bluuebunny/crossref_metadata_2025 huggingface dataset:
Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women
Authors: Moreau Kerrie L. , Meditz Amie , Deane Kevin D. , Kohrt Wendy M.
Published: January 2012

The mechanisms mediating arterial stiffening with aging and menopause are not completely understood. We determined whether administration of tetrahydrobiopterin (BH4), a critical cofactor for endothelial nitric oxide synthase to produce nitric oxide, would increase vascular endothelial-dependent vasodilatory tone and decrease arterial stiffness in estrogen-deficient postmenopausal women. Additionally, we examined whether the beneficial effects of estrogen on vascular function were possibly related to BH4. Arterial stiffness (carotid artery compliance) and endothelial-dependent vasodilation [brachial artery flow-mediated dilation (FMD)] were measured in postmenopausal ( n = 24; 57 ± 1 yr, mean ± SE) and eumenorrheic premenopausal ( n = 9; 33 ± 2 yr) women before and 3 h after the oral administration of BH4. Subsequently, in postmenopausal women, vascular testing (before and after BH4) was repeated following randomization to either 2 days of transdermal estradiol or placebo. Baseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than in premenopausal women ( P < 0.0001). BH4administration increased carotid artery compliance (0.61 ± 0.05 to 0.73 ± 0.04 mm2·mmHg−1·10−1vs. baseline, P < 0.0001) and brachial artery FMD ( P < 0.001) in postmenopausal women but had no effect in premenopausal women ( P = 0.62). Carotid artery compliance (0.59 ± 0.05 to 0.78 ± 0.06 mm2·mmHg−1·10−1, P < 0.001) and FMD increased in postmenopausal women in response to estradiol ( P = 0.02) but were not further improved with the coadministration of BH4, possibly because estrogen increased BH4bioavailability. Carotid artery compliance and FMD increased with BH4in the placebo group ( P = 0.02). Although speculative, these results suggest that reduced vascular BH4may be an important contributor to arterial stiffening in estrogen-deficient postmenopausal women, related in part to reduced endothelial-dependent vasodilatory tone.
Lipopolysaccharide disrupts the directional persistence of alveolar myofibroblast migration through EGF receptor
Authors: Li Huiping , Yuan Xiaobing , Tang Jun , Zhang Yongjun
Published: January 2012

Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification with decreased alveolar number and increased airspace size. Formation of alveoli involves a process known as secondary septation triggered by myofibroblasts. This study investigated the underlying mechanisms of altered lung morphogenesis in a rat model of BPD induced by intra-amniotic injection of lipopolysaccharide (LPS). Results showed that LPS disrupted alveolar morphology and led to abnormal localization of myofibroblasts in the lung of newborn rats, mostly in primary septa with few in secondary septa. To identify potential mechanisms, in vitro experiments were carried out to observe the migration behavior of myofibroblasts. The migration speed of lung myofibroblasts increased with LPS treatment, whereas the directional persistence decreased. We found that LPS induced activation of EGFR and overexpression of its ligand, TGF-α in myofibroblasts. AG1478, an EGFR inhibitor, abrogated the enhanced locomotivity of myofibroblasts by LPS and also increased the directional persistence of myofibroblast migration. Myofibroblasts showed a high asymmetry of phospho-EGFR localization, which was absent after LPS treatment. Application of rhTGF-α to myofibroblasts decreased the directional persistence. Our findings indicated that asymmetry of phospho-EGFR localization in myofibroblasts was important for cell migration and its directional persistence. We speculate that LPS exposure disrupts the asymmetric localization of phospho-EGFR, leading to decreased stability of cell polarity and final abnormal location of myofibroblasts in vivo, which is critical to secondary septation and may contribute to the arrested alveolar development in BPD.
Ciclesonide inhibits TNFα- and IL-1β-induced monocyte chemotactic protein-1 (MCP-1/CCL2) secretion from human airway smooth muscle cells
Authors: Patel Jamie K. , Clifford Rachel L. , Deacon Karl , Knox Alan J.
Published: January 2012

Monocyte chemotactic protein-1 (MCP-1) is a member of the CC family of cytokines. It has monocyte and lymphocyte chemotactic activity and stimulates histamine release from basophils. MCP-1 is implicated in the pathogenesis of inflammatory diseases, including asthma. The airway smooth muscle (ASM) layer is thickened in asthma, and the growth factors and cytokines secreted by ASM cells play a role in the inflammatory response of the bronchial wall. Glucocorticoids and β2-agonists are first-line drug treatments for asthma. Little is known about the effect of asthma treatments on MCP-1 production from human ASM cells. Here, we determined the effect of ciclesonide (a glucocorticoid) and formoterol (a β2-agonist) on MCP-1 production from human ASM cells. TNFα and IL-1β induced MCP-1 secretion from human ASM cells. Formoterol had no effect on MCP-1 expression, while ciclesonide significantly inhibited IL-1β- and TNFα-induced MCP-1. Furthermore, ciclesonide inhibited IL-1β- and TNFα-induced MCP-1 mRNA and IL-1β- and TNFα-induced MCP-1 promoter and enhancer luciferase reporters. Western blots showed that ciclesonide had no effect on IκB degradation. Finally, ciclesonide inhibited an NF-κB luciferase reporter. Our data show that ciclesonide inhibits IL-1β- and TNFα-induced MCP-1 production from human ASM cells via a transcriptional mechanism involving inhibition of NF-κB binding.
Abnormal platelet aggregation in idiopathic pulmonary arterial hypertension: role of nitric oxide
Authors: Aytekin Metin , Aulak Kulwant S. , Haserodt Sarah , Chakravarti Ritu , Cody Joseph , Minai Omar A. , Dweik Raed A.
Published: January 2012

