Publications by authors named "C Offutt"

19 Publications

Estrogen modulates mesenchyme-epidermis interactions in the adult nipple.

Development 2017 04 13;144(8):1498-1509. Epub 2017 Mar 13.

Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA

Maintenance of specialized epidermis requires signals from the underlying mesenchyme; however, the specific pathways involved remain to be identified. By recombining cells from the ventral skin of the transgenic mice [which overexpress parathyroid hormone-related protein (PTHrP) in their developing epidermis and mammary glands] with those from wild type, we show that transgenic stroma is sufficient to reprogram wild-type keratinocytes into nipple-like epidermis. To identify candidate nipple-specific signaling factors, we compared gene expression signatures of sorted Pdgfrα-positive ventral and wild-type fibroblasts, identifying differentially expressed transcripts that are involved in WNT, HGF, TGFβ, IGF, BMP, FGF and estrogen signaling. Considering that some of the growth factor pathways are targets for estrogen regulation, we examined the upstream role of this hormone in maintaining the nipple. Ablation of estrogen signaling through ovariectomy produced nipples with abnormally thin epidermis, and we identified TGFβ as a negatively regulated target of estrogen signaling. Estrogen treatment represses Tgfβ1 at the transcript and protein levels in fibroblasts , while ovariectomy increases levels in ventral skin. Moreover, ectopic delivery of Tgfβ1 protein into nipple connective tissue reduced epidermal proliferation. Taken together, these results show that specialized nipple epidermis is maintained by estrogen-induced repression of TGFβ signaling in the local fibroblasts.
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http://dx.doi.org/10.1242/dev.141630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399661PMC
April 2017

Expansion of specialized epidermis induced by hormonal state and mechanical strain.

Mech Dev 2015 May 10;136:73-86. Epub 2015 Feb 10.

Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA; Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address:

In mammals, some sites of specialized skin such as the palms, soles, and lips grow proportionally with the animal. However, other types of specialized skin such as the nipple and anal/genital region are dramatically altered with changes of reproductive status. The specific cell types that mediate the growth of these sites have not been identified. In the mouse, we observed a dramatic expansion of the specialized epidermis of the nipple, coupled to changes in connective tissue and hair shaft density, which we designate as areola formation. During this process thymidine analog uptake was elevated in the epidermis and hair follicles. Although there were no changes in connective tissue cell proliferation, we did observe an altered expression of extracellular matrix genes. In addition, the fibroblasts of the virgin nipple areola and region showed increased transcript and protein levels for estrogen, progesterone, relaxin, and oxytocin relative to those of ventral skin. To determine the role of pregnancy, lactation hormonal milieu, and localized mechanical strain on areola formation, we created models that separated these stimuli and evaluated changes in gross structure, proliferation and protein expression. While modest increases of epidermal proliferation and remodeling of connective tissue occurred as a result of individual stimuli, areola formation required exposure to pregnancy hormones, as well as mechanical strain.
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http://dx.doi.org/10.1016/j.mod.2015.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448117PMC
May 2015

Efficacy and safety of pateclizumab (anti-lymphotoxin-α) compared to adalimumab in rheumatoid arthritis: a head-to-head phase 2 randomized controlled study (The ALTARA Study).

Arthritis Res Ther 2014 Oct 30;16(5):467. Epub 2014 Oct 30.

Introduction: Tumor necrosis factor (TNF) and, possibly, lymphotoxin alpha (LTα) signaling contribute to inflammation and rheumatoid arthritis (RA) pathogenesis. Pateclizumab (anti-lymphotoxin- alpha; MLTA3698A) is a humanized monoclonal antibody that blocks and depletes anti-LTα. This phase 2, randomized, head-to-head, active- and placebo-controlled trial examined the safety and efficacy of pateclizumab compared to adalimumab in RA patients with an inadequate response to disease-modifying antirheumatic drugs (DMARD-IR).

Methods: Patients (n = 214) with active RA (≥ 6 swollen and tender joints, C-reactive protein ≥ 10 mg/L) on oral DMARDs were randomized (2:2:1) to receive pateclizumab 360 mg, adalimumab 40 mg, or placebo subcutaneously every 2 weeks. The primary endpoint, 4-variable, 28-joint disease activity score erythrocyte sedimentation rate (DAS28(4)-ESR) response, was evaluated at 12 weeks using an analysis of covariance (ANCOVA) model with adjustments for concomitant DMARD use and geographic region. Secondary efficacy endpoints included American College of Rheumatology (ACR) 20, ACR50, and ACR70 responses at Day 85. Pharmacokinetics, pharmacodynamics, and immunogenicity of pateclizumab were assessed.

