Sefik E.,Harvard University |
Geva-Zatorsky N.,Harvard University |
Oh S.,Harvard University |
Konnikova L.,Brigham and Women's Hospital |
And 16 more authors.
Science | Year: 2015
T regulatory cells that express the transcription factor Foxp3 (Foxp3+ Tregs) promote tissue homeostasis in several settings. We now report that symbiotic members of the human gut microbiota induce a distinct Treg population in the mouse colon, which constrains immuno-inflammatory responses. This induction - which we find to map to a broad, but specific, array of individual bacterial species - requires the transcription factor Rorγ, paradoxically, in that Rorγ is thought to antagonize FoxP3 and to promote T helper 17 (TH17) cell differentiation. Rorγ's transcriptional footprint differs in colonic Tregs and TH17 cells and controls important effector molecules. Rorγ, and the Tregs that express it, contribute substantially to regulating colonic TH1/TH17 inflammation. Thus, the marked context-specificity of Rorγ results in very different outcomes even in closely related cell types.
Shindler K.S.,University of Pennsylvania |
Ventura E.,Thomas Jefferson University |
Dutt M.,University of Pennsylvania |
Elliott P.,GSK Company |
And 2 more authors.
Journal of Neuro-Ophthalmology | Year: 2010
Background: Neuronal loss in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), correlates with permanent neurological dysfunction. Current MS therapies have limited the ability to prevent neuronal damage. Methods: We examined whether oral therapy with SRT501, a pharmaceutical grade formulation of resveratrol, reduces neuronal loss during relapsing-remitting EAE. Resveratrol activates SIRT1, an NAD-dependent deacetylase that promotes mitochondrial function. Results: Oral SRT501 prevented neuronal loss during optic neuritis, an inflammatory optic nerve lesion in MS and EAE. SRT501 also suppressed neurological dysfunction during EAE remission, and spinal cords from SRT501-treated mice had significantly higher axonal density than vehicle-treated mice. Similar neuroprotection was mediated by SRT1720, another SIRT1-activating compound; and sirtinol, an SIRT1 inhibitor, attenuated SRT501 neuroprotective effects. SIRT1 activators did not prevent inflammation. Conclusions: These studies demonstrate that SRT501 attenuates neuronal damage and neurological dysfunction in EAE by a mechanism involving SIRT1 activation. SIRT1 activators are a potential oral therapy in MS. © 2010 by North American Neuro-Ophthalmology Society.
Cook D.,Concord Hospital |
Krassas G.,Scius Solutions Pty Ltd |
Huang T.,GSK Company
Australian Family Physician | Year: 2010
Background: Acne vulgaris can have a substantial impact on a patient's quality of life; there can be significant psychosocial consequences and it can leave permanent physical scarring. Early and effective acne treatment is important. Objective: To describe the outcome of an accredited clinical audit investigating general practitioner management of acne vulgaris and to provide an outline of current 'best practice' acne management. Discussion: The audit was conducted over two cycles with GPs receiving educational material between cycles. Eighty-five GPs contributed data on 1638 patients. General practitioner management of acne was assessed against a set of preset standards and some acne treatment was found to be inconsistent with best practice, particularly for patients with moderate and moderate to severe acne, where many patients were either being undertreated or treatment with antibiotic therapy was suboptimal. It is likely that this treatment gap is overestimated due to practical limitations of the audit process; however, the audit revealed a need to address the main sources of apparent divergence from best practice to improve the quality use of acne therapies.
Eastman W.J.,GSK Company |
Malahias S.,GSK Company |
Delconte J.,GSK Company |
DiBenedetti D.,RTI Health Solutions
Cutis | Year: 2014
There is limited information available regarding patient preferences and attributes of topical product formulations for specific dermatologic conditions. This study focused on product attributes that were most desirable for 3 dermatologic condit ions: acne, atopic dermatitis (AD), and plaque psoriasis (PP). Six focus groups were conducted with participants self-reporting 1 of these conditions and use of 2 or more topical treatments. Discussion focused on symptoms, treatments tried, and vehicle attributes. Fifty-four subjects participated: acne, n = 19; AD, n = 18; and PP, n = 17. The most commonly reported prescription medication vehicles were creams and ointments, followed by lotions, gels, and foams. Itching and redness were the only symptoms spontaneously reported across all 6 focus groups. The attributes considered most important across all conditions included: moisturizing, absorbs/disappears/ dries quickly, available in various formulations, does not bleach or stain skin/hair/clothing, is not greasy or oily, is not sticky or tacky, is long lasting/long acting, is fragrance or odor free, is easy to apply/simple to use, and can use all the time. Preferences attributable to acne included: easy to dispense/dispenses right amount, nondrying, product goes on/spreads smoothly, container is not easily broken/does not leak, and creamy. Preferences attributable to AD included: not noticeable to others/conceals area, good consistency, and cooling. Patient preference for product vehicle is relevant to adherence as compliance is a major factor for high rates of failure for dermatologic treatments.