Idiopathic pulmonary arterial hypertension (IPAH) is a rare and progressive disease. Several processes are believed to lead to the fatal progressive pulmonary arterial narrowing seen in IPAH including vasoconstriction, cellular proliferation inflammation, vascular remodeling, abnormalities in the lung matrix, and in situ thrombosis. Nitric oxide (NO) produced by NO synthases (NOS) is a potent vasodilator and plays important roles in many other processes including platelet function. Reduced NO levels in patients with IPAH are known to contribute to the development of pulmonary hypertension and its complications. Platelet defects have been implied in IPAH, but original research supporting this hypothesis has been limited. Normal platelets are known to have NOS activity, but little is known about NOS expression and NO production by platelets in patients with IPAH. Here we characterized the phenotype of the platelets in IPAH and show a defect in their ability to be activated in vitro by thrombin receptor activating protein but not adenosine diphosphate. We also show that endothelial NOS (eNOS) levels in these platelets are reduced and demonstrate that NO is an important regulator of platelet function. Thus reduced levels of eNOS in platelets could impact their ability to regulate their own function appropriately.
TLR2 ligand engagement upregulates airway smooth muscle TNFα-induced cytokine production
Authors: Manetsch Melanie , Seidel Petra , Heintz Udo , Che Wenchi , Hughes J. Margaret , Ge Qi , Sukkar Maria B. , Ammit Alaina J.
Published: January 2012

Airway inflammation and respiratory infections are important factors contributing to disease exacerbation in chronic airway diseases such as asthma and chronic obstructive pulmonary disease. Airway smooth muscle (ASM) cells express Toll-like receptors (TLRs) and may be involved in the amplification of airway inflammatory responses during infectious exacerbations. We determined whether infectious stimuli (mimicked using Pam3CSK4, a synthetic bacterial lipopeptide that binds to TLR2/TLR1) further enhance ASM cell inflammatory responses to TNFα in vitro and the signaling pathways involved. Human ASM cells were pretreated for 1 h with Pam3CSK4 (1 μg/ml) in the absence or presence of TNFα (10 ng/ml), and IL-6 and IL-8 release was measured after 24 h. As expected, stimulation with Pam3CSK4 or TNFα alone induced significant IL-6 and IL-8 release. Furthermore, Pam3CSK4 significantly increased TNFα-induced IL-6 and IL-8 mRNA expression and protein release and neutrophil chemotactic activity. The potentiating effect of Pam3CSK4 on TNFα-induced inflammatory responses was not due to enhanced TLR2 expression nor did it involve augmentation of NF-κB or MAPK signaling pathways. Rather, Pam3CSK4 induced cAMP response element (CRE) binding protein phosphorylation and induced CRE-mediated transcriptional regulation, suggesting that Pam3CSK4 and TNFα are acting in concert to enhance ASM cytokine secretion via parallel transcriptional pathways. Our findings suggest that ASM cells may be involved in the amplification of airway inflammatory responses during infectious exacerbations in chronic airway disease.
Activation of HGF/c-Met signaling by ultrafine carbon particles and its contribution to alveolar type II cell proliferation
Authors: Chang Chih-Ching , Chiu Jia-Jhen , Chen Shan-Ling , Huang Hui-Chun , Chiu Hui-Fen , Lin Bo-Huei , Yang Chun-Yuh
Published: January 2012

