bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross-talk between HER2 and MED1 Regulates Tamoxifen Resistance of Human Breast Cancer Cells
Authors: Cui Jiajun , Germer Katherine , Wu Tianying , Wang Jiang , Luo Jia , Wang Shao-chun , Wang Qianben , Zhang Xiaoting
Published: September 2012

Despite the fact that most breast cancer patients have estrogen receptor (ER) α-positive tumors, up to 50% of the patients are or soon develop resistance to endocrine therapy. It is recognized that HER2 activation is one of the major mechanisms contributing to endocrine resistance. In this study, we report that the ER coactivator MED1 is a novel cross-talk point for the HER2 and ERα pathways. Tissue microarray analysis of human breast cancers revealed that MED1 expression positively correlates most strongly with HER2 status of the tumors. MED1 was highly phosphorylated, in a HER2-dependent manner, at the site known to be critical for its activation. Importantly, RNAi-mediated attenuation of MED1 sensitized HER2-overexpressing cells to tamoxifen treatment. MED1 and its phosphorylated form, but not the corepressors N-CoR and SMRT, were recruited to the ERα target gene promoter by tamoxifen in HER2-overexpressing cells. Significantly, MED1 attenuation or mutation of MED1 phosphorylation sites was sufficient to restore the promoter recruitment of N-CoR and SMRT. Notably, we found that MED1 is required for the expression of not only traditional E2-ERα target genes but also the newly described EGF-ERα target genes. Our results additionally indicated that MED1 is recruited to the HER2 gene and required for its expression. Taken together, these findings support a key role for MED1 in HER2-mediated tamoxifen resistance and suggest its potential usage as a therapeutic target to simultaneously block both ERα and HER2 pathways for the treatment of this type of endocrine resistant breast cancer. Cancer Res; 72(21); 5625–34. ©2012 AACR.
Microdistribution and Long-term Retention of 239Pu (NO3)4 in the Respiratory Tracts of an Acutely Exposed Plutonium Worker and Experimental Beagle Dogs
Authors: Nielsen Christopher E. , Wilson Dulaney A. , Brooks Antone L. , McCord Stacey L. , Dagle Gerald E. , James Anthony C. , Tolmachev Sergei Y. , Thrall Brian D. , Morgan William F.
Published: September 2012

The long-term retention of inhaled soluble forms of plutonium raises concerns as to the potential health effects in persons working in nuclear energy or the nuclear weapons program. The distributions of long-term retained inhaled plutonium-nitrate [239Pu (NO3)4] deposited in the lungs of an accidentally exposed nuclear worker (Human Case 0269) and in the lungs of experimentally exposed beagle dogs with varying initial lung depositions were determined via autoradiographs of selected histologic lung, lymph node, trachea, and nasal turbinate tissue sections. These studies showed that both the human and dogs had a nonuniform distribution of plutonium throughout the lung tissue. Fibrotic scar tissue effectively encapsulated a portion of the plutonium and prevented its clearance from the body or translocation to other tissues and diminished dose to organ parenchyma. Alpha radiation activity from deposited plutonium in Human Case 0269 was observed primarily along the subpleural regions while no alpha activity was seen in the tracheobronchial lymph nodes of this individual. However, relatively high activity levels in the tracheobronchial lymph nodes of the beagles indicated the lymphatic system was effective in clearing deposited plutonium from the lung tissues. In both the human case and beagle dogs, the appearance of retained plutonium within the respiratory tract was inconsistent with current biokinetic models of clearance for soluble forms of plutonium. Bound plutonium can have a marked effect on the dose to the lungs and subsequent radiation exposure has the potential to increase cancer risk. Cancer Res; 72(21); 5529–36. ©2012 AACR.
CDK1 Regulates Mediator of DNA Damage Checkpoint 1 during Mitotic DNA Damage
Authors: Yu Bing , Dalton W. Brian , Yang Vincent W.
Published: September 2012

Cells engage sophisticated programs of DNA damage response (DDR) and repair to guard against genetic mutations. Although there is significant knowledge concerning DDR in interphase cells, much less is known about these processes in mitosis. Direct interaction between MDC1, a master DDR organizer, and a marker of DNA damage, histone γH2AX, is required to trigger robust repair. Here we show that the DNA damage-induced interaction between MDC1 and γH2AX is attenuated in mitosis. Furthermore, inhibition in the activity of the core mitotic regulator CDK1, either by pharmacologic inhibition or siRNA attenuation, enhances MDC1–γH2AX colocalization in mitosis. Our findings offer key new insights into how DDR is controlled during mitosis. Cancer Res; 72(21); 5448–53. ©2012 AACR.
Personalized Medicine in a Phase I Clinical Trials Program: The MD Anderson Cancer Center Initiative
Authors: Tsimberidou Apostolia-Maria , Iskander Nancy G. , Hong David S. , Wheler Jennifer J. , Falchook Gerald S. , Fu Siqing , Piha-Paul Sarina , Naing Aung , Janku Filip , Luthra Rajyalakshmi , Ye Yang , Wen Sijin , Berry Donald , Kurzrock Razelle
Published: September 2012

Purpose: We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations.

Patient and Methods: Patients with advanced cancer were treated in the Clinical Center for Targeted Therapy. Molecular analysis was conducted in the MD Anderson Clinical Laboratory Improvement Amendments (CLIA)–certified laboratory. Patients whose tumors had an aberration were treated with matched targeted therapy, when available. Treatment assignment was not randomized. The clinical outcomes of patients with molecular aberrations treated with matched targeted therapy were compared with those of consecutive patients who were not treated with matched targeted therapy.