Results: Pateclizumab reduced the DAS28(4)-ESR response (-1.89) at 12 weeks, however, this did not reach statistical significance compared to placebo (-1.54), while adalimumab (-2.52) differed significantly from both placebo and pateclizumab. Pateclizumab 12-week ACR20, ACR50 and ACR70 response rates (64%, 33%, and 14%) suggested clinical activity but were not statistically significant compared to placebo rates (46%, 24%, and 8%, respectively). CXCL13 serum levels decreased significantly following pateclizumab and adalimumab administration, demonstrating pharmacological target engagement by both drugs. Overall, adverse events (AEs) were comparable among all cohorts. Infections were the most common AE, occurring with comparable frequency in all groups. Serious AEs occurred in 0% of pateclizumab, 5.9% of adalimumab, and 2.3% of placebo patients, with serious infection in 2.3% of adalimumab patients and none in pateclizumab and placebo patients.

Conclusions: Pateclizumab had a good safety profile in patients inadequately responsive to DMARDs, but no statistically significant improvement in RA signs and symptoms after 12 weeks of treatment. Adalimumab demonstrated efficacy and safety comparable to published results in this head-to-head comparison in DMARD-IR RA patients.

Trial Registration: ClinicalTrials.gov NCT01225393, Registered 18 October 2010.
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http://dx.doi.org/10.1186/s13075-014-0467-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243296PMC
October 2014

Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel monoclonal antibody targeting lymphotoxin α: results of a phase I randomized, placebo-controlled trial.

Arthritis Res Ther 2012 Jan 8;14(1):R6. Epub 2012 Jan 8.

Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.

Introduction: Pateclizumab (MLTA3698A) is a humanized mAb against lymphotoxin α (LTα), a transiently expressed cytokine on activated B and T cells (Th1, Th17), which are implicated in rheumatoid arthritis (RA) pathogenesis. This study was conducted to assess the safety, tolerability, < NOTE: For clarity and per AMA/S-W Style, please restore the use of Oxford/serial commas (ie: David likes vanilla, strawberry, and chocolate ice cream) throughout. and biologic activity of single and multiple doses of intravenous (IV) or subcutaneous (SC) pateclizumab in RA patients.

Methods: The single ascending dose (SAD) phase in patients with stable RA consisted of six cohorts (4:1 active:placebo at 0.3 mg/kg IV, 1.0 mg/kg IV, 1.0 mg/kg SC, 3.0 mg/kg IV, 3.0 mg/kg SC, and 5.0 mg/kg IV; n = 5/cohort). In the multiple ascending dose (MAD) phase, patients with prespecified RA disease activity received three doses of pateclizumab or placebo (4:1) every 2 weeks (1.0 mg/kg SC, n = 10; 3.0 mg/kg SC, n = 20; or 5.0 mg/kg IV, n = 5). Safety and tolerability were assessed throughout, and clinical activity was determined after three doses (Week 6).

Results: We observed no serious adverse events (AEs) or dose-limiting toxicities, and the majority of AEs were mild to moderate. The pharmacokinetic profiles were linear, and clearance was independent of dose. Reductions in levels of serum CXCL13 were observed, supporting the biologic activity of pateclizumab on the LTα pathway. Patients receiving pateclizumab in the 3.0 mg/kg MAD group (3.0 mg/kg SC) demonstrated ACR20, ACR50, and ACR70 response rates at week 6 of 75%, 56% and 25%, respectively, compared with 57%, 29%, and 0% in the placebo group. The median Disease Activity Score in 28 joints, C-reactive protein, reduction was 28% for pateclizumab, versus 8.4% for placebo.

Conclusions: Pateclizumabwas generally well-tolerated in RA patients. Preliminary evidence of clinical activity was observed in active RA patients at the dose level targeted for clinical effect.
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http://dx.doi.org/10.1186/ar3554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392792PMC
January 2012

PTHrP P3 promoter activity in breast cancer cell lines: role of Ets1 and CBP (CREB binding protein).

Mol Cell Endocrinol 2007 Mar 1;268(1-2):75-84. Epub 2007 Feb 1.

Institut Cochin, Université Paris Descartes, CNRS, (UMR 8104), France.

Parathyroid hormone-related protein (PTHrP) is produced by many tumors including breast cancer. We have reported that Ets1 factor activates P3 PTHrP promoter in our model of tumorigenic breast cancer cell and not in pre- or non-tumorigenic cell lines, thus contributing to an increased PTHrP production. In this study, gel retardation assays revealed that Etsl and its promoter binding site (EBS) specifically formed complexes whose abundance correlates with Ets1 levels in the three cell lines. Coexpression of Etsl and CBP induced a synergistic activation of the P3 promoter only in the tumorigenic cell line. This synergism required the integrity of the EBS and was abrogated by E1A. All breast cancer cell lines showed high basal concentrations of phosphorylated CREB. Moreover a CRE-like sequence was also required for Ets1/CBP synergy and, finally, CREB expression was found to enhance the PTHrP P3 promoter activity. Thus a multipartite complex of transcription factors and coactivators seems to regulate PTHrP transcription and contribute to the alterations that promote tumorigenic behavior in breast epithelial cells.
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http://dx.doi.org/10.1016/j.mce.2007.01.014DOI Listing
March 2007
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