Publications by authors named "Carlos A Martínez"

34 Publications

PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease.

J Med Chem 2021 01 24;64(1):326-342. Epub 2020 Dec 24.

Pfizer Medicine Design, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States.

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at , a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. (PF-07059013) has advanced to phase 1 clinical trials.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01518DOI Listing
January 2021

Outpatient Microsurgical Breast Reconstruction.

Plast Reconstr Surg Glob Open 2020 Sep 23;8(9):e3109. Epub 2020 Sep 23.

Houston Plastic Craniofacial and Sinus Surgery, Houston, Tex.

Background: The extensive nature of perforator-based breast reconstructions, combined with the need for postoperative flap monitoring, often leads to long hospitalizations. We present an early report demonstrating the feasibility and advantages of a modified operative technique and recovery protocol, allowing us to perform outpatient breast reconstructions with the DIEP flap. This follow-up comprises the experience gained, which is expanded to other perforator-based flaps and not limited to DIEP breast reconstructions.

Methods: We have implemented a general protocol in patients undergoing breast reconstruction with autologous flaps, promoting early mobilization and discharge by improving postoperative pain and decreasing opioid requirements. This protocol includes intraoperative local anesthesia, a microfascial incision for DIEP harvest with rib preservation, along with prophylactic anticoagulation.

Results: Ninety-two consecutive patients underwent autologous tissue-based breast reconstruction with DIEP, IGAP, and PAP flaps. No intraoperative complications were reported. All patients were discharged within 23 hours, without evidence of flap compromise. One patient required operative takeback for evacuation of a hematoma on postoperative day 4. No partial or total flap losses were documented. The aim of any procedure should be to get to the patient back to the preoperative status as quickly as possible, as prolonged hospitalizations are associated with higher incidences of infection, deep venous thrombosis, overall dissatisfaction, and higher overall costs of care.

Conclusions: By using a modified operative technique, multimodal pain control, and postoperative anticoagulant therapy, outpatient perforator-flap-based breast reconstructions can be performed with high success and low complication rates.
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http://dx.doi.org/10.1097/GOX.0000000000003109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544295PMC
September 2020

Use of Single-recipient Vessels for Cross-chest Abdominal Flap-based Breast Augmentation as an Outpatient.

Plast Reconstr Surg Glob Open 2020 Jul 15;8(7):e2978. Epub 2020 Jul 15.

Houston Plastic Craniofacial and Sinus Surgery, Houston, Tex.

Breast reconstruction with autologous tissue following mastectomy for breast cancer has become the standard of care. Microvascular breast augmentation is an alternative for patients with failed breast prostheses, including painful capsular contractures or poor cosmetic outcomes. We present a series of 4 patients who underwent microvascular breast augmentation with cross-chest flap recipient vessels.

Methods: We perform a bilateral DIEP flap reconstruction in an outpatient setting following a modified recovery protocol, focused on decreasing postoperative pain and narcotic requirements, allowing early ambulation and discharge. This includes harvest of the flap via abdominal microfascial incisions and rib-sparing vessel dissection. Cosmetic microvascular augmentation of the contralateral breast was performed via cross-chest flap recipient vessel anastomoses, where the pedicle was tunneled across the chest and anastomosed to the primary flap.

Results: Four patients underwent flap-based breast augmentation with cross-chest recipient vessels. Two patients underwent immediate DIEP flap breast reconstruction of the affected side and contralateral flap-based augmentation, while 2 patients underwent bilateral breast augmentation with DIEP flaps for cosmetic purposes due to undesired cosmetic results following implant-based augmentations. No intraoperative complications were reported, and all patients were discharged within 23 hours without signs of flap compromise or need for operative take-backs. Mean follow-up was 23 weeks.

Conclusions: The DIEP flap is recognized as an option for breast augmentation, although its limitations are several, including the pain and recovery associated with autologous tissue-based breast reconstruction. Enhanced recovery protocols help reduce this burden, making it more acceptable and feasible.
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http://dx.doi.org/10.1097/GOX.0000000000002978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413810PMC
July 2020

Plasma Lipid Profile Reveals Plasmalogens as Potential Biomarkers for Colon Cancer Screening.

Metabolites 2020 Jun 25;10(6). Epub 2020 Jun 25.

Laboratory of Multidisciplinary Research, São Francisco University, Bragança Paulista, São Paulo 12916-900, Brazil.

In this era of precision medicine, there is an increasingly urgent need for highly sensitive tests for detecting tumors such as colon cancer (CC), a silent disease where the first symptoms may take 10-15 years to appear. Mass spectrometry-based lipidomics is an emerging tool for such clinical diagnosis. We used ultra-performance liquid chromatography coupled to electrospray ionization quadrupole time-of-flight mass spectrometry operating in high energy collision spectral acquisition mode (MS) mode (UPLC-QTOF-MS) and gas chromatography (GC) to investigate differences between the plasmatic lipidic composition of CC patients and control (CTR) subjects. Key enzymes in lipidic metabolism were investigated using immuno-based detection assays. Our partial least squares discriminant analysis (PLS-DA) resulted in a suitable discrimination between CTR and CC plasma samples. Forty-two statistically significant discriminating lipids were putatively identified. Ether lipids showed a prominent presence and accordingly, a decrease in glyceronephosphate O-acyltransferase (GNPAT) enzyme activity was found. A receiver operating characteristic (ROC) curve built for three plasmalogens of phosphatidylserine (PS), named PS(P-36:1), PS(P-38:3) and PS(P-40:5), presented an area under the curve (AUC) of 0.998, and sensitivity and specificity of 100 and 85.7% respectively. These results show significant differences in CC patients' plasma lipid composition that may be useful in discriminating them from CTR individuals with a special role for plasmalogens.
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http://dx.doi.org/10.3390/metabo10060262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345851PMC
June 2020

Mitochondrial complex III is necessary for endothelial cell proliferation during angiogenesis.