Results: Of 1,144 patients analyzed, 460 (40.2%) had 1 or more aberration. In patients with 1 molecular aberration, matched therapy (n = 175) compared with treatment without matching (n = 116) was associated with a higher overall response rate (27% vs. 5%; P < 0.0001), longer time-to-treatment failure (TTF; median, 5.2 vs. 2.2 months; P < 0.0001), and longer survival (median, 13.4 vs. 9.0 months; P = 0.017). Matched targeted therapy was associated with longer TTF compared with their prior systemic therapy in patients with 1 mutation (5.2 vs. 3.1 months, respectively; P < 0.0001). In multivariate analysis in patients with 1 molecular aberration, matched therapy was an independent factor predicting response (P = 0.001) and TTF (P = 0.0001).

Conclusion: Keeping in mind that the study was not randomized and patients had diverse tumor types and a median of 5 prior therapies, our results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials. Clin Cancer Res; 18(22); 6373–83. ©2012 AACR.
U.S. Food and Drug Administration Approval Summary: Brentuximab Vedotin for the Treatment of Relapsed Hodgkin Lymphoma or Relapsed Systemic Anaplastic Large-Cell Lymphoma
Authors: de Claro R. Angelo , McGinn Karen , Kwitkowski Virginia , Bullock Julie , Khandelwal Aakanksha , Habtemariam Bahru , Ouyang Yanli , Saber Haleh , Lee Kyung , Koti Kallappa , Rothmann Mark , Shapiro Marjorie , Borrego Francisco , Clouse Kathleen , Chen Xiao Hong , Brown Janice , Akinsanya Lara , Kane Robert , Kaminskas Edvardas , Farrell Ann , Pazdur Richard
Published: September 2012

The U.S. Food and Drug Administration (FDA) describes the accelerated approval of brentuximab vedotin for patients with relapsed Hodgkin lymphoma and relapsed systemic anaplastic large-cell lymphoma (sALCL). FDA analyzed the results of two single-arm trials, enrolling 102 patients with Hodgkin lymphoma and 58 patients with sALCL. Both trials had primary endpoints of objective response rate (ORR) and key secondary endpoints of response duration and complete response (CR) rate. For patients with Hodgkin lymphoma, ORR was 73% (95% CI, 65–83%); median response duration was 6.7 months, and CR was 32% (95% CI, 23–42%). For patients with sALCL, ORR was 86% (95% CI, 77–95%), median response duration was 12.6 months, and CR was 57% (95% CI, 44–70%). The most common adverse reactions were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. FDA granted accelerated approval of brentuximab vedotin for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of patients with sALCL after failure of at least one prior multiagent chemotherapy regimen. Clin Cancer Res; 18(21); 5845–9. ©2012 AACR.
Inhibition of Monocarboxylate Transporter 2 Induces Senescence-Associated Mitochondrial Dysfunction and Suppresses Progression of Colorectal Malignancies In Vivo
Authors: Lee Inkyoung , Lee Sook-Ja , Kang Won Ki , Park Chaehwa
Published: September 2012

Senescence, an inherent tumor suppressive mechanism, is a critical determinant for chemotherapy. In the present study, we show that the monocarboxylate transporter 2 (MCT2) protein was tumor-selectively expressed in human colorectal malignancies and knockdown of MCT2 induces mitochondrial dysfunction, cell-cycle arrest, and senescence without additional cellular stress in colorectal cancer cell lines. Moreover, the reactive oxygen species (ROS) scavenger, N-acetylcysteine, blocked MCT2 knockdown-induced growth arrest and cellular senescence, indicating a pivotal role of ROS in this pathway. Dramatic induction of mitochondrial superoxide generation and decrease in ATP production was observed, indicating that mitochondrial dysfunction is the major mechanism underlying MCT2 knockdown-induced ROS generation. Senescence-associated DNA damage was also evident from the increase in promyelocytic leukemia bodies, γH2AX foci, and SAHF. Conversely, overexpression of MCT2 prevented doxorubicin-induced ROS accumulation (P = 0.0002) and cell growth inhibition (P = 0.001). MCT2 knockdown suppressed KRAS mutant colorectal tumor growth in vivo. In addition, MCT2 knockdown and cytostatic drug combination further enhanced the antitumor effect. These findings support the use of MCT2 as a promising target for inhibition of colorectal cancer. Mol Cancer Ther; 11(11); 2342–51. ©2012 AACR.
Roles of Estrogen Receptor and p21Waf1 in Bortezomib-Induced Growth Inhibition in Human Breast Cancer Cells
Authors: Maynadier Marie , Shi Jingxue , Vaillant Ophélie , Gary-Bobo Magali , Basile Ilaria , Gleizes Michel , Cathiard Anne-Marie , Wah Jonathan Lee Tin , Sheikh M. Saeed , Garcia Marcel
Published: September 2012