Hepatocyte growth factor (HGF) is a potent mitogen and motogen for various epithelial cells. The present study aimed to explore the role of HGF and c-Met receptor in ultrafine carbon particle-induced alveolar type II epithelial (type II) cell proliferation. ICR mice were intratracheally instilled with 100 μg ultrafine carbon black (ufCB) and killed at 21, 48, and 72 days postexposure to examine type II cell proliferation, HGF release, and c-Met activation. In vivo and in vitro applications of neutralizing anti-HGF antibody were used to investigate the causal role of HGF in cell proliferation. The Met kinase inhibitor SU11274 and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 were used to delineate the involvement of c-Met/ERK1/2 in rat L2 pulmonary epithelial cell proliferation. The results demonstrated that in vivo exposure to 100 μg ufCB caused increased HGF in bronchoalveolar lavage fluid, as well as increased HGF production, c-Met phosphorylation, and cell proliferation in type II cells. In vitro study revealed that ufCB caused a dose-dependent increase in HGF release, c-Met phosphorylation, and cell proliferation. Importantly, treatment with the neutralizing anti-HGF antibody significantly blocked ufCB-induced in vivo and in vitro type II cell proliferation. Moreover, SU11274 and PD98059 significantly reduced ufCB-increased L2 cell proliferation. Results from Western blotting demonstrated that SU11274 successfully suppressed ufCB-induced phosphorylation of c-Met and ERK1/2. In summary, the activation of HGF/c-Met signaling is a major pathway involved in ufCB-induced type II cell proliferation.
Oncogenicity of the Developmental Transcription Factor Sox9
Authors: Matheu Ander , Collado Manuel , Wise Clare , Manterola Lorea , Cekaite Lina , Tye Angela J. , Canamero Marta , Bujanda Luis , Schedl Andreas , Cheah Kathryn S.E. , Skotheim Rolf I. , Lothe Ragnhild A. , López de Munain Adolfo , Briscoe James , Serrano Manuel , Lovell-Badge Robin
Published: January 2012

SOX9 [sex-determining region Y (SRY)-box 9 protein], a high mobility group box transcription factor, plays critical roles during embryogenesis and its activity is required for development, differentiation, and lineage commitment in various tissues including the intestinal epithelium. Here, we present functional and clinical data of a broadly important role for SOX9 in tumorigenesis. SOX9 was overexpressed in a wide range of human cancers, where its expression correlated with malignant character and progression. Gain of SOX9 copy number is detected in some primary colorectal cancers. SOX9 exhibited several pro-oncogenic properties, including the ability to promote proliferation, inhibit senescence, and collaborate with other oncogenes in neoplastic transformation. In primary mouse embryo fibroblasts and colorectal cancer cells, SOX9 expression facilitated tumor growth and progression whereas its inactivation reduced tumorigenicity. Mechanistically, we have found that Sox9 directly binds and activates the promoter of the polycomb Bmi1, whose upregulation represses the tumor suppressor Ink4a/Arf locus. In agreement with this, human colorectal cancers showed a positive correlation between expression levels of SOX9 and BMI1 and a negative correlation between SOX9 and ARF in clinical samples. Taken together, our findings provide direct mechanistic evidence of the involvement of SOX9 in neoplastic pathobiology, particularly, in colorectal cancer. Cancer Res; 72(5); 1301–15. ©2012 AACR.
Role of Neurofilament Light Polypeptide in Head and Neck Cancer Chemoresistance
Authors: Chen Baishen , Chen Ju , House Michael G. , Cullen Kevin J. , Nephew Kenneth P. , Guo Zhongmin
Published: January 2012

Resistance to cisplatin-based chemotherapy is responsible for therapeutic failure of many common human cancers including cancer of head and neck (HNC). Mechanisms underlying cisplatin resistance remain unclear. In this study, we identified neurofilament light polypeptide (NEFL) as a novel hypermethylated gene associated with resistance to cisplatin-based chemotherapy in HNC. Analysis of 14 HNC cell lines revealed that downregulation of NEFL expression significantly correlated with increased resistance to cisplatin. Hypermethylation of NEFL promoter CpG islands was observed in cell lines as examined by bisulfite DNA sequencing and methylation-specific PCR (MSP) and tightly correlated with reduced NEFL mRNA and protein expression. Furthermore, in patient samples with HNC (n = 51) analyzed by quantitative MSP, NEFL promoter hypermethylation was associated with resistance to cisplatin-based chemotherapy [relative risk (RR), 3.045; 95% confidence interval (CI), 1.459–6.355; P = 0.007] and predicted diminished overall and disease-free survival for patients treated with cisplatin-based chemotherapy. Knockdown of NEFL by siRNA in the highly cisplatin-sensitive cell line PCI13 increased (P < 0.01) resistance to cisplatin. In cisplatin-resistant O11 and SCC25cp cells, restored expression of NEFL significantly increased sensitivity to the drug. Furthermore, NEFL physically associated with tuberous sclerosis complex 1 (TSC1), a known inhibitor of the mTOR pathway, and NEFL downregulation led to functional activation of mTOR pathway and consequentially conferred cisplatin resistance. This is the first study to show a role for NEFL in HNC chemoresistance. Our findings suggest that NEFL methylation is a novel mechanism for HNC chemoresistance and may represent a candidate biomarker predictive of chemotherapeutic response and survival in patients with HNC. Mol Cancer Res; 10(3); 305–15. ©2012 AACR.
Migfilin Regulates Esophageal Cancer Cell Motility through Promoting GSK-3β–Mediated Degradation of β-Catenin
Authors: He Huan , Ding Fang , Li Yi , Luo Aiping , Chen Hongyan , Wu Chuanyue , Liu Zhihua
Published: January 2012

Migfilin, a protein component of focal adhesions, has been implicated in regulation of cell–extracellular matrix adhesion and motility but the underlying mechanisms are not fully elucidated. In this study, we have determined the functions of migfilin in esophageal cancer cells and the mechanisms involved. We show that the expression level of migfilin is negatively associated with clinical metastasis, and enforced expression of migfilin suppressed cell motility through decreased free β-catenin level. Overexpression of migfilin resulted in destabilization of β-catenin in concomitance with reduction of its transcriptional activity. Knockdown of migfilin by siRNA, transfection of a mutant β-catenin at Ser37 which is a critical phosphorylation site of GSK-3β, GSK-3β inhibitor LiCl, or proteasome inhibitor MG132 reversed the migfilin-mediated β-catenin degradation and transcription inhibition. Moreover, migfilin promoted β-catenin degradation by reinforcing the association between β-catenin and GSK-3β. In addition, exogenously expressed β-catenin partially restored migfilin-induced suppression of cell invasion. Collectively, these results suggest that the expression level of migfilin in ESCCs is inversely correlated with clinical metastasis status, and migfilin inhibits ESCC cell invasion at least in part through promoting degradation of β-catenin. Mol Cancer Res; 10(3); 273–81. ©2012 AACR.
Increased PARP-1 Association with DNA in Alkylation Damaged, PARP-Inhibited Mouse Fibroblasts
Authors: Kedar Padmini S. , Stefanick Donna F. , Horton Julie K. , Wilson Samuel H.
Published: January 2012

Treatment of base excision repair–proficient mouse fibroblasts with the DNA alkylating agent methyl methanesulfonate (MMS) and a small molecule inhibitor of PARP-1 results in a striking cell killing phenotype, as previously reported. Earlier studies showed that the mechanism of cell death is apoptosis and requires DNA replication, expression of PARP-1, and an intact S-phase checkpoint cell signaling system. It is proposed that activity-inhibited PARP-1 becomes immobilized at DNA repair intermediates, and that this blocks DNA repair and interferes with DNA replication, eventually promoting an S-phase checkpoint and G2-M block. Here we report studies designed to evaluate the prediction that inhibited PARP-1 remains DNA associated in cells undergoing repair of alkylation-induced damage. Using chromatin immunoprecipitation with anti–PARP-1 antibody and qPCR for DNA quantification, a higher level of DNA was found associated with PARP-1 in cells treated with MMS plus PARP inhibitor than in cells without inhibitor treatment. These results have implications for explaining the extreme hypersensitivity phenotype after combination treatment with MMS and a PARP inhibitor. Mol Cancer Res; 10(3); 360–8. ©2012 AACR.
Effect of 2-Month Controlled Green Tea Intervention on Lipoprotein Cholesterol, Glucose, and Hormone Levels in Healthy Postmenopausal Women
Authors: Wu Anna H. , Spicer Darcy , Stanczyk Frank Z. , Tseng Chiu-Chen , Yang Chung S. , Pike Malcolm C.
Published: January 2012

There have been no controlled intervention studies to investigate the effects of green tea on circulating hormone levels, an established breast cancer risk factor. We conducted a double-blind, randomized, placebo-controlled intervention study to investigate the effect of the main green tea catechin, epigallocatechin gallate (EGCG), taken in a green tea extract, polyphenon E (PPE). Postmenopausal women (n = 103) were randomized into three arms: placebo, 400-mg EGCG as PPE, or 800-mg EGCG as PPE as capsules per day for 2 months. Urinary tea catechin and serum estrogen, androgen, lipid, glucose-related markers, adiponectin, and growth factor levels were measured at baseline and at the end of months 1 and 2 of intervention. On the basis of urinary tea catechin concentrations, compliance was excellent. Supplementation with PPE did not produce consistent patterns of changes in estradiol (E2), estrone (E1), or testosterone (T) levels. Low-density lipoprotein (LDL)-cholesterol decreased significantly in both PPE groups but was unchanged in the placebo group; the change in LDL-cholesterol differed between the placebo and PPE groups (P = 0.02). Glucose and insulin levels decreased nonsignificantly in the PPE groups but increased in the placebo group; statistically significant differences in changes in glucose (P = 0.008) and insulin (P = 0.01) were found. In summary, green tea (400- and 800-mg EGCG as PPE; ∼5–10 cups) supplementation for 2 months had suggestive beneficial effects on LDL-cholesterol concentrations and glucose-related markers. Cancer Prev Res; 5(3); 393–402. ©2012 AACR.
Effects of Energy Restriction and Wheel Running on Mammary Carcinogenesis and Host Systemic Factors in a Rat Model
Authors: Zhu Zongjian , Jiang Weiqin , Zacher Jarrod H. , Neil Elizabeth S. , McGinley John N. , Thompson Henry J.
Published: January 2012

Limiting energy availability via diet or physical activity has health benefits; however, it is not known whether these interventions have similar effects on the development of cancer. Two questions were addressed as follows: (i) Does limiting energy availability by increasing physical activity have the same effect on mammary carcinogenesis as limiting caloric intake? and (ii) Are host systemic factors, implicated as risk biomarkers for breast cancer, similarly affected by these interventions? Female Sprague Dawley rats were injected with 50-mg 1-methyl-1-nitrosourea per kg body weight at 21 days of age and randomized to one of five groups (30 rats per group) as follows: (i) sham running wheel control; (ii) restricted fed to 85% of the sham control; (iii and iv) voluntary running in a motorized activity wheel (37 m/min) to a maximum of 3,500 m/d or 1,750 m/d; and (v) sedentary ad libitum fed control with no access to a running wheel. The three energetics interventions inhibited the carcinogenic response, reducing cancer incidence (P = 0.01), cancer multiplicity (P < 0.001), and cancer burden (P < 0.001) whereas prolonging cancer latency (P = 0.004) although differences among energetics interventions were not significant. Of the plasma biomarkers associated with the development of cancer, the energetics interventions reduced bioavailable insulin-like growth factor-1 (IGF-1), insulin, interleukin-6, serum amyloid protein, TNF-α, and leptin and increased IGF-binding protein 3 (IGFBP-3) and adiponectin. Plasma-fasting glucose, C-reactive protein, estradiol, and progesterone were unaffected. The plasma biomarkers of greatest value in predicting the carcinogenic response were adiponectin > IGF-1/IGFBP-3 > IGFBP-3 > leptin > IGF-1. Cancer Prev Res; 5(3); 414–22. ©2012 AACR.
Risk Factors for Malignant Melanoma in White and Non-White/Non–African American Populations: The Multiethnic Cohort
Authors: Park Sungshim Lani , Le Marchand Loïc , Wilkens Lynne R. , Kolonel Laurence N. , Henderson Brian E. , Zhang Zuo-Feng , Setiawan Veronica Wendy
Published: January 2012

It is unknown whether the established risk factors for malignant melanoma in whites influence malignant melanoma risk in non-whites. We examined the risk factors for melanoma among 39,325 whites and 101,229 non-whites/multiracials [Japanese American (47.5%), Latino American (34.8%), Native Hawaiian (2.1%), and multiracial (15.6%), excluding African Americans] in the Multiethnic Cohort study. With an average follow-up of 12.7 years, 581 invasive malignant melanoma (IMM) and 412 melanoma in situ (MIS) cases were identified, of which 107 IMM and 74 MIS were among non-whites/multiracials. The relative risks (RR) and 95% confidence intervals (CI) were estimated by Cox proportional hazards models using days from cohort entry as the underlying time variable. Among non-white/multiracial males, location of IMM tumors differed from those of white males (P < 0.001); and non-white/multiracial females were more likely to be diagnosed with later stage of disease (P < 0.001). After adjusting for potential confounders, age at cohort entry, male sex, higher education, and sunburn susceptibility phenotypes were associated with an increased risk of IMM in non-whites/multiracials (P < 0.05). The risk estimates for age at cohort entry and lighter hair and eye color were greater in non-whites/multiracials than in whites (Pheterogeneity = 0.062, 0.016, and 0.005, respectively). For MIS risk, RRs between whites and non-whites/multiracials also differed for study location and education (Pheterogeneity ≤ 0.015). In conclusion, similar to whites, age at cohort entry, male sex, and susceptibility to sunburn phenotypes may be predictive of malignant melanoma risk in non-white populations excluding African Americans. Cancer Prev Res; 5(3); 423–34. ©2012 AACR.
Uterine Serous Carcinoma: Increased Familial Risk for Lynch-Associated Malignancies
Authors: Dewdney Summer B. , Kizer Nora T. , Andaya Abegail A. , Babb Sheri A. , Luo Jingqin , Mutch David G. , Schmidt Amy P. , Brinton Louise A. , Broaddus Russell R. , Ramirez Nilsa C. , Huettner Phyllis C. , McMeekin Donald Scott , Darcy Kathleen , Ali Shamshad , Judson Patricia L. , Mannel Robert S. , Lele Shashikant B. , O'Malley David M. , Goodfellow Paul J.
Published: January 2012

Serous uterine cancer is not a feature of any known hereditary cancer syndrome. This study evaluated familial risk of cancers for patients with serous uterine carcinoma, focusing on Lynch syndrome malignancies. Fifty serous or mixed serous endometrial carcinoma cases were prospectively enrolled. Pedigrees were developed for 29 probands and tumors were assessed for DNA mismatch repair (MMR) abnormalities. Standardized incidence ratios for cancers in relatives were estimated. A second-stage analysis was undertaken using data from Gynecologic Oncology Group (GOG)-210. Incidence data for cancers reported in relatives of 348 patients with serous and mixed epithelial and 624 patients with endometrioid carcinoma were compared. Nineteen of 29 (65.5%) patients in the single-institution series reported a Lynch-related cancer in relatives. Endometrial and ovarian cancers were significantly overrepresented and a high number of probands (6 of 29, 20.7%) reported pancreatic cancers. None of the probands' tumors had DNA MMR abnormalities. There was no difference in endometrial or ovarian cancer incidence in relatives of serous and endometrioid cancer probands in the case–control study. Pancreatic cancers were, however, significantly more common in relatives of patients with serous cancer [OR, 2.39; 95% confidence interval (CI), 1.06–5.38]. We identified an excess of endometrial, ovarian, and pancreatic cancers in relatives of patients with serous cancer in a single-institution study. Follow-up studies suggest that only pancreatic cancers are overrepresented in relatives. DNA MMR defects in familial clustering of pancreatic and other Lynch-associated malignancies are unlikely. The excess of pancreatic cancers in relatives may reflect an as yet unidentified hereditary syndrome that includes uterine serous cancers. Cancer Prev Res; 5(3); 435–43. ©2012 AACR.
Altered Systemic Hemodynamic and Baroreflex Response to Angiotensin II in Postural Tachycardia Syndrome
Authors: Mustafa Hossam I. , Raj Satish R. , Diedrich André , Black Bonnie K. , Paranjape Sachin Y. , Dupont William D. , Williams Gordon H. , Biaggioni Italo , Robertson David
Published: January 2012

Background—

Postural tachycardia syndrome (POTS) is characterized by excessive orthostatic tachycardia and significant functional disability. We have previously found that patients with POTS have increases in plasma angiotensin II (Ang II) that are twice as high as healthy subjects despite normal blood pressures (BPs). In this study, we assess systemic and renal hemodynamic and functional responses to Ang II infusion in patients with POTS compared with healthy controls.

Methods and Results—

Following a 3-day sodium-controlled diet, we infused Ang II (3 ng/kg per minute) for 1 hour in patients with POTS (n=15) and healthy controls (n=13) in the supine position. All study subjects were women with normal BP. Ages were similar for patients with POTS and controls (mean±SEM, 30±2 versus 26±1 years;
P
=0.11). We measured the changes from baseline mean arterial pressure, renal plasma flow, plasma renin activity, aldosterone, urine sodium, and baroreflex sensitivity in both groups. In response to Ang II infusion, patients with POTS had a blunted increase compared with controls in mean arterial pressure (10±1 versus 14±1 mm Hg,
P
=0.01) and diastolic BP (9±1 versus 13±1 mm Hg,
P
=0.01) but not systolic BP (13±2 versus 15±2 mm Hg,
P
=0.40). Renal plasma flow decreased similarly with Ang II infusion in patients with POTS versus controls (−166±20 versus −181±17 mL/min per 1.73 kg/m
2
,
P
=0.58). Postinfusion, the decrease in plasma renin activity (−0.9±0.2 versus −0.6±0.2 ng/mL per hour,
P
=0.43) and the increase in aldosterone (17±1 versus 15±2 pg/mL,
P
=0.34) were similar in both groups. The decrease in urine sodium excretion was similar in patients with POTS and controls (−49±12 versus −60±16 mEq/g creatinine,
P
=0.55). The spontaneous baroreflex sensitivity at baseline was significantly lower in patients with POTS compared with controls (10.1±1.2 versus 16.8±1.5 ms/mm Hg,
P
=0.003), and it was further reduced with Ang II infusion.

Conclusions—

Patients with POTS have blunted vasopressor response to Ang II and impaired baroreflex function. This impaired vasoconstrictive response might be exaggerated with upright posture and may contribute to the subsequent orthostatic tachycardia that is the hallmark of this disorder.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00962949.
Incidence and Long-Term Follow-Up of Silent Cerebral Lesions After Pulmonary Vein Isolation Using a Remote Robotic Navigation System as Compared With Manual Ablation
Authors: Rillig Andreas , Meyerfeldt Udo , Tilz Roland Richard , Talazko Jochen , Arya Anita , Zvereva Vlada , Birkemeyer Ralf , Miljak Tomislav , Hajredini Bajram , Wohlmuth Peter , Fink Ulrich , Jung Werner
Published: January 2012

Background—

The incidence of silent cerebral lesions (SCL) after atrial fibrillation (AF) ablation is highly variable, depending on the technology used. Recently, an increased risk for SCL has been described for a novel, nonirrigated ablation tool using multielectrode phased radiofrequency (PVAC). The aim of this prospective study was to evaluate the incidence and long-term follow-up of SCL in patients undergoing robotically assisted pulmonary vein isolation (RA-PVI) as compared with manual PVI.

Methods and Results—

Circumferential PVI using irrigated radiofrequency current was performed on 70 patients (41 patients with paroxysmal AF, 59%). Fifty patients underwent RA-PVI and 20 patients underwent a manual approach. Cerebral MRI was performed the day before and the day after the ablation procedure; follow-up MRI was performed on 9 of 12 (75%) patients after a follow-up period of 21 months. SCLs were found in 12 of 70 (17%) patients in this study; the incidence of SCLs was similar in patients undergoing RA-PVI as compared with manually ablated patients (n=9, 18% versus n=3, 15%; probability value=1.0). In 1 patient undergoing manual PVI (1%), an SCL with asymptomatic subarachnoid hemorrhage was detected; the bleeding completely resolved within 1 month. Transient ischemic attack occurred in 1 (1%) patient 2 days after manual PVI. After a median follow-up period of 21 months, no residual SCLs were detected.

Conclusions—

The incidence of SCL using the robotic navigation system was 18% in this study. Incidence and size of SCL appears to be similar after RA-PVI as compared with manual PVI. Repeat MRI showed no residual SCLs at long-term follow-up.
A Connexin40 Mutation Associated With a Malignant Variant of Progressive Familial Heart Block Type I
Authors: Makita Naomasa , Seki Akiko , Sumitomo Naokata , Chkourko Halina , Fukuhara Shigetomo , Watanabe Hiroshi , Shimizu Wataru , Bezzina Connie R. , Hasdemir Can , Mugishima Hideo , Makiyama Takeru , Baruteau Alban , Baron Estelle , Horie Minoru , Hagiwara Nobuhisa , Wilde Arthur A.M. , Probst Vincent , Le Marec Hervé , Roden Dan M. , Mochizuki Naoki , Schott Jean-Jacques , Delmar Mario
Published: January 2012

Background—

Progressive familial heart block type I (PFHBI) is a hereditary arrhythmia characterized by progressive conduction disturbances in the His-Purkinje system. PFHBI has been linked to genes such as
SCN5A
that influence cardiac excitability but not to genes that influence cell-to-cell communication. Our goal was to explore whether nucleotide substitutions in genes coding for connexin proteins would associate with clinical cases of PFHBI and if so, to establish a genotype-cell phenotype correlation for that mutation.

Methods and Results—

We screened 156 probands with PFHBI. In addition to 12 sodium channel mutations, we found a germ line
GJA5
(connexin40 [Cx40]) mutation (Q58L) in 1 family. Heterologous expression of Cx40-Q58L in connexin-deficient neuroblastoma cells resulted in marked reduction of junctional conductance (Cx40-wild type [WT], 22.2±1.7 nS, n=14; Cx40-Q58L, 0.56±0.34 nS, n=14;
P
<0.001) and diffuse localization of immunoreactive proteins in the vicinity of the plasma membrane without formation of gap junctions. Heteromeric cotransfection of Cx40-WT and Cx40-Q58L resulted in homogenous distribution of proteins in the plasma membrane rather than in membrane plaques in ≈50% of cells; well-defined gap junctions were observed in other cells. Junctional conductance values correlated with the distribution of gap junction plaques.

Conclusions—

Mutation Cx40-Q58L impairs gap junction formation at cell-cell interfaces. This is the first demonstration of a germ line mutation in a connexin gene that associates with inherited ventricular arrhythmias and emphasizes the importance of Cx40 in normal propagation in the specialized conduction system.
Acculturation and Outcomes Among Patients With Heart Failure
Authors: Peterson Pamela N. , Campagna Elizabeth J. , Maravi Moises , Allen Larry A. , Bull Sheana , Steiner John F. , Havranek Edward P. , Dickinson L. Miriam , Masoudi Frederick A.
Published: January 2012

Background—

Acculturation to US society among minority patients may—beyond race and ethnicity alone—influence health outcomes beyond race and ethnicity alone. In particular, those who are foreign-born and who do not speak English as their primary language may have greater challenges interacting with the health care system and thus be at greater risk for adverse outcomes.

Methods and Results—

We studied patients hospitalized with a principal discharge diagnosis of heart failure between January 2000 and December 2007 in an integrated delivery system that cares for minority patients. Individuals were defined as having low acculturation if their primary language was not English and their country of birth was outside of the United States. Multivariable logistic regression and Cox proportional hazards regression were used to determine the independent risk of 30-day rehospitalization and 1-year mortality, respectively. Candidate adjustment variables included demographics (age, sex, race/ethnicity), coexisting illnesses, laboratory values, left ventricular systolic function, and characteristics of the index admission. Of 1268 patients, 30% (n=379) were black, 39% (n=498) were Hispanic, and 27% (n=348) were white. Eighteen percent (n=228) had low acculturation. After adjustment, low acculturation was associated with a higher risk of readmission at 30 days (odds ratio, 1.70; 95% confidence interval, 1.07–2.68) but not 1-year all-cause mortality (hazard ratio, 0.69; 95% confidence interval, 0.42–1.14).

Conclusions—

Patients with heart failure who are foreign-born and do not speak English as their primary language have a greater risk of rehospitalization, independent of clinical factors and race/ethnicity. Future studies should evaluate whether culturally concordant interventions focusing on such patients may improve outcomes for this patient population.
Decline in Heart Transplant Wait List Mortality in the United States Following Broader Regional Sharing of Donor Hearts
Authors: Singh Tajinder P. , Almond Christopher S. , Taylor David O. , Graham Dionne A.
Published: January 2012

Background—

A change in allocation algorithm in July 2006 allowed broader regional sharing of donor hearts in the United States (US). We assessed if the allocation change has been associated with a decline in wait list mortality in the US.

Methods and Results—

We compared baseline characteristics and outcomes in patients ≥18 years old listed for a primary heart transplant in the US before (July 1, 2004–July 11, 2006, Era1) and after (July 12, 2006–June 30, 2009, Era 2) the change in allocation algorithm. Of 11 864 patients in the study, 4503 were listed during Era 1 and 7361 during Era 2. Patients listed during Era 2 were more likely to be listed status 1A, have an implantable cardioverter-defibrillator, and supported on a continuous flow assist device (
P
<0.001 for distribution. Patients listed in Era 2 were at a 17% lower risk of dying on the wait list or becoming too sick to transplant (adjusted hazard ratio, 0.83, 95% CI 0.75, 0.93). Transplant recipients in Era 2 were more likely to be transplanted as status 1A (37% versus 48%, respectively,
P
<0.001). Post-transplant in-hospital mortality (6.3% versus 5.4%; adjusted odds ratio, 0.86 for Era 2, 95% CI 0.79, 1.06) and 1-year survival were similar.

Conclusions—

The risk of death on the wait list or becoming too sick to transplant has decreased by 17% in the US since the allocation algorithm allowing broader regional sharing was implemented in 2006. The shift in hearts to sicker candidates has not resulted in higher in-hospital or first year post-transplant mortality.
Gremlin Plays a Key Role in the Pathogenesis of Pulmonary Hypertension
Authors: Cahill Edwina , Costello Christine M. , Rowan Simon C. , Harkin Susan , Howell Katherine , Leonard Martin O. , Southwood Mark , Cummins Eoin P. , Fitzpatrick Susan F. , Taylor Cormac T. , Morrell Nicholas W. , Martin Finian , McLoughlin Paul
Published: January 2012

Background—

Pulmonary hypertension occurs in chronic hypoxic lung diseases, significantly worsening morbidity and mortality. The important role of altered bone morphogenetic protein (BMP) signaling in pulmonary hypertension was first suspected after the identification of heterozygous BMP receptor mutations as the underlying defect in the rare heritable form of pulmonary arterial hypertension. Subsequently, it was demonstrated that BMP signaling was also reduced in common forms of pulmonary hypertension, including hypoxic pulmonary hypertension; however, the mechanism of this reduction has not previously been elucidated.

Methods and Results—

Expression of 2 BMP antagonists, gremlin 1 and gremlin 2, was higher in the lung than in other organs, and gremlin 1 was further increased in the walls of small intrapulmonary vessels of mice during the development of hypoxic pulmonary hypertension. Hypoxia stimulated gremlin secretion from human pulmonary microvascular endothelial cells in vitro, which inhibited endothelial BMP signaling and BMP-stimulated endothelial repair. Haplodeficiency of gremlin 1 augmented BMP signaling in the hypoxic mouse lung and reduced pulmonary vascular resistance by attenuating vascular remodeling. Furthermore, gremlin was increased in the walls of small intrapulmonary vessels in idiopathic pulmonary arterial hypertension and the rare heritable form of pulmonary arterial hypertension in a distribution suggesting endothelial localization.

Conclusions—

These findings demonstrate a central role for increased gremlin in hypoxia-induced pulmonary vascular remodeling and the increased pulmonary vascular resistance in hypoxic pulmonary hypertension. High levels of basal gremlin expression in the lung may account for the unique vulnerability of the pulmonary circulation to heterozygous mutations of BMP type 2 receptor in pulmonary arterial hypertension.
Societies in Political Transition: A Comparative Study of Burma Under Ne Win and Indonesia Under Suharto
Authors: Kipgen Nehginpao
Published: January 2012

This article explores the different patterns of political transitions under two military dictatorships in Southeast Asia. Burma and Indonesia were former colonies which gained independence from the British and the Netherlands in 1948 and 1945 respectively. General Ne Win ruled Burma for over two decades (1962–88) and General Suharto ruled Indonesia for over three decades (1967–98). The article examines why Burma remained a military dictatorship after the downfall of the Ne Win-led Burma Socialist Program Party (BSPP) government, while Indonesia transitioned to a democratic society with the collapse of the Suharto-led New Order government. The article argues that a lack of a unified and established civilian leadership, coupled with the army’s reluctance to relinquish power, led to another military coup in Burma, whereas the military in Indonesia encouraged the emergence of a civilian government by establishing and strengthening bureaucracies.
Quantitative Evidence of the Continuing Significance of Race
Authors: Brewster Zachary W. , Rusche Sarah Nell
Published: January 2012

Despite popular claims that racