating the severity of lung damage as measured by a composite score (p < 0.05). Furthermore, SD-282 significantly reduced activated p38 MAPK in the lymphocytes and epithelial cells (p < 0.001). Simultaneously, identical studies were conducted with an anti-fibrotic TGFβR1 kinase inhibitor (SD-208) which demonstrated anti-fibrotic but not anti-inflammatory properties. These findings suggest that the p38α-selective MAPK inhibitor may have dual therapeutic potential in attenuating both the inflammatory component and the fibrotic component of asthma and other Th2-polarized inflammatory lung diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121334PMC
http://dx.doi.org/10.2147/jaa.s4199DOI Listing
November 2008

A p38 mitogen-activated protein kinase inhibitor arrests active alveolar bone loss in a rat periodontitis model.

J Periodontol 2007 Oct;78(10):1992-8

Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109-1078, USA.

Background: Gram-negative bacterial species, such as Actinobacillus actinomycetemcomitans, contain lipopolysaccharide (LPS) that initiates the innate immune system, resulting in inflammatory alveolar bone loss. LPS activates Toll-like receptors on membrane surfaces, stimulating many intracellular signaling cascades, including the p38 mitogen-activated protein kinase (MAPK). Activation of p38 signaling mediates inflammatory cytokine expression, contributing toward osteoclastogenesis and bone loss. The aim of this study was to determine whether the novel, orally active p38 MAPK inhibitor SD282 could arrest progression of LPS-induced alveolar bone destruction in rats.

Methods: Three groups of female Sprague-Dawley rats received LPS injections to the palatal molar gingiva three times per week for 4 weeks to establish periodontitis. From weeks 5 through 8, two groups received the drug SD282 (N = 14) or 1% polyethylene glycol drug vehicle (N = 14) via oral gavage in addition to LPS injections. The third group continued to receive only LPS injections (N = 8). Microcomputed tomography was used to measure volumetric alveolar bone loss, expressed as bone volume fraction (BVF). Expression of interleukin (IL)-1 and -6 and tumor necrosis factor-alpha (TNF-alpha) was assessed by immunohistochemistry, and osteoclasts were enumerated by tartrate-resistant acid phosphatase staining.

Results: By 4 weeks, severe alveolar bone resorption was seen in LPS-injected animals. Administration of SD282 significantly blocked additional volumetric bone loss in the LPS-only versus LPS + SD282 groups (0.37 +/- 0.01 BVF versus 0.43 +/- 0.01 BVF; P < 0.01). Significant reductions in IL-1beta (P < 0.01 ), TNF-alpha (P < 0.05), and osteoclast formation (P < 0.01) occurred in the presence of SD282.

Conclusions: An orally active p38 MAPK inhibitor reduced LPS-induced inflammatory cytokine expression, osteoclastogenesis, and alveolar bone loss in rats. Within the limits of the current study, SD282 arrested periodontal disease progression, thus highlighting the therapeutic potential of this novel class of inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1902/jop.2007.070101DOI Listing
October 2007

p38alpha-selective mitogen-activated protein kinase inhibitor SD-282 reduces inflammation in a subchronic model of tobacco smoke-induced airway inflammation.

J Pharmacol Exp Ther 2008 Mar 4;324(3):921-9. Epub 2007 Dec 4.

Scios Inc., Fremont, California, USA.

Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation, which is relatively insensitive to inhaled corticosteroids. The extent of the pulmonary inflammation in COPD correlates with disease severity, and it is thought to play a significant role in disease progression. We have evaluated a selective p38alpha-selective mitogen-activated protein kinase (MAPK) inhibitor, indole-5-carboxamide (ATP-competitive inhibitor of p38 kinase) (SD-282), in an 11-day model of tobacco smoke (TS)-induced pulmonary inflammation in A/J mice, by using dexamethasone as a reference steroid. Two oral treatment paradigms were evaluated in this TS model: prophylactic with daily pretreatment before each daily exposure, and therapeutic with daily treatment for 6 days commencing after 5 days of smoke exposure. Bronchoalveolar lavage and histological evaluation of lung sections taken after exposure to TS revealed an inflammatory response composed of increased numbers of macrophages and neutrophils and enhanced mucin staining. Phospho-p38 staining in macrophages and type II epithelial cells after TS exposure was also observed. Given prophylactically or therapeutically, dexamethasone failed to inhibit any of the TS-induced inflammatory changes. By contrast, SD-282 inhibited TS-induced increases in macrophages and neutrophils. Furthermore, SD 282 reduced TS-induced increases in cyclooxygenase-2 and interleukin-6 levels, and phospho-p38 expression in the lungs. In conclusion, SD-282 markedly reduced TS-induced inflammatory responses when given prophylactically or therapeutically whereas dexamethasone was ineffective. This is the first evidence that a p38alpha-selective MAPK inhibitor can exert pulmonary anti-inflammatory activity in a TS exposure model when given in a therapeutic mode, establishing the potential of p38 MAPK inhibitors as a therapy for COPD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.107.127092DOI Listing
March 2008

Inhibiting TGF-beta signaling restores immune surveillance in the SMA-560 glioma model.

Neuro Oncol 2007 Jul 23;9(3):259-70. Epub 2007 May 23.

Scios Inc., Fremont, CA 94555, USA.

Transforming growth factor-beta (TGF-beta) is a proinvasive and immunosuppressive cytokine that plays a major role in the malignant phenotype of gliomas. One novel strategy of disabling TGF-beta activity in gliomas is to disrupt the signaling cascade at the level of the TGF-beta receptor I (TGF-betaRI) kinase, thus abrogating TGF-beta-mediated invasiveness and immune suppression. SX-007, an orally active, small-molecule TGF-betaRI kinase inhibitor, was evaluated for its therapeutic potential in cell culture and in an in vivo glioma model. The syngeneic, orthotopic glioma model SMA-560 was used to evaluate the efficacy of SX-007. Cells were implanted into the striatum of VM/Dk mice. Dosing began three days after implantation and continued until the end of the study. Efficacy was established by assessing survival benefit. SX-007 dosed at 20 mg/kg p.o. once daily (q.d.) modulated TGF-beta signaling in the tumor and improved the median survival. Strikingly, approximately 25% of the treated animals were disease-free at the end of the study. Increasing the dose to 40 mg/kg q.d. or 20 mg/kg twice daily did not further improve efficacy. The data suggest that SX-007 can exert a therapeutic effect by reducing TGF-beta-mediated invasion and reversing immune suppression. SX-007 modulates the TGF-beta signaling pathway and is associated with improved survival in this glioma model. Survival benefit is due to reduced tumor invasion and reversal of TGF-beta-mediated immune suppression, allowing for rejection of the tumor. Together, these results suggest that treatment with a TGF-betaRI inhibitor may be useful in the treatment of glioblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1215/15228517-2007-010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1907409PMC
July 2007

Inhibition of p38alpha mitogen-activated protein kinase prevents the development of osteolytic bone disease, reduces tumor burden, and increases survival in murine models of multiple myeloma.

Cancer Res 2007 May 10;67(10):4572-7. Epub 2007 May 10.

Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.

The bone microenvironment plays a critical role in supporting the growth and survival of multiple myeloma as well as in the development of osteolytic bone disease. Signaling through p38alpha mitogen-activated protein kinase (MAPK) mediates synthesis of multiple myeloma cell growth factors, and its inhibition reduces proliferation in vitro. However, it is unclear whether targeting p38alpha MAPK prevents multiple myeloma growth and the development of bone disease in vivo. In this study, we determined whether SCIO-469, a selective p38alpha MAPK inhibitor, inhibits multiple myeloma growth and prevents bone disease in the 5T2MM and 5T33MM models. SCIO-469 decreased constitutive p38alpha MAPK phosphorylation of both 5T2MM and 5T33MM cells in vitro. This was associated with decreased DNA synthesis and an induction of apoptosis when the cells were cultured with bone marrow stromal cells. Treatment of C57Bl/KaLwRij mice bearing 5T33MM cells with SCIO-469 inhibited p38alpha MAPK phosphorylation and was associated with a significant decrease in serum paraprotein, an almost complete reduction in tumor cells in the bone marrow, a decrease in angiogenesis, and a significant increase in disease-free survival. Injection of 5T2MM murine myeloma cells into C57Bl/KaLwRij mice resulted in myeloma bone disease characterized by increased osteoclast occupation of the bone surface, reduced cancellous bone, and the development of osteolytic bone lesions. Treatment of 5T2MM-injected mice with SCIO-469 reduced this development of bone disease. Together, these data show that targeting p38alpha MAPK with SCIO-469 decreases myeloma burden in vivo, in addition to preventing the development of myeloma bone disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-06-4361DOI Listing
May 2007

Mitogen-activated protein kinase phosphatase-1 is a mediator of breast cancer chemoresistance.

Cancer Res 2007 May;67(9):4459-66

The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

The mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 is overexpressed in a large proportion of breast cancers, and in some systems interferes with chemotherapy-mediated proapoptotic signaling through c-Jun-NH(2)-terminal kinase (JNK). We therefore sought to examine whether MKP-1 is a mediator of breast cancer chemoresistance using A1N4-myc human mammary epithelial cells, and BT-474 and MDA-MB-231 breast carcinoma cells. Transient or stable overexpression of MKP-1 reduced caspase activation and DNA fragmentation while enhancing viability in the face of treatment with alkylating agents (mechlorethamine), anthracylines (doxorubicin), and microtubule inhibitors (paclitaxel). This overexpression was associated with suppression of JNK activation, and JNK blockade alone induced similar effects. In contrast, reduction of MKP-1 levels using a small interfering RNA, or its targeted inactivation, enhanced sensitivity to these drugs, and this was associated with increased JNK activity. Pharmacologic reduction of MKP-1 by pretreatment with a novel p38 MAPK inhibitor, SD-282, suppressed MKP-1 activation by mechlorethamine, enhanced active JNK levels, and increased alkylating agent-mediated apoptosis. Combination treatment with doxorubicin and mechlorethamine had similar effects, and the enhanced efficacy of this regimen was abolished by forced overexpression of MKP-1. These results suggest that the clinical efficacy of combinations of alkylating agents and anthracyclines are due to the ability of the latter to target MKP-1. Moreover, they support the hypothesis that MKP-1 is a significant mediator of breast cancer chemoresistance, and provide a rationale for development and translation of other agents targeting MKP-1 into the clinical arena to overcome resistance and induce chemosensitization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-06-2644DOI Listing
May 2007