Proteasome inhibitors such as bortezomib constitute novel therapeutic agents that are currently in clinical use and in clinical trials. In some neoplasms, cyclin-dependent kinase inhibitors (CKI) such as p21WAF1 have been proposed as key targets of proteasome inhibitors. p21WAF1 expression can be modulated by p53, a tumor suppressor, and especially in breast cancer cells, by estrogen receptor alpha (ERα), which is highly relevant to cancer growth. We investigated the effects of bortezomib using a panel of six cancer cell lines with variable status of ERα or p53 and found that bortezomib inhibited the growth of all cell lines in the same concentration range irrespective of the ERα expression or the mutational status of p53. Bortezomib treatment significantly enhanced p21WAF1 protein levels in all cell lines but with different mechanisms according to ERα status. In ERα-positive cells, bortezomib treatment caused a strong increase in p21WAF1 mRNA, whereas in ERα-negative cells it predominantly enhanced p21WAF1 protein levels suggesting a posttranslational mechanism of p21WAF1 regulation in the ERα-negative cells. Moreover, the antiproliferative activity of bortezomib was prevented by ERα silencing or p21WAF1 knockdown in ERα-positive cells. Collectively, our results highlight the potential roles of ERα and p21WAF1 in growth inhibition of cancer cells mediated by proteasome inhibitors, such as bortezomib. Mol Cancer Res; 10(11); 1473–81. ©2012 AACR.
SUZ12 Promotes Human Epithelial Ovarian Cancer by Suppressing Apoptosis via Silencing HRK
Authors: Li Hua , Cai Qi , Wu Hong , Vathipadiekal Vinod , Dobbin Zachary C. , Li Tianyu , Hua Xiang , Landen Charles N. , Birrer Michael J. , Sánchez-Beato Margarita , Zhang Rugang
Published: September 2012

Epithelial ovarian cancer (EOC) ranks first as the cause of death for gynecological cancers in the United States. SUZ12 is a component of the polycomb repressive complex 2 (PRC2) and is essential for PRC2-mediated gene silencing by generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3). The role of SUZ12 in EOC has never been investigated. Here, we show that SUZ12 is expressed at significantly higher levels in human EOC (n = 117) compared with either normal human ovarian surface epithelium (n = 35, P < 0.001) or fallopian tube epithelium (n = 15, P < 0.001). There is a positive correlation between expression of SUZ12 and EZH2 in human EOC (P < 0.001). In addition, expression of SUZ12 positively correlates with Ki67, a marker of cell proliferation (P < 0.001), and predicts shorter overall survival (P = 0.0078). Notably, knockdown of SUZ12 suppresses the growth of human EOC cells in vitro and in vivo in both orthotopic and subcutaneous xenograft EOC models. In addition, SUZ12 knockdown decreases the levels of H3K27Me3 and triggers apoptosis of human EOC cells. Mechanistically, we identified Harakiri (HRK), a proapoptotic gene, as a novel SUZ12 target gene, and showed that HRK upregulation mediates apoptosis induced by SUZ12 knockdown in human EOC cells. In summary, we show that SUZ12 promotes the proliferation of human EOC cells by inhibiting apoptosis and HRK is a novel SUZ12 target gene whose upregulation contributes to apoptosis induced by SUZ12 knockdown. Mol Cancer Res; 10(11); 1462–72. ©2012 AACR.
The Lymphotactin Receptor Is Expressed in Epithelial Ovarian Carcinoma and Contributes to Cell Migration and Proliferation
Authors: Kim Mijung , Rooper Lisa , Xie Jia , Rayahin Jamie , Burdette Joanna E. , Kajdacsy-Balla Andre A. , Barbolina Maria V.
Published: September 2012

Chemokine receptor-ligand interactions are important to support functioning of both normal and pathologic cells. The expression and function of chemokine receptors in epithelial ovarian carcinoma (EOC) is largely unknown. Here, we report that the lymphotactin receptor (XCR1) was expressed in primary and metastatic human epithelial ovarian carcinoma (EOC) specimens and cell lines. In contrast, expression of XCR1 was not detected in the normal ovary or in human normal ovarian surface epithelial cells. Our data indicate that XCL1 and XCL2 are either present in the malignant ascites or expressed by the ovarian carcinoma cells. The addition of lymphotactin (XCL1 and XCL2) stimulated migration and proliferation of XCR1-positive cells. Reduction of XCR1 expression in ovarian carcinoma cell line SKOV-3 resulted in abrogated diaphragm and peritoneal wall tumor formation and in reduced frequency of colonic, splenetic, and liver nodules in an in vivo xenograft mouse model. Taken together, our data suggest that XCR1 is expressed early during the course of tumorigenic transformation and contributes towards increased cell migration and proliferation, which can facilitate the prometastatic behavior of EOC cells. Mol Cancer Res; 10(11); 1419–29. ©2012 AACR.
Multiphoton Tomographic Imaging: A Potential Optical Biopsy Tool for Detecting Gastrointestinal Inflammation and Neoplasia
Authors: Makino Tomoki , Jain Manu , Montrose David C. , Aggarwal Amit , Sterling Joshua , Bosworth Brian P. , Milsom Jeffrey W. , Robinson Brian D. , Shevchuk Maria M. , Kawaguchi Kathy , Zhang Ning , Brown Christopher M. , Rivera David R. , Williams Wendy O. , Xu Chris , Dannenberg Andrew J. , Mukherjee Sushmita
Published: September 2012