Nat Metab 2019 01 7;1(1):158-171. Epub 2019 Jan 7.

Departments of Medicine and Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.

Endothelial cells (ECs) require glycolysis for proliferation and migration during angiogenesis; however, the necessity for the mitochondrial respiratory chain during angiogenesis is not known. Here we report that inhibition of respiratory chain complex III impairs proliferation, but not migration of ECs by decreasing the NAD+/NADH ratio. To determine whether mitochondrial respiration is necessary for angiogenesis , we conditionally ablate a subunit of the respiratory chain complex III (QPC) in ECs. Loss of QPC decreases respiration, resulting in diminished EC proliferation, and impairment in retinal and tumor angiogenesis. Loss of QPC does not decrease genes associated with anabolism or nucleotides levels in ECs, but diminishes amino acid levels. Our findings indicate that mitochondrial respiration is necessary for angiogenesis, and that the primary role of mitochondria in ECs is to serve as biosynthetic organelles for cell proliferation.
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http://dx.doi.org/10.1038/s42255-018-0011-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521885PMC
January 2019

Metabolite and transcript profiling of Guinea grass (Panicum maximum Jacq) response to elevated [CO] and temperature.

Metabolomics 2019 03 25;15(4):51. Epub 2019 Mar 25.

Department of Plant Biology & Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1201 W. Gregory Drive, 147 ERML, Urbana, IL, 61801, USA.

Introduction: By mid-century, global atmospheric carbon dioxide concentration ([CO]) is predicted to reach 600 μmol mol with global temperatures rising by 2 °C. Rising [CO] and temperature will alter the growth and productivity of major food and forage crops across the globe. Although the impact is expected to be greatest in tropical regions, the impact of climate-change has been poorly studied in those regions.

Objectives: This experiment aimed to understand the effects of elevated [CO] (600 μmol mol) and warming (+ 2 °C), singly and in combination, on Panicum maximum Jacq. (Guinea grass) metabolite and transcript profiles.

Methods: We created a de novo assembly of the Panicum maximum transcriptome. Leaf samples were taken at two time points in the Guinea grass growing season to analyze transcriptional and metabolite profiles in plants grown at ambient and elevated [CO] and temperature, and statistical analyses were used to integrate the data.

Results: Elevated temperature altered the content of amino acids and secondary metabolites. The transcriptome of Guinea grass shows a clear time point separations, with the changes in the elevated temperature and [CO] combination plots.

Conclusion: Field transcriptomics and metabolomics revealed that elevated temperature and [CO] result in alterations in transcript and metabolite profiles associated with environmental response, secondary metabolism and stomatal function. These metabolic responses are consistent with greater growth and leaf area production under elevated temperature and [CO]. These results show that tropical C grasslands may have unpredicted responses to global climate change, and that warming during a cool growing season enhances growth and alleviates stress.
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http://dx.doi.org/10.1007/s11306-019-1511-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434026PMC
March 2019

Serine Metabolism Supports Macrophage IL-1β Production.

Cell Metab 2019 04 14;29(4):1003-1011.e4. Epub 2019 Feb 14.

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Serine is a substrate for nucleotide, NADPH, and glutathione (GSH) synthesis. Previous studies in cancer cells and lymphocytes have shown that serine-dependent one-carbon units are necessary for nucleotide production to support proliferation. Presently, it is unknown whether serine metabolism impacts the function of non-proliferative cells, such as inflammatory macrophages. We find that in macrophages, serine is required for optimal lipopolysaccharide (LPS) induction of IL-1β mRNA expression, but not inflammasome activation. The mechanism involves a requirement for glycine, which is made from serine, to support macrophage GSH synthesis. Cell-permeable GSH, but not the one-carbon donor formate, rescues IL-1β mRNA expression. Pharmacological inhibition of de novo serine synthesis in vivo decreased LPS induction of IL-1β levels and improved survival in an LPS-driven model of sepsis in mice. Our study reveals that serine metabolism is necessary for GSH synthesis to support IL-1β cytokine production.
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http://dx.doi.org/10.1016/j.cmet.2019.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447453PMC
April 2019

Mitochondrial complex III is essential for suppressive function of regulatory T cells.

Nature 2019 01 9;565(7740):495-499. Epub 2019 Jan 9.

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Regulatory T cells (T cells), a distinct subset of CD4 T cells, are necessary for the maintenance of immune self-tolerance and homeostasis. Recent studies have demonstrated that T cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4 effector subsets. Furthermore, the T cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of T cells. Here we report that T cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting T cell number. Mice that lack mitochondrial complex III specifically in T cells displayed a loss of T cell-suppression capacity without altering T cell proliferation and survival. T cells deficient in complex III showed decreased expression of genes associated with T function, whereas Foxp3 expression remained stable. Loss of complex III in T cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases. Thus, T cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.
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http://dx.doi.org/10.1038/s41586-018-0846-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345596PMC
January 2019

Impacts of warming and water deficit on antioxidant responses in Panicum maximum Jacq.

Physiol Plant 2019 Feb;165(2):413-426

Universidade Estadual Paulista (UNESP), Faculdade de Ciências Agrárias e Veterinárias (FCAV), Departamento de Biologia Aplicada à Agropecuária, Jaboticabal, SP, Brazil.

Agricultural activities are affected by many biotic and abiotic stresses associated with global climate change. Predicting the response of plants to abiotic stress under future climate scenarios requires an understanding of plant biochemical performance in simulated stress conditions. In this study, the antioxidant response of Panicum maximum Jacq. cv. Mombaça exposed to warming (+2°C above ambient temperature) (eT), water deficit (wS) and the combination eT + wS was analysed under field conditions using a temperature free-air-controlled enhancement facility. Warming was applied during the entire growth period. Data were collected at 13, 19 and 37 days after the start of the water deficit treatment (DAT) and at two sampling times (6:00 and 12:00 h). A significant decrease in chlorophyll was observed under the wS treatment, but an increment in total chlorophyll was observed in eT + wS, particularly at 19 DAT. Significant increase in H O content, malondialdehyde and protein oxidation was observed in the wS treatment at noon of the third sampling. In the combined wS + eT stress treatment, the activity of the enzymatic antioxidant system increased, particularly of superoxide dismutase (SOD; EC 1.15.1.1) and ascorbate peroxidase (APX; EC 1.11.1.11). The chlorophyll fluorescence images showed that the photochemical performance was not significantly affected by the treatments. In conclusion, under simulated future warming and water stress conditions, the photosystem II (PSII) activity of P. maximum acclimated to moderate warming and a water-stressed environment associated with a relatively favourable antioxidant response, particularly in the activity of APX and SOD.
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http://dx.doi.org/10.1111/ppl.12907DOI Listing
February 2019

A Retrospective Analysis of Colorectal Serrated Lesions from 2005 to 2014 in a Single Center: Importance of the Establishment of Diagnostic Patterns.

Gastroenterol Res Pract 2018 21;2018:5946057. Epub 2018 Oct 21.

Department of Surgery, Medical Sciences School, Campinas State University, Campinas 13083-887, Brazil.

Background: Serrated colorectal lesions are increasingly recognized as an important process in the development of colorectal cancer. Endoscopic and histological diagnosis may be difficult, and knowledge of the serrated lesions is important for the establishment of strategies for treating colorectal lesions. We aimed to analyze serrated lesions diagnosed at a single center and evaluate if there was an increase in their identification over the years.

Design And Setting: A retrospective analysis of colonoscopy reports was performed at a specialized center from 2005 to 2014.

Methods: Colonoscopy reports about any resected endoscopic lesions were reviewed and subjected to histological diagnosis from 2005 to 2014. Then, serrated lesions were evaluated based on morphological characterization, location, size, occurrence of synchronous lesions, and the patient's history of colorectal cancer and polyps.

Results: A total of 2126 colonoscopy examination reports were reviewed, and 3494 lesions were analyzed. On histopathological examination, 1089 (31.2%) were classified as hyperplastic polyps, 22 (0.6%) as sessile serrated adenomas, and 21 (0.6%) as traditional serrated adenomas. There was an increase in the number of cases of sessile and traditional serrated adenomas diagnosed after 2010. Before 2010, two cases of sessile serrated adenomas and seven cases of traditional serrated adenomas were diagnosed; after 2010, 20 cases of sessile serrated adenoma and 14 cases of traditional serrated adenomas were diagnosed.

Conclusion: There was an increase in the diagnosis of sessile serrated adenomas over the years, which can be attributed to better accuracy in colonoscopy and histological classification.
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http://dx.doi.org/10.1155/2018/5946057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215568PMC
October 2018

The Outpatient DIEP: Safety and Viability following a Modified Recovery Protocol.

Plast Reconstr Surg Glob Open 2018 Sep 14;6(9):e1898. Epub 2018 Sep 14.

Houston Plastic Craniofacial & Sinus Surgery, Houston, Tex.

Background: Breast reconstruction with autologous tissue is considered the current state-of-the-art choice following mastectomies, and the deep inferior epigastric perforator (DIEP) flap is often among the favored techniques. Commonly referred to patients as a combination between a tummy tuck and a breast augmentation, it significantly differs by the required expertise and long hospital stays. We present a series attesting to the feasibility and effectiveness of performing this type of reconstruction in an outpatient setting following our recovery protocol.

Methods: Patients undergoing DIEP flap breast reconstruction followed a recovery protocol that included intraoperative local anesthesia, microfascial incision technique for DIEP harvest, double venous system drainage technique, rib and chest muscle preservation, and prophylactic anticoagulation agents.

Results: Fourteen patients totaling 27 flaps underwent breast reconstruction following our protocol. All patients were discharged within the initial 23 hours, and no take-backs, partial, or total flap failures were recorded. A case of abdominal incision breakdown was seen in 1 patient during a postoperative visit, without evidence of frank infection. No further complications were observed in the 12-week average observation period.

Conclusion: With the proper use of a microfascial incision, complemented by rib sparing and appropriate use of injectable anesthetics, routine breast reconstructions with the DIEP flap can be safely performed in an outpatient setting with discharge in the 23-hour window.
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http://dx.doi.org/10.1097/GOX.0000000000001898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191230PMC
September 2018

USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia.

Clin Cancer Res 2019 01 17;25(1):222-239. Epub 2018 Sep 17.

Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.

Purpose: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes.

Experimental Design: To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models.

Results: We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth and .

Conclusions: These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320313PMC
January 2019

Experimental Air Warming of a , Vogel Dominated Tropical Pasture Affects Soil Respiration and Nitrogen Dynamics.