Yoshizaki T.,University of California at San Diego |
Schenk S.,University of California at San Diego |
Imamura T.,University of California at San Diego |
Babendure J.L.,University of California at San Diego |
And 8 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2010
Chronic inflammation is an important etiology underlying obesity-related disorders such as insulin resistance and type 2 diabetes, and recent findings indicate that the macrophage can be the initiating cell type responsible for this chronic inflammatory state. The mammalian silent information regulator 2 homolog SIRT1 modulates several physiological processes important for life span, and a potential role of SIRT1 in the regulation of insulin sensitivity has been shown. However, with respect to inflammation, the role of SIRT1 in regulating the proinflammatory pathway within macrophages is poorly understood. Here, we show that knockdown of SIRT1 in the mouse macrophage RAW264.7 cell line and in intraperitoneal macrophages broadly activates the JNK and IKK inflammatory pathways and increases LPS-stimulated TNFα secretion. Moreover, gene expression profiles reveal that SIRT1 knockdown leads to an increase in inflammatory gene expression. We also demonstrate that SIRT1 activators inhibit LPS-stimulated inflammatory pathways, as well as secretion of TNFα, in a SIRT1-dependent manner in RAW264.7 cells and in primary intraperitoneal macrophages. Treatment of Zucker fatty rats with a SIRT1 activator leads to greatly improved glucose tolerance, reduced hyperinsulinemia, and enhanced systemic insulin sensitivity during glucose clamp studies. These in vivo insulin-sensitizing effects were accompanied by a reduction in tissue inflammation markers and a decrease in the adipose tissue macrophage proinflammatory state, fully consistent with the in vitro effects of SIRT1 in macrophages. In conclusion, these results define a novel role for SIRT1 as an important regulator of macrophage inflammatory responses in the context of insulin resistance and raise the possibility that targeting of SIRT1 might be a useful strategy for treating the inflammatory component of metabolic diseases. Copyright © 2010 American Physiological Society.
Draelos Z.D.,Duke University |
Potts A.,GSK company |
Alio Saenz A.B.,GSK company
Cutis | Year: 2010
The multiple etiologic factors involved in acne vulgaris make the use of several medications necessary to treat the condition. Use of a fixed combination of clindamycin phosphate 1.2% and tretinoin 0.025% in conjunction with a benzoyl peroxide (BPO) wash 4% targets several pathologic factors simultaneously and mitigates the potential for clindamycin-induced Propionibacterium acnes-resistant strains. New formulations may allow such regimens to be effectively used without overly reduced tolerability resulting from the irritation potential of tretinoin and BPO. This randomized, single-blind study investigated the local tolerability, irritation potential, and safety of an aqueous-based gel (clindamycin phosphate 1.2%-tretinoin 0.025% [CT gel]) when used in conjunction with a BPO wash 4% in participants with mild to moderate acne vulgaris. Participants applied the CT gel once daily in the evening for 4 weeks in conjunction with once-daily morning use of either BPO wash 4% or nonmedicated soap-free cleanser lotion (SFC). Local tolerability and irritation potential were assessed by participants and investigators using separate 6-point scales. The frequency and severity of dryness, scaling, erythema, burning/stinging, and itching increased during the first week of treatment in both treatment arms but decreased thereafter. Local tolerability reactions were slightly more frequent in the CT gel + BPO wash group versus the CT gel + SFC group at week 1 but were generally mild and improved within 1 to 2 weeks. In conclusion, therapy with CT gel + BPO wash appears safe and well-tolerated in participants with mild to moderate acne vulgaris. © Cutis 2010.
Jayasundara K.,GSK Inc |
Soobiah C.,Li Ka Shing Knowledge Institute |
Thommes E.,GSK Inc |
Thommes E.,University of Guelph |
And 4 more authors.
BMC Infectious Diseases | Year: 2014
Background: The natural (i.e. unvaccinated population) attack rate of an infectious disease is an important parameter required for understanding disease transmission. As such, it is an input parameter in infectious disease mathematical models. Influenza is an infectious disease that poses a major health concern worldwide and the natural attack rate of this disease is crucial in determining the effectiveness and cost-effectiveness of public health interventions and informing surveillance program design. We estimated age-stratified, strain-specific natural attack rates of laboratory-confirmed influenza in unvaccinated individuals. Methods: Utilizing an existing systematic review, we calculated the attack rates in the trial placebo arms using a random effects model and a meta-regression analysis (GSK study identifier: 117102). Results: This post-hoc analysis included 34 RCTs (Randomized Control Trials) contributing to 47 influenza seasons from 1970 to 2009. Meta-regression analyses showed that age and type of influenza were important covariates. The attack rates (95% CI (Confidence Interval)) in adults for all influenza, type A and type B were 3.50% (2.30%, 4.60%), 2.32% (1.47%, 3.17%) and 0.59% (0.28%, 0.91%) respectively. For children, they were 15.20% (11.40%, 18.90%), 12.27% (8.56%, 15.97%) and 5.50% (3.49%, 7.51%) respectively. Conclusions: This analysis demonstrated that unvaccinated children have considerably higher exposure risk than adults and influenza A can cause more disease than influenza B. Moreover, a higher ratio of influenza B:A in children than adults was observed. This study provides a new, stratified and up to-date natural attack rates that can be used in influenza infectious disease models and are consistent with previous published work in the field. © Jayasundara et al.; licensee BioMed Central Ltd.
Howells L.M.,University of Leicester |
Berry D.P.,University of Leicester |
Elliott P.J.,GSK Company |
Jacobson E.W.,GSK Company |
And 5 more authors.
Cancer Prevention Research | Year: 2011
The phytochemical resveratrol has undergone extensive preclinical investigation for its putative cancer chemopreventive properties. Low systemic availability of the parent compound due to rapid and extensive metabolism may confound its usefulness as a potential agent to prevent malignancies in organs remote from the site of absorption. Micronization allows increased drug absorption, thus increasing availability. Here we describe a pilot study of SRT501, micronized resveratrol, given as 5.0 g daily for 14 days, to patients with colorectal cancer and hepatic metastases scheduled to undergo hepatectomy. The purpose of the study was to assess the safety, pharmacokinetics, and pharmacodynamics of the formulation. SRT501 was found to be well tolerated. Mean plasma resveratrol levels following a single dose of SRT501 administration were 1,942 ± 1,422 ng/mL, exceeding those published for equivalent doses of nonmicronized resveratrol by 3.6-fold. Resveratrol was detectable in hepatic tissue following SRT501 administration (up to 2,287 ng/g). Cleaved caspase-3, a marker of apoptosis, significantly increased by 39% in malignant hepatic tissue following SRT501 treatment compared with tissue from the placebo-treated patients. SRT501 warrants further clinical exploration to assess its potential clinical utility. ©2011 AACR.
Dhawan S.S.,Center for Dermatology Clinical Research Inc |
Dhawan S.S.,Stanford University |
Gwazdauskas J.,GSK company
Cutis | Year: 2013
Acne is a multifactorial chronic dermatosis that can be effectively treated with adjuvant medications. The objective of our study was to compare the tolerability and efficacy of 2 adjuvant therapies combining clindamycin phosphate 1.2%-benzoyl peroxide 5% (CLNP-BPO5) or clindamycin phosphate 1.2%-benzoyl peroxide 2.5% (CLNPBPO2.5) fixed-dose gels with tazarotene (TZ) cream 0.1% (CLNP-BPO5/TZ vs CLNP-BPO2.5/TZ) when applied topically once daily for 12 weeks in participants with moderate to severe facial acne. Forty participants were randomized to receive CLNP-BPO5/TZ or CLNP-BPO2.5/TZ in a parallel-group study and were evaluated at baseline as well as weeks 1, 2, 4, 8, and 12 (or at early termination). In both groups, tolerability assessments increased by week 1 but gradually returned toward baseline levels by week 12. At week 4, the mean change in burning/stinging was significantly higher in the CLNP-BPO5/TZ group compared with the CLNP-BPO2.5/TZ group (P<.05). No other significant differences were observed for the tolerability, efficacy, quality of life (QOL), or participant preference assessments. Our study shows that CLNP-BPO5 or CLNP-BPO2.5 fixed-dose gels in combination with TZ cream 0.1% are generally well-tolerated and effective treatments of moderate to severe facial acne when applied once daily for up to 12 weeks. Copyright Cutis 2013.
PubMed | Li Ka Shing Knowledge Institute and GSK Inc
Type: | Journal: BMC infectious diseases | Year: 2015
The natural (i.e. unvaccinated population) attack rate of an infectious disease is an important parameter required for understanding disease transmission. As such, it is an input parameter in infectious disease mathematical models. Influenza is an infectious disease that poses a major health concern worldwide and the natural attack rate of this disease is crucial in determining the effectiveness and cost-effectiveness of public health interventions and informing surveillance program design. We estimated age-stratified, strain-specific natural attack rates of laboratory-confirmed influenza in unvaccinated individuals.Utilizing an existing systematic review, we calculated the attack rates in the trial placebo arms using a random effects model and a meta-regression analysis (GSK study identifier: 117102).This post-hoc analysis included 34 RCTs (Randomized Control Trials) contributing to 47 influenza seasons from 1970 to 2009. Meta-regression analyses showed that age and type of influenza were important covariates. The attack rates (95% CI (Confidence Interval)) in adults for all influenza, type A and type B were 3.50% (2.30%, 4.60%), 2.32% (1.47%, 3.17%) and 0.59% (0.28%, 0.91%) respectively. For children, they were 15.20% (11.40%, 18.90%), 12.27% (8.56%, 15.97%) and 5.50% (3.49%, 7.51%) respectively.This analysis demonstrated that unvaccinated children have considerably higher exposure risk than adults and influenza A can cause more disease than influenza B. Moreover, a higher ratio of influenza B:A in children than adults was observed. This study provides a new, stratified and up to-date natural attack rates that can be used in influenza infectious disease models and are consistent with previous published work in the field.