Endoscopy is widely used to detect and remove premalignant lesions with the goal of preventing gastrointestinal (GI) cancers. Because current endoscopes do not provide cellular resolution, all suspicious lesions are biopsied and subjected to histologic evaluation. Technologies that facilitate directed biopsies should decrease both procedure-related morbidity and cost. Here we explore the use of multiphoton microscopy (MPM), an optical biopsy tool that relies on intrinsic tissue emissions, to evaluate pathology in both experimental and human GI specimens, using hematoxylin and eosin (H&E)-stained sections from these tissues for comparison. After evaluating the entire normal mouse GI tract, MPM was used to investigate disease progression in mouse models of colitis and colorectal carcinogenesis. MPM provided sufficient histologic detail to identify all relevant substructures in ex vivo normal GI tissue, visualize both acute and resolving stages of colitis, and show the progression of colorectal carcinogenesis. Next, ex vivo specimens from human subjects with celiac sprue, inflammatory bowel disease, and colorectal neoplasia were imaged by MPM. Finally, colonic mucosa in live anesthetized rats was imaged in vivo using a flexible endoscope prototype. In both animal models and human specimens, MPM images showed a striking similarity to the results of H&E staining, as shown by the 100% concordance achieved by the study pathologists' diagnoses. In summary, MPM is a promising technique that accurately visualizes histology in fresh, unstained tissues. Our findings support the continued development of MPM as a technology to enhance the early detection of GI pathologies including premalignant lesions. Cancer Prev Res; 5(11); 1280–90. ©2012 AACR.
Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Authors: Byers Lauren Averett , Wang Jing , Nilsson Monique B. , Fujimoto Junya , Saintigny Pierre , Yordy John , Giri Uma , Peyton Michael , Fan You Hong , Diao Lixia , Masrorpour Fatemeh , Shen Li , Liu Wenbin , Duchemann Boris , Tumula Praveen , Bhardwaj Vikas , Welsh James , Weber Stephanie , Glisson Bonnie S. , Kalhor Neda , Wistuba Ignacio I. , Girard Luc , Lippman Scott M. , Mills Gordon B. , Coombes Kevin R. , Weinstein John N. , Minna John D. , Heymach John V.
Published: September 2012

Small cell lung cancer (SCLC) is an aggressive malignancy distinct from non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Using an integrative proteomic and transcriptomic analysis, we investigated molecular differences contributing to the distinct clinical behavior of SCLCs and NSCLCs. SCLCs showed lower levels of several receptor tyrosine kinases and decreased activation of phosphoinositide 3-kinase (PI3K) and Ras/mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) pathways but significantly increased levels of E2F1-regulated factors including enhancer of zeste homolog 2 (EZH2), thymidylate synthase, apoptosis mediators, and DNA repair proteins. In addition, PARP1, a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLCs. SCLC growth was inhibited by PARP1 and EZH2 knockdown. Furthermore, SCLC was significantly more sensitive to PARP inhibitors than were NSCLCs, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy.

Significance: SCLC is a highly lethal cancer with a 5-year survival rate of less than 10%. To date, no molecularly targeted agents have prolonged survival in patients with SCLCs. As a step toward identifying new targets, we systematically profiled SCLCs with a focus on therapeutically relevant signaling pathways. Our data reveal fundamental differences in the patterns of pathway activation in SCLCs and NSCLCs and identify several potential therapeutic targets for SCLCs, including PARP1 and EZH2. On the basis of these results, clinical studies evaluating PARP and EZH2 inhibition, together with chemotherapy or other agents, warrant further investigation. Cancer Discov; 2(9); 798–811. ©2012 AACR.

Read the Commentary on this article by Rosell and Wannesson, p. 769.

This article is highlighted in the In This Issue feature, p. 753.
Paracrine Signaling between Carcinoma Cells and Mesenchymal Stem Cells Generates Cancer Stem Cell Niche via Epithelial–Mesenchymal Transition
Authors: Räsänen Kati , Herlyn Meenhard
Published: September 2012

Summary: Li and colleagues present data that cancer cell–derived interleukin-1 induces prostaglandin E2 and cytokine secretion in mesenchymal stem cells (MSC) to activate β-catenin signaling in the cancer cell. This paracrine signaling between carcinoma cells and MSC leads to the creation of a cancer stem cell niche via epithelial–mesenchymal transition. Cancer Discov; 2(9); 775–7. ©2012 AACR.

Commentary on Li et al., p. 840.
Maximal Electric Separation–Guided Placement of Right Ventricular Lead Improves Responders in Cardiac Resynchronization Defibrillator Therapy
Authors: Miranda Rodrigo I. , Nault Michael , Johri Amer , Simpson Christopher S. , Michael Kevin A. , Abdollah Hoshiar , Baranchuk Adrian , Redfearn Damian P.
Published: September 2012

Background—

Cardiac resynchronization therapy is widely used for the treatment of heart failure. Recent data suggest that electric separation during left ventricular pacing varies within the right ventricle (RV). We hypothesized that placement of the RV lead guided by maximal electric separation (MES) would improve response to cardiac resynchronization therapy compared with standard apical placement.

Methods and Results—

A single-blind, randomized controlled trial was conducted. Patients eligible for cardiac resynchronization therapy-D were enrolled. Left ventricular lead placement was performed at the coronary sinus branch. The RV outflow tract, septum, and apex were mapped during left ventricular pacing and MES recorded. Patients were randomized to receive either apical placement or RV lead placement at the site mapping MES. Left ventricular ejection fraction, 6-minute walk distance, and New York Heart Association functional class were recorded at baseline and 3 months by blinded observers. Response was defined as at least one of the following: 5% absolute increase in ejection fraction, 50 m increase in 6-minute walk distance, or an increase by
>
1 functional class. Primary end point was improvement in ejection fraction at 3 months. Fifty patients were randomized (25 MES-guided and 25 apical). Baseline characteristics were similar in the 2 groups. Electric separation was lower in the apex (143±23 versus 168±25 ms in MES group;
P
=0.01). MES was most commonly septal and rarely apical (4/50 patients). Responders in the MES-guided versus apical group are as follows: Echo 21 versus 13 patients (
P
=0.032), 6-minute walk distance 19 versus 12 patients (
P
=0.079), and functional class 22 versus 15 patients (
P
=0.051). No dislodgment or reposition for suboptimal defibrillation tests was reported.