Front Plant Sci 2017 1;8:46. Epub 2017 Feb 1.

Department of Biology, University of São Paulo Ribeirao Preto, Brazil.

Warming due to global climate change is predicted to reach 2°C in tropical latitudes. There is an alarming paucity of information regarding the effects of air temperature on tropical agroecosystems, including foraging pastures. Here, we investigated the effects of a 2°C increase in air temperature over ambient for 30 days on an established tropical pasture (Ribeirão Preto, São Paulo, Brazil) dominated by the legume Vogel, using a T-FACE (temperature free-air controlled enhancement) system. We tested the effects of air warming on soil properties [carbon (C), nitrogen (N), and their stable isotopic levels (δC and δN), as well as soil respiration and soil enzymatic activity] and aboveground characteristics (foliar C, N, δC, δN, leaf area index, and aboveground biomass) under field conditions. Results show that experimental air warming moderately increased soil respiration rates compared to ambient temperature. Soil respiration was positively correlated with soil temperature and moisture during mid-day (when soil respiration was at its highest) but not at dusk. Foliar δC were not different between control and elevated temperature treatments, indicating that plants grown in warmed plots did not show the obvious signs of water stress often seen in warming experiments. The N isotopic composition of leaves from plants grown at elevated temperature was lower than in ambient plants, suggesting perhaps a higher proportion of N-fixation contributing to tissue N in warmed plants when compared to ambient ones. Soil microbial enzymatic activity decreased in response to the air warming treatment, suggesting a slower decomposition of organic matter under elevated air temperature conditions. Decreased soil enzyme capacity and increases in soil respiration and plant biomass in plots exposed to high temperature suggest that increased root activity may have caused the increase seen in soil respiration in this tropical pasture. This response along with rapid changes in soil and plant N may differ from what has been shown in temperate grasslands.
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http://dx.doi.org/10.3389/fpls.2017.00046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5285360PMC
February 2017

The Nipple-Areola Preserving Mastectomy: The Value of Adding a Delay Procedure.

Plast Reconstr Surg Glob Open 2016 Nov 23;4(11):e1098. Epub 2016 Nov 23.

Houston Plastic Craniofacial & Sinus Surgery, Houston, Tex.

Background: Conservative mastectomy procedures, such as the nipple-sparing mastectomy (NSM), present appealing options for patients with small invasive or noninvasive malignancies and those needing prophylactic mastectomies. Despite outstanding postoperative cosmetic results, nipple-areola complex (NAC) and mastectomy skin flap (MSF) survival remains a concern. We present our two-stage nipple-areola preserving (NAP) mastectomy, which aims to decrease the rate of NAC loss and MSF necrosis after conservative mastectomies.

Material And Methods: Seventy patients who underwent NSM because of malignant and benign conditions were divided into 2 groups: those who underwent our two-stage NAP mastectomy were matched to the group of mastectomy patients without preservation techniques. Demographic data and postoperative results were retrospectively assessed.

Results: The NAP group comprised 45 flaps (24 patients), and the NSM group comprised 75 flaps (46 patients). None were actively smoking. The mean time between the delay of the flap and breast reconstruction was 17.6 days (range, of 10-35 days) in the NAP group. No signs of NAC vascular compromise were observed in the NAP group. Nipple necrosis rates were significantly greater ( = 0.0136) in the NSM group: 9 cases in the NSM group versus none within the NAP group. Two patients within the NAP group required nipple excision at the time of their mastectomies after biopsies performed at the time of the NAC delay were positive for malignancy or atypia.

Conclusions: Vascular delay techniques favor the blood supply of a tissue after a surgical wound, effectively improving the survival of the NAC and MSF after nipple-sparing mastectomies.
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http://dx.doi.org/10.1097/GOX.0000000000001098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142480PMC
November 2016

Deep Inferior Epigastric Artery Perforator Flap Breast Reconstruction in Patients With Previous Bariatric Surgery: Is It Safe and Feasible?

Ann Plast Surg 2016 Feb;76(2):216-20

From the *Houston Plastic and Craniofacial Surgery; and †Division of Plastic Surgery, Department of Surgery, The University of Texas School of Medicine at Houston, TX.

Background: Obesity is widely recognized as a major health concern and a leading cause of preventable death. The correlation between obesity and breast cancer has been thoroughly described by several authors. Bariatric surgery is often associated with redundant abdominal tissue, often leading patients to consider body-contouring procedures. Autologous tissue breast reconstruction using the deep inferior epigastric artery perforator (DIEP) flap has advantages because it is tissue that is normally discarded during postbariatric body contouring.

Methods: We conducted a retrospective chart review of 18 DIEP flaps performed by the senior author in 9 patients for breast reconstruction between February 2008 and May 2013. All patients underwent mastectomies. All patients underwent bariatric surgery preceding breast reconstruction. Breast reconstruction was performed immediately in 13 cases and delayed in 5 cases.

Results: Mean age of the study population was 44.6 years (range, 41-57 years). The mean maximum body mass index of the patients was 44 (range, 37.6-52.1), and the mean current body mass index at the time of the reconstruction was 30.7 (range, 24.3-38.1). No intraoperative complications were reported. No fascia or muscle was taken during flap dissection. Mean operative time was 632 minutes (range, from 480 to 750 minutes). Average hospital stay was 4 days. No partial or total flap loss was reported. There were no postoperative hernias or bulges at the abdominal donor site.