Conclusions—

MES-guided placement of the RV lead improves cardiac resynchronization therapy responders compared with standard apical placement.
The Study of Antiarrhythmic Medications in Infancy (SAMIS)
Authors: Sanatani Shubhayan , Potts James E. , Reed John H. , Saul J. Philip , Stephenson Elizabeth A. , Gibbs Karen A. , Anderson Charles C. , Mackie Andrew S. , Ro Pamela S. , Tisma-Dupanovic Svjetlana , Kanter Ronald J. , Batra Anjan S. , Fournier Anne , Blaufox Andrew D. , Singh Harinder R. , Ross Bertrand A. , Wong Kenny K. , Bar-Cohen Yaniv , McCrindle Brian W. , Etheridge Susan P.
Published: September 2012

Background—

Supraventricular tachycardia (SVT) is one of the most common conditions requiring emergent cardiac care in children, yet its management has never been subjected to a randomized controlled clinical trial. The purpose of this study was to compare the efficacy and safety of the 2 most commonly used medications for antiarrhythmic prophylaxis of SVT in infants: digoxin and propranolol.

Methods and Results—

This was a randomized, double-blind, multicenter study of infants <4 months with SVT (atrioventricular reciprocating tachycardia or atrioventricular nodal reentrant tachycardia), excluding Wolff-Parkinson-White, comparing digoxin with propranolol. The primary end point was recurrence of SVT requiring medical intervention. Time to recurrence and adverse events were secondary outcomes. Sixty-one patients completed the study, 27 randomized to digoxin and 34 to propranolol. SVT recurred in 19% of patients on digoxin and 31% of patients on propranolol (
P
=0.25). No first recurrence occurred after 110 days of treatment. The 6-month recurrence-free status was 79% for patients on digoxin and 67% for patients on propranolol (
P
=0.34), and there were no first recurrences in either group between 6 and 12 months. There were no deaths and no serious adverse events related to study medication.

Conclusions—

There was no difference in SVT recurrence in infants treated with digoxin versus propranolol. The current standard practice may be treating infants longer than required and indicates the need for a placebo-controlled trial.

Clinical Trial Registration Information—

http://clinicaltrials.gov
; NCT-00390546.
PPARγ Regulates Resistance Vessel Tone Through a Mechanism Involving RGS5-Mediated Control of Protein Kinase C and BKCa Channel Activity
Authors: Ketsawatsomkron Pimonrat , Lorca Ramón A. , Keen Henry L. , Weatherford Eric T. , Liu Xuebo , Pelham Christopher J. , Grobe Justin L. , Faraci Frank M. , England Sarah K. , Sigmund Curt D.
Published: September 2012

Rationale:

Activation of peroxisome proliferator−activated receptor-γ (PPARγ) by thiazolidinediones lowers blood pressure, whereas PPARγ mutations cause hypertension. Previous studies suggest these effects may be mediated through the vasculature, but the underlying mechanisms remain unclear.

Objective:

To identify PPARγ mechanisms and transcriptional targets in vascular smooth muscle and their role in regulating resistance artery tone.

Methods and Results:

We studied mesenteric artery (MA) from transgenic mice expressing dominant-negative (DN) mutant PPARγ driven by a smooth muscle cell−specific promoter. MA from transgenic mice exhibited a robust increase in myogenic tone. Patch clamp analysis revealed a reduced large conductance Ca
2+
-activated K
+
(BKCa) current in freshly dissociated smooth muscle cell from transgenic MA. Inhibition of protein kinase C corrected both enhanced myogenic constriction and impaired the large conductance Ca
2+
-activated K
+
channel function. Gene expression profiling revealed a marked loss of the regulator of G protein signaling 5
(RGS5)
mRNA in transgenic MA, which was accompanied by a substantial increase in angiotensin II–induced constriction in MA. Small interfering RNA targeting RGS5 caused augmented myogenic tone in intact mesenteric arteries and increased activation of protein kinase C in smooth muscle cell cultures. PPARγ and PPARδ each bind to a PPAR response element close to the
RGS5
promoter.
RGS5
expression in nontransgenic MA was induced after activation of either PPARγ or PPARδ, an effect that was markedly blunted by DN PPARγ.

Conclusions:

We conclude that RGS5 in smooth muscle is a PPARγ and PPARδ target, which when activated blunts angiotensin II–mediated activation of protein kinase C, and preserves the large conductance Ca
2+
-activated K
+
channel activity, thus providing tight control of myogenic tone in the microcirculation.
Formation of the Collateral Circulation Is Regulated by Vascular Endothelial Growth Factor-A and A Disintegrin and Metalloprotease Family Members 10 and 17
Authors: Lucitti Jennifer L. , Mackey Jessica K. , Morrison Jeffrey C. , Haigh Jody J. , Adams Ralf H. , Faber James E.
Published: September 2012

Rationale:

The density of native (preexisting) collaterals varies widely and is a significant determinant of variation in severity of stroke, myocardial infarction, and peripheral artery disease. However, little is known about mechanisms responsible for formation of the collateral circulation in healthy tissues.

Objective:

We previously found that variation in vascular endothelial growth factor (VEGF) expression causes differences in collateral density of newborn and adult mice. Herein, we sought to determine mechanisms of collaterogenesis in the embryo and the role of VEGF in this process.

Methods and Results:

Pial collaterals begin forming between embryonic day 13.5 and 14.5 as sprout-like extensions from arterioles of existing cerebral artery trees. Global VEGF-A overexpressing mice (
Vegf

hi/+

) formed more, and
Vegf

lo/+

formed fewer, collaterals during embryogenesis, in association with differences in vascular patterning. Conditional global reduction of
Vegf
or
Flk1
only during collaterogenesis significantly reduced collateral formation, but now without affecting vascular patterning, and the effects remained in adulthood. Endothelial-specific
Vegf
reduction had no effect on collaterogenesis. Endothelial-specific reduction of a disintegrin-and-metalloprotease-domain-10 (
Adam10
) and inhibition of γ-secretase increased collateral formation, consistent with their roles in VEGF-induced Notch1 activation and suppression of prosprouting signals. Endothelial-specific knockdown of
Adam17
reduced collateral formation, consistent with its roles in endothelial cell migration and embryonic vascular stabilization, but not in activation of ligand-bound Notch1. These effects also remained in adulthood.

Conclusions:

Formation of pial collaterals occurs during a narrow developmental window via a sprouting angiogenesis-like mechanism, requires paracrine VEGF stimulation of fetal liver kinase 1-Notch signaling, and adult collateral number is dependent on embryonic collaterogenesis.
Trends in Blood Pressure and Hypertension Detection, Treatment, and Control 1980 to 2009
Authors: Luepker Russell V. , Steffen Lyn M. , Jacobs David R. , Zhou Xia , Blackburn Henry
Published: September 2012

Background—

Hypertension is common and treatable, but detection and control remain a major health challenge. This study sought to determine population trends in blood pressure and in the control of hypertension in the Minneapolis/St. Paul area (2010 population, 2.85 million) from 1980 to 2009.

Methods and Results—

Surveys of risk factors were performed every 5 years among randomly selected adults aged 25 to 74 years. Data on hypertension knowledge and use of medications were collected by interview. Blood pressure was measured by standardized methods, with hypertension defined as blood pressure ≥140 mm Hg systolic and/or 90 mm Hg diastolic or controlled at <140 and/or 90 mm Hg with medications. Six surveys included 11 192 men and 12 795 women. Mean systolic blood pressure fell from 124.9 mm Hg in 1980 to 1982 to 121.1 mm Hg in 2007 to 2009 for men (
P
<0.0001) and from 120.1 to 114.7 mm Hg for women (
P
<0.0001). Similar trends for diastolic blood pressure were observed. The percentage of adults with uncontrolled blood pressure (≥140 and/or 90 mm Hg) with or without medication use fell from 20.3% to 5.8% (
P
<0.001) for men and from 13.1% to 2.7% (
P
<0.0001) for women. Antihypertensive medication use rose to >50% among all adults aged 55 to 74 years. Sixty-six percent of men and 72% of women with hypertension had their hypertension treated or controlled by 2007 to 2009. A majority of the decline in mean population blood pressure was the result of control with aggressive use of antihypertensive drugs. Stroke mortality in this population fell in parallel.

Conclusions—

The rate of hypertension detection and control in this community is among the highest observed in a US population and already exceeds Healthy People 2020 goals.
Long-Term Cardiovascular Risk of Nonsteroidal Anti-Inflammatory Drug Use According to Time Passed After First-Time Myocardial Infarction
Authors: Olsen Anne-Marie Schjerning , Fosbøl Emil L. , Lindhardsen Jesper , Folke Fredrik , Charlot Mette , Selmer Christian , Bjerring Olesen Jonas , Lamberts Morten , Ruwald Martin H. , Køber Lars , Hansen Peter R. , Torp-Pedersen Christian , Gislason Gunnar H.
Published: September 2012

Background—

The cardiovascular risk after the first myocardial infarction (MI) declines rapidly during the first year. We analyzed whether the cardiovascular risk associated with using nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with the time elapsed following first-time MI.

Methods and Results—

We identified patients aged 30 years or older admitted with first-time MI in 1997 to 2009 and subsequent NSAID use by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. We calculated the incidence rates of death and a composite end point of coronary death or nonfatal recurrent MIs associated with NSAID use in 1-year time intervals up to 5 years after inclusion and analyzed risk by using multivariable adjusted time-dependent Cox proportional hazards models. Of the 99 187 patients included, 43 608 (44%) were prescribed NSAIDs after the index MI. There were 36 747 deaths and 28 693 coronary deaths or nonfatal recurrent MIs during the 5 years of follow-up. Relative to noncurrent treatment with NSAIDs, the use of any NSAID in the years following MI was persistently associated with an increased risk of death (hazard ratio 1.59 [95% confidence interval, 1.49–1.69]) after 1 year and hazard ratio 1.63 [95% confidence interval, 1.52–1.74] after 5 years) and coronary death or nonfatal recurrent MI (hazard ratio, 1.30 [95% confidence interval,l 1.22–1.39] and hazard ratio, 1.41 [95% confidence interval, 1.28–1.55]).

Conclusions—

The use of NSAIDs is associated with persistently increased coronary risk regardless of time elapsed after first-time MI. We advise long-term caution in the use of NSAIDs for patients after MI.
Patterns of Outpatient Antihypertensive Medication Use During Pregnancy in a Medicaid Population
Authors: Bateman Brian T. , Hernandez-Diaz Sonia , Huybrechts Krista F. , Palmsten Kristin , Mogun Helen , Ecker Jeffrey L. , Fischer Michael A.
Published: September 2012

Hypertensive disorders occur in approximately 6% to 8% of all pregnancies and are a significant source of maternal and fetal morbidity. Little is known about the range of agents routinely used in practice. We used Medicaid claims from 2000 to 2007 to identify completed pregnancies. We included women who were Medicaid beneficiaries from at least 3 months prior to last menstrual period to 1 month postdelivery, and were successfully linked to infant records. Maternal exposure to antihypertensive medications was derived from Medicaid pharmacy claim files, and duration of exposure was assigned based on the days’ supply dispensed. We identified 1 106 757 Medicaid patients in our cohort, of whom 48 453 (4.4%) were exposed to antihypertensive medications during pregnancy. The prevalence of antihypertensive use increased from 3.5% to 4.9% during the study period. Antihypertensive medication users were older than nonusers, more likely to be white or black, and more likely to have comorbid diabetes mellitus and renal disease. Overall, 1.9% of pregnant women were exposed during the first trimester, 1.7% during the second trimester, and 3.2% during the third trimester. The range of antihypertensive medications to which patients were exposed was highly heterogeneous and frequently included agents other than methyldopa or labetalol. Angiotensin-converting enzyme inhibitor exposure, which is contraindicated in late pregnancy, occurred in 928 (4.9%) antihypertensive medication users in the second trimester and 383 (1.1%) in the third trimester. Antihypertensive use during pregnancy is relatively common and increasing. The wide range of agents used during pregnancy includes medications considered contraindicated during pregnancy.
Neuropeptide Y Promoter Polymorphism Modifies Effects of a Weight-Loss Diet on 2-Year Changes of Blood Pressure
Authors: Zhang Xiaomin , Qi Qibin , Liang Jun , Hu Frank B. , Sacks Frank M. , Qi Lu
Published: September 2012

Neuropeptide Y (NPY) is implicated in the regulation of blood pressure (BP), and NPY pathways in the hypothalamus are sensitive to dietary fat. We evaluated the potential effect of a functional variant rs16147 located in the
NPY
gene promoter region on the association between 2-year diet intervention and change in multiple BP measures in the randomized Preventing Overweight Using Novel Dietary Strategies Trial. The
NPY
rs16147 was genotyped in 723 obese adults who were randomly assigned to 1 of 4 diets differing in the target percentages of energy derived from fat, protein, and carbohydrate. The changes of 4 BP phenotypes, including systolic BP, diastolic BP, pulse pressure, and mean arterial pressure, during 2-year diet intervention were analyzed. In the total participants and participants with hypertension, we observed significant and consistent interactions between rs16147 genotype and dietary fat intake on changes in multiple BP phenotypes at 2 years (all
P
for interactions <0.05). The risk allele (C allele) was associated with a greater reduction of BP phenotypes in response to low-fat diet, whereas an opposite genetic effect was observed in response to high-fat diet. In addition, the C allele was related to greater changes in 4 BP phenotypes in hypertensive compared with nonhypertensive participants. Our data suggest that
NPY
rs16147 may modulate the association between dietary fat intake and changes in BP phenotypes, and the C allele exerts a long-term beneficial effect on lowering BP in response to low-fat diet in obese and hypertensive subjects.
Genome-Wide Association Study of Intracranial Aneurysms Confirms Role of Anril and SOX17 in Disease Risk
Authors: Foroud Tatiana , Koller Daniel L. , Lai Dongbing , Sauerbeck Laura , Anderson Craig , Ko Nerissa , Deka Ranjan , Mosley Thomas H. , Fornage Myriam , Woo Daniel , Moomaw Charles J. , Hornung Richard , Huston John , Meissner Irene , BaileyWilson Joan E. , Langefeld Carl , Rouleau Guy , Connolly E. Sander , Worrall Bradford B. , Kleindorfer Dawn , Flaherty Matthew L. , Martini Sharyl , Mackey Jason , De Los Rios La Rosa Felipe , Brown Robert D. , Broderick Joseph P. ,   the FIA Study Investigators
Published: September 2012

Background—

Genomewide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA.

Method—

We utilized 2 complementary samples, one recruited on the basis of a dense family history of IA (discovery sample 1: 388 IA cases and 397 controls) and the other without regard to family history (discovery sample 2: 1095 IA cases and 1286 controls). Imputation was used to generate a common set of single nucleotide polymorphisms (SNP) across samples, and a logistic regression model was used to test for association in each sample. Results from each sample were then combined in a metaanalysis.

Results—

There was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genomewide significance. However, the metaanalysis yielded genomewide significance for SNP on chromosome 9p (
CDKN2BAS
; rs6475606;
P
=3.6 × 10
−8
) and provided further evidence to support the previously reported association of IA with SNP in
SOX17
on chromosome 8q (rs1072737;
P
=8.7 × 10
−5
). Analyses suggest that the effect of smoking acts multiplicatively with the SNP genotype, and smoking has a greater effect on risk than SNP genotype.

Conclusion—

In addition to replicating several previously reported loci, we provide further evidence that the association on chromosome 9p is attributable to variants in
CDKN2BAS
(also known as
ANRIL
, an antisense noncoding RNA).
Lipoprotein Phospholipase A2 and Cerebral Microbleeds in the Framingham Heart Study
Authors: Romero José Rafael , Preis Sarah R. , Beiser Alexa S. , DeCarli Charles , Lee Dong Young , Viswanathan Anand , Benjamin Emelia J. , Fontes Joao , Au Rhoda , Pikula Aleksandra , Wang Jimmy , Kase Carlos S. , Wolf Philip A. , Irrizary Michael C. , Seshadri Sudha
Published: September 2012

Background and Purpose—

Cerebral microbleeds (CMB) attributable to cerebral amyloid angiopathy generally occur in lobar regions, whereas those attributable to hypertensive vasculopathy are deep. Inflammation may be an underlying mechanism for CMB, with varying associations according to CMB location. Lipoprotein phospholipase-A2 (Lp-PLA2) is a circulating enzyme marker of vascular inflammation associated with risk of ischemic stroke and dementia. We hypothesized that higher Lp-PLA2 levels would be related to higher prevalence of CMB, with possible regional specificity.

Methods—

Framingham Offspring participants aged 65 years or older with available Lp-PLA2 measures and brain magnetic resonance imaging were included. Logistic regression models were used to relate Lp-PLA2 activity and mass to presence of CMB, adjusted for age, sex, medication use (aspirin, anticoagulants, and statins), systolic blood pressure,
APOE
, current smoking, and diabetes.

Results—

Eight-hundred nineteen participants (mean age, 73 years; 53% women) were included; 106 (13%) had CMB, 82 (10%) were lobar, and 27 (3%) were deep. We did not observe significant associations of CMB and LpPLA2 measures in multivariable adjusted analyses. However, there was a significant interaction between
APOE
genotype and Lp-PLA2 activity in their relation to presence of deep CMB (
P
interaction=0.01). Among persons with
APOE
ɛ
3
/ɛ
3
, the odds ratio for deep CMB was 0.95 (confidence interval, 0.59-1.53;
P
=0.83), whereas among those with at least 1 ɛ
2
or ɛ
4
allele, odds ratio was 3.46 (confidence interval, 1.43-8.36;
P
=0.006).

Conclusions—

In our community-based sample of older adults, there was no significant association of Lp-PLA2 with total or lobar CMB. The association of higher levels of Lp-PLA2 activity with deep CMB among those with at least 1
APOE
ɛ
2
or ɛ
4
allele merits replication.
Assessing the Concurrent Validity of the Revised Kinder, Lydenberg, and Domini Corporate Social Performance Indicators
Authors: Hart Timothy A. , Sharfman Mark
Published: September 2012

This article examines the concurrent validity of the Kinder, Lydenberg, Domini Research & Analytics (KLD) corporate social performance (CSP) measures. Because KLD changed its evaluation methods to richer approaches, a new look at the concurrent validity of the indicators is necessary. To do this new look, the authors examine the new “Binary” and “Continuous” versions of the KLD and compare them with previous versions of KLD. The results suggest that the continuous scores provide better measurement characteristics than do the binary version. Overall, the new versions of the KLD data demonstrate concurrent validity with the original version.
Market Reform, Programmatic (De)alignment, and Party System Stability in Latin America
Authors: Roberts Kenneth M.
Published: September 2012

Although democratic regimes in Latin America since the early 1980s have been surprisingly durable, party systems in much of the region continue to experience very high levels of electoral instability. A critical juncture approach to institutional change suggests that variation in party system stability is related to the impact of market liberalization in the 1980s and 1990s on the programmatic alignment—or dealignment—of partisan competition. Market reforms that were adopted by conservative leaders and opposed by a major leftist rival aligned party systems programmatically, allowing societal opposition to be channeled into institutionalized forms of competition that were highly stable in the postadjustment era. By contrast, bait-and-switch reforms adopted by populist or leftist leaders were programmatically dealigning for party systems, leaving them vulnerable to highly destabilizing reactive sequences in the aftermath to the reform process—including mass social protests, the demise of historic conservative parties, and the outflanking of traditional populist or leftist parties by more radical, anti-neoliberal outsiders. The political dynamics of market-based economic adjustment thus heavily conditioned the ways in which party systems would process the postadjustment revival of populist and leftist alternatives in the region.
Elections and Ethnic Civil War
Authors: Cederman Lars-Erik , Gleditsch Kristian Skrede , Hug Simon
Published: September 2012

Existing research on how democratization may influence the risk of civil war tends to consider only changes in the overall level of democracy and rarely examines explicitly the postulated mechanisms relating democratization to incentives for violence. The authors argue that typically highlighted key mechanisms imply that elections should be especially likely to affect ethnic groups’ inclination to resort to violence. Distinguishing between types of conflict and the order of competitive elections, the authors find that ethnic civil wars are more likely to erupt after competitive elections, especially after first and second elections following periods of no polling. When disaggregating to the level of individual ethnic groups and conflicts over territory or government, the authors find some support for the notion that ethno-nationalist mobilization and sore-loser effects provoke postelectoral violence. More specifically, although large groups in general are more likely to engage in governmental conflicts, they are especially likely to do so after noncompetitive elections. Competitive elections, however, strongly reduce the risk of conflict.
Time Management, Passion, and Collaboration
Authors: Duffy Ryan D. , Torrey Carrie L. , Bott Elizabeth M. , Allan Blake A. , Schlosser Lewis Z.
Published: September 2012

The present study interviewed 17 of the most research-productive counseling psychologists within APA-accredited counseling psychology programs. Using Consensual Qualitative Research, seven domains emerged from the interviews: root of productivity, personality characteristics, productivity strategies, work environment, nonwork life, impact, and tips. Within these domains, 13 general categories emerged and 19 typical categories emerged. Overall, these participants were successful early in their careers, received mentorship/support while in graduate school, chose research topics that were salient to them and about which they were passionate, effectively managed their time, collaborated well with students and professionals, had a structured approach to writing, worked in a supportive research environment, and spent a considerable amount of time outside of work with family or participating in hobbies. Based on the results, practical suggestions are offered for individuals within the field of counseling psychology who wish to be productive researchers.
Conflicting Norms Highlight the Need for Action
Authors: McDonald Rachel I. , Fielding Kelly S. , Louis Winnifred R.
Published: September 2012

Previous research has not addressed the possibility that people may face conflicting norms of pro-environmental behavior from their multiple in-groups. Across two studies, the authors test competing hypotheses: People may be demotivated by norm conflict, or conversely, norm conflict may motivate people to action. The results of both studies suggest a clearly motivating effect of conflict. Norm conflict was associated with decreased water usage (i.e., increased water conservation) in Study 1, and increased pro-environmental behavior intentions in Study 2. The effects of conflict were partially mediated by perceived effectiveness in Study 2. Although these initial findings indicate that conflict motivates rather than hinders behavioral engagement, future research should investigate whether the nature of the influence of norm conflict depends on factors such as issue importance.