Conclusions: This series represents the largest group of patients undergoing DIEP flap breast reconstruction after bariatric surgery. In the hands of experienced microsurgeons, breast reconstruction with the DIEP flap in postbariatric patients represents a low-risk option with high satisfaction.
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http://dx.doi.org/10.1097/SAP.0000000000000526DOI Listing
February 2016

Delayed Mammoplasty with Silicone Gel Implants following DIEP Flap Breast Reconstruction.

Plast Reconstr Surg Glob Open 2015 Oct 20;3(10):e540. Epub 2015 Oct 20.

Department of Surgery, The University of Texas School of Medicine, Houston, Tex.; Houston Plastic & Craniofacial Surgery, Houston, Tex.

Unlabelled: The deep inferior epigastric artery perforator (DIEP) flap is a state-of-the-art option for breast reconstruction. However, thin patients with medium- to large-size native breasts are not ideal candidates due to the limited amount of available tissue. We reviewed our experience utilizing the DIEP flap in combination with prosthetic implants.

Methods: We conducted a retrospective chart review of 7 patients, totaling 11 implants, who underwent breast reconstruction with the DIEP flap and subsequent mammoplasty. All cases underwent previous mastectomies. No implant placement was offered at the time of their DIEP flap reconstruction. Immediate breast reconstruction with the DIEP flap was performed in 9 cases, whereas 2 required delayed reconstruction secondary to postmastectomy radiotherapy. No patients received postreconstruction radiotherapy. Breast asymmetry and inadequate volume were the primary indications for mammoplasty. For all cases, we used smooth, round silicone gel implants, which were placed in the subpectoral region.

Results: Mean age was 43 years. One patient was actively smoking. Four patients underwent bilateral implant placement. The mean time of delay between breast reconstruction and mammoplasty was 61 weeks. Average volume of silicone implants was 229 mL. A medial pedicle vertical mastopexy was performed in 1 patient on a nonreconstructed breast to achieve symmetry. Five patients underwent nipple reconstruction. All patients underwent delayed mammoplasty without intraoperative complications and good aesthetic results.

Conclusions: Delayed mammoplasty following DIEP flap breast reconstruction is a safe and feasible procedure for patients who seek an aesthetic and natural-looking breast but lack adequate abdominal tissue.
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http://dx.doi.org/10.1097/GOX.0000000000000527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634177PMC
October 2015

The Nipple-Areola Preserving Mastectomy: A Multistage Procedure Aiming to Improve Reconstructive Outcomes following Mastectomy.

Plast Reconstr Surg Glob Open 2015 Oct 20;3(10):e538. Epub 2015 Oct 20.

Department of Surgery, Division of Plastic Surgery, University of Texas School of Medicine at Houston, Texas.

Unlabelled: Ischemia of the nipple-areola complex (NAC) and periareolar tissue is commonly seen following tissue-preserving mastectomies for small invasive and noninvasive cancers. The nipple-areola preserving mastectomy is a multistage procedure in which the NAC and central mastectomy flap tissue is surgically delayed to improve the survivability in patients undergoing mastectomies followed by reconstruction.

Methods: We conducted a retrospective chart review of 20 patients undergoing the 2-stage nipple-areola preserving mastectomy: the first stage comprised undermining the NAC and raising the breast skin flaps, with placement of a silicone sheet in the dissected pocket. The second stage followed 2-3 weeks after the NAC delay, with patients undergoing nipple-sparing mastectomies.

Results: Mean age was 46.2 years (range, 23-59 years). Indications included breast cancer in 18 patients and BRCA gene mutation prophylaxis in 2 patients. None were actively smoking. Mean time between delay of flaps and breast reconstructions was 16 days (range, 10-35 days). One patient underwent bilateral nipple resection at the time of mastectomies due to a subareolar nipple biopsy positive for ductal carcinoma in situ. One patient underwent left nipple excision after a skin nipple biopsy was positive for metaplasia. No signs of NAC vascular compromise were observed in any of the cases.

Conclusions: Our 2-stage approach benefits patients undergoing nipple-sparing mastectomy, especially those at high-risk, by safely increasing survivability of the native breast skin envelope and NAC, while improving oncologic outcomes by identification of subareolar malignancies and sentinel node status before mastectomy and reconstruction.
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http://dx.doi.org/10.1097/GOX.0000000000000516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634175PMC
October 2015

Effect of APE1 T2197G (Asp148Glu) polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in patients with colorectal cancer.

Int J Mol Sci 2014 Sep 29;15(10):17333-43. Epub 2014 Sep 29.

Laboratory of Microbiology and Molecular Biology, Clinical Pharmacology and Gastroenterology Unit, Sao Francisco University Medical School, Bragança Paulista, SP. 12916-900, Brazil.

It has been hypothesized that genetic variation in base excision repair (BER) might modify colorectal adenoma risk. Thus, we evaluated the influence of APE1 T2197G (Asp148Glu) polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in normal and tumor samples from patients with colorectal cancer. The results indicate a downregulation of OGG1 and an upregulation of XRCC1 expression in tumor tissue. Regarding the anatomical location of APE1, OGG1 and PARP-1, a decrease in gene expression was observed among patients with cancer in the rectum. In patients with or without some degree of tumor invasion, a significant downregulation in OGG1 was observed in tumor tissue. Interestingly, when taking into account the tumor stage, patients with more advanced grades (III and IV) showed a significant repression for APE1, OGG1 and PARP-1. XRCC1 expression levels were significantly enhanced in tumor samples and were correlated with all clinical and histopathological data. Concerning the polymorphism T2197G, GG genotype carriers exhibited a significantly reduced expression of genes of the BER repair system (APE1, XRCC1 and PARP1). In summary, our data show that patients with colorectal cancer present expression changes in several BER genes, suggesting a role for APE1, XRCC1, PARP1 and OGG1 and APE1 polymorphism in colorectal carcinogenesis.
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http://dx.doi.org/10.3390/ijms151017333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227165PMC
September 2014

Effect of MLH1 -93G>A on gene expression in patients with colorectal cancer.

Med Oncol 2014 Sep 13;31(9):160. Epub 2014 Aug 13.

Unidade Integrada de Farmacologia e Gastroenterologia, Laboratory of Microbiology and Molecular Biology, Sao Francisco University Medical School, Av. São Francisco de Assis, 218. Jd. São José, Bragança Paulista, SP, Brazil.

The DNA repair machinery plays a key role in maintaining genomic stability by preventing the emergence of mutations. Furthermore, the -93G>A polymorphism in the MLH1 gene has been associated with an increased risk of developing colorectal cancer. Therefore, the aim of this study was to examine the expression pattern and effect of this polymorphism in normal and tumour samples from patients with colorectal cancer. The MLH1 -93G>A (rs1800734) polymorphism was detected by PCR-RFLP in 49 cases of colorectal cancer. MLH1 expression was investigated using real-time quantitative PCR. The results indicate a significant decrease in MLH1 expression in tumour samples compared to their normal counterparts. The MLH1 gene was also significantly repressed in samples from patients who had some degree of tumour invasion into other organs. Similarly, those patients who were in a more advanced tumour stage (TNM III and IV) exhibited a significant reduction in MLH1 gene expression. Finally, the mutant genotype AA of MLH1 was associated with a significant decrease in the expression of this gene. This finding suggests that this polymorphism could increase the risk of developing colorectal cancer by a defective mismatch repair system, particularly through the loss of MLH1 expression in an allele-specific manner.
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http://dx.doi.org/10.1007/s12032-014-0160-zDOI Listing
September 2014

Pasteurella multocida infection of a tissue expander following breast reconstruction.

J Plast Reconstr Aesthet Surg 2014 Jul 5;67(7):e180-1. Epub 2014 Feb 5.

Division of Plastic Surgery, Department of Surgery, The University of Texas School of Medicine at Houston, TX, USA; Houston Plastic & Craniofacial Surgery, 6400 Fannin, Suite 2290, Houston, TX 77030, USA.

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http://dx.doi.org/10.1016/j.bjps.2014.01.023DOI Listing
July 2014

A synthetic biology approach to the development of transcriptional regulatory models and custom enhancer design.

Methods 2013 Jul 1;62(1):91-8. Epub 2013 Jun 1.

Department of Ecology and Evolution, University of Chicago, Chicago, IL 60637, USA.

Synthetic biology offers novel opportunities for elucidating transcriptional regulatory mechanisms and enhancer logic. Complex cis-regulatory sequences--like the ones driving expression of the Drosophila even-skipped gene--have proven difficult to design from existing knowledge, presumably due to the large number of protein-protein interactions needed to drive the correct expression patterns of genes in multicellular organisms. This work discusses two novel computational methods for the custom design of enhancers that employ a sophisticated, empirically validated transcriptional model, optimization algorithms, and synthetic biology. These synthetic elements have both utilitarian and academic value, including improving existing regulatory models as well as evolutionary questions. The first method involves the use of simulated annealing to explore the sequence space for synthetic enhancers whose expression output fit a given search criterion. The second method uses a novel optimization algorithm to find functionally accessible pathways between two enhancer sequences. These paths describe a set of mutations wherein the predicted expression pattern does not significantly vary at any point along the path. Both methods rely on a predictive mathematical framework that maps the enhancer sequence space to functional output.
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http://dx.doi.org/10.1016/j.ymeth.2013.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924567PMC
July 2013

Cytochrome P450 bioreactors in the pharmaceutical industry: challenges and opportunities.

Curr Top Med Chem 2013 ;13(12):1470-90

Pfizer Biocatalysis Center of Emphasis, Chemical R&D, PharmaTherapeutics - Pharmaceutical Sciences, MS 4073 Eastern Point Road, Groton, CT 06340, USA.

Cytochrome P450 (CYP) bioreactors play a major role in establishing the practical use of this enzyme family in academia and industry. The current demand for enzymatic hydroxylations of unactivated carbons in the parmaceutical industry includes the preparation of drug metabolites and various hydroxylated synthetic precursors as well as the enzyme mediated lead diversification and natural product synthesis, most of which require multigram scale synthesis. To date, the large scale application of CYPs in the synthesis of oxygenated compounds is limited by many challenges. This review describes relevant examples of CYP oxidations and also presents the strategies available to overcome such challenges. At present, P450 catalyzed reactions can only be performed at substrate concentrations ranging from 1-25 mM, unlike other biocatalytic redox reactions like ketone reductases, typically performed at substrate loads greater than 500 mM. The emergence of powerful expression methods and a large number of CYP mutants developed for specific applications holds the promise for future industrial applications. The search for higher volumetric productivities is however a task that needs to be addressed not only through the use of protein engineering as the primary tool but significant emphasis needs to be placed on process development through exploring multiple operating schemes, optimizing reaction media and modifying microbial strains needed for heterologous expression.
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http://dx.doi.org/10.2174/15680266113139990111DOI Listing
May 2014

Efficacy and safety of ingredients found in preworkout supplements.

Am J Health Syst Pharm 2013 Apr;70(7):577-88

Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, USA.

Purpose: Published evidence on common ingredients of "energy drinks" and other dietary supplements widely used by consumers in hopes of enhancing athletic performance is reviewed.

Summary: Preworkout products- unregulated dietary supplements- typically contain "proprietary blends" of multiple ingredients, including caffeine, dimethylamylamine, creatine, arginine, β-alanine, taurine, and phosphates. While some dietary supplement labels instruct consumers to seek the advice of a health care professional before using the products, the labels usually do not disclose all ingredients or their precise amounts, and evidence to support the purported performance-enhancing benefits is generally lacking. There is limited evidence to support the use of some preworkout supplement ingredients. For example, in one small placebo-controlled study (n = 12), the use of the energy drink Red Bull (containing caffeine and taurine) 40 minutes before a simulated cycling time trial appeared to provide a meaningful ergogenic benefit; in another small study (n = 12), the use of a similar caffeine-containing product (Redline) by strength-trained athletes was found to improve reaction time, energy, and mental focus relative to placebo use. However, published evidence on the use of the other ingredients listed above is scant, inconclusive, or conflicting. Adverse effects reported in association with preworkout supplements include gastrointestinal symptoms, cardiac arrhythmia, blood pressure increases, and potential effects on lipids and blood glucose.

Conclusion: Although evidence exists to support the performance-enhancement efficacy of some preworkout ingredients as standalone agents, published data on combination products are scant, inconclusive, or conflicting. The safety of these products may be compromised if users consume larger-than-recommended amounts or use more than one product.
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http://dx.doi.org/10.2146/ajhp120118DOI Listing
April 2013

Microsatellite markers for Aspidosperma polyneuron (Apocynaceae), an endangered tropical tree species.

Am J Bot 2011 Nov 14;98(11):e300-2. Epub 2011 Oct 14.

Programa de Pós-graduação em Biologia Comparada, Departamento de Biologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes 3900, 14040-901 Ribeirão Preto, São Paulo, Brazil.

Premise Of The Study: This study was designed to develop and characterize a preliminary set of nuclear microsatellite markers for Aspidosperma polyneuron, an endangered tropical tree species.

Methods And Results: Leaf samples were collected from a group of mature A. polyneuron trees in a large area along the Pardo and Mogi-Guaçu river basins in São Paulo State in the southeastern region of Brazil. Twenty-five simple sequence repeat (SSR) markers were developed and 16 of 30 samples had polymorphic loci. The number of alleles per locus ranged from two to 17 (average = 7.06). A high diversity (H(e) = 0.65) and parentage exclusion probability for the first (0.9995) and second (0.9999) parents were measured.

Conclusions: These 16 polymorphic markers suggest a high potential for genetic diversity, gene flow, and mating system analyses in A. polyneuron.
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http://dx.doi.org/10.3732/ajb.1100222DOI Listing
November 2011

Soybean and fish oil mixture increases IL-10, protects against DNA damage and decreases colonic inflammation in rats with dextran sulfate sodium (DSS) colitis.

Lipids Health Dis 2010 Jul 8;9:68. Epub 2010 Jul 8.

Departamento de Ciências Biológicas, Universidade Federal de São Paulo, Campus Diadema, SP, Brazil.

It was investigated whether dietary polyunsaturated fatty acids (PUFA) could influence colonic injury, tissue DNA damage, cytokines and myeloperoxidase activity (MPO) and plasma corticosterone in DSS-induced colitis rats. Male weaning Wistar rats were fed for 47 days with an AIN-93 diet with control (C), fish (F) or a mixture of fish and soybean oil (SF). The colitis was induced from day 36 until day 42 by 3% DSS in drinking water. On day 48, blood samples were collected for corticosterone determination. The distal colon was excised for histological analysis and to quantify the cytokine (IL-4, IL-10 and INF-gamma), MPO and DNA damage. The disease activity index (DAI) was recorded daily during colitis induction. The DAI, MPO, histological analyses showed decreases only in the SF group compared with the C group. IL-10 was increased and DNA damage was reduced in the groups F and SF, and an inverse correlation between these variables was found. There were no differences in corticosterone, IFN-gamma and IL-4 levels. Soybean and fish oil mixture may be effective in improving colonic injury and DNA damage, and it could be an important complementary therapy in UC to reduce the use of anti-inflammatory drugs and prevent colorectal cancer.
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http://dx.doi.org/10.1186/1476-511X-9-68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909993PMC
July 2010

Modeling the basin of attraction as a two-dimensional manifold from experimental data: applications to balance in humans.

Chaos 2010 Mar;20(1):013119

Instituto de Ciencias Matemticas, CSIC-UAM-UC3M-UCM, c/Serrano 121, 28006 Madrid, Spain.

We present a method of modeling the basin of attraction as a three-dimensional function describing a two-dimensional manifold on which the dynamics of the system evolves from experimental time series data. Our method is based on the density of the data set and uses numerical optimization and data modeling tools. We also show how to obtain analytic curves that describe both the contours and the boundary of the basin. Our method is applied to the problem of regaining balance after perturbation from quiet vertical stance using data of an elite athlete. Our method goes beyond the statistical description of the experimental data, providing a function that describes the shape of the basin of attraction. To test its robustness, our method has also been applied to two different data sets of a second subject and no significant differences were found between the contours of the calculated basin of attraction for the different data sets. The proposed method has many uses in a wide variety of areas, not just human balance for which there are many applications in medicine, rehabilitation, and sport.
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http://dx.doi.org/10.1063/1.3337690DOI Listing
March 2010

Complex equilibria in the maintenance of boundaries: experiments with mussel beds.

Ecology 2009 Apr;90(4):985-95

Center for Environmental Analysis, California State University at Los Angeles, Los Angeles, California 90032, USA.

Stationary boundaries of sedentary species may belie dynamic processes that form them. Our aim was to test an implication of an evolving body of theory, that such boundaries are manifestations of complex regulatory dynamics. On rocky shores of British Columbia, large-scale field experiments altered the densities of predatory sea stars (Pisaster ochraceus), causing shifts in the location of the lower vertical boundaries of their prey, sea mussels (Mytilus californianus). While control mussel beds remained unchanged, experimental reductions of sea star densities caused the downward extension of the lower boundaries, and experimental increases in sea stars densities caused the upward recession of the lower boundary well into the zone presumed to be a spatial refuge from predation. Cleared plots prepared within the initial boundaries were recolonized to varying degrees, depending on predator densities. After 30 months, plots on sea star removal sites showed high densities of adult mussels, control plots showed intermediate densities, and sea star addition plots showed only a sparse cover of alternative prey. Observations by divers at high tide showed that as small prey were depleted progressively from removal, to control, to addition sites, correspondingly larger mussels were attacked, including very large individuals comprising the lower boundary of addition sites. The findings contradict classic theory of zonation based on static prey refuges and support an alternative theory in which boundaries are maintained by complex, spatially structured equilibria.
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http://dx.doi.org/10.1890/08-0919.1DOI Listing
April 2009

Transferability and characterization of nine microsatellite markers for the tropical tree species Tabebuia roseo-alba.

Mol Ecol Resour 2009 Jan;9(1):434-7

Plant Genetic Laboratory Graduate Program in Genetics, Department of Genetics, FMRP Graduate Program in Comparative Biology, Department of Biology, FFCLRP, University of Sao Paulo, Av. Bandeirantes, 3900, 14040-900, Ribeirao Preto, SP, Brazil.

Microsatellite loci that were previously developed in the tropical tree Tabebuia aurea were used for the genetic analysis of Tabebuia roseo-alba populations. Nine of 10 simple sequence repeat markers were amplified, and the polymorphism was assessed in 58 individuals sampled from two stands in southeastern Brazil. All loci were polymorphic with Mendelian inheritance. The allele numbers were high, ranging from 5 to 13 in population I and 3 to 7 in population II, with means of 8.9 and 5.5, respectively. We conclude that these markers can be efficiently used for parentage and gene-flow studies.
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http://dx.doi.org/10.1111/j.1755-0998.2008.02483.xDOI Listing
January 2009

Analysis of oxidative DNA damage in patients with colorectal cancer.

Clin Colorectal Cancer 2008 Jul;7(4):267-72

Unidade Integrada de Farmacologia e Gastroenterologia, Universidade São Francisco, Bragança Paulista, São Paulo, Brazil.

Purpose: The aim of this study was to measure the levels of oxidative DNA damage in cells isolated from the colon mucosa in patients with colorectal cancer and to compare normal and neoplastic tissues and make correlations with anatomopathologic variables.

Patients And Methods: Thirty-three patients with colorectal adenocarcinoma were studied. The oxidative DNA damage was evaluated by means of the alkaline version of the comet assay.

Results: For all the patients studied, it was found that the cells obtained from the neoplastic tissue presented oxidative DNA damage greater than in the cells from normal tissue. The cells isolated from the neoplastic mucosal tissue of the colon presented significantly greater mean extent of DNA strand breakage than the cells isolated from normal tissue. Additionally, the patients at earlier stages of the Dukes and TNM classifications presented higher levels of oxidative damage than those at more advanced stages.

Conclusion: Assessment of the levels of oxidative damage at the different stages of colorectal carcinogenesis is of great interest because it enables evaluation of the effectiveness of antioxidant substances that could be used as preventive measures against the initial oxidative aggressive action on the colonic mucosa.
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http://dx.doi.org/10.3816/CCC.2008.n.034DOI Listing
July 2008

Spreading of a corepressor linked to action of long-range repressor hairy.

Mol Cell Biol 2008 Apr 19;28(8):2792-802. Epub 2008 Feb 19.

Department of Biochemistry and Molecular Biology and Genetics Program, Michigan State University, East Lansing, MI 48824-1319, USA.

Transcriptional repressor proteins play key roles in the control of gene expression in development. For the Drosophila embryo, the following two functional classes of repressors have been described: short-range repressors such as Knirps that locally inhibit the activity of enhancers and long-range repressors such as Hairy that can dominantly inhibit distal elements. Several long-range repressors interact with Groucho, a conserved corepressor that is homologous to mammalian TLE proteins. Groucho interacts with histone deacetylases and histone proteins, suggesting that it may effect repression by means of chromatin modification; however, it is not known how long-range effects are mediated. Using embryo chromatin immunoprecipitation, we have analyzed a Hairy-repressible gene in the embryo during activation and repression. When inactivated, repressors, activators, and coactivators cooccupy the promoter, suggesting that repression is not accomplished by the displacement of activators or coactivators. Strikingly, the Groucho corepressor is found to be recruited to the transcribed region of the gene, contacting a region of several kilobases, concomitant with a loss of histone H3 and H4 acetylation. Groucho has been shown to form higher-order complexes in vitro; thus, our observations suggest that long-range effects may be mediated by a "spreading" mechanism, modifying chromatin over extensive regions to inhibit transcription.
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http://dx.doi.org/10.1128/MCB.01203-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2293098PMC
April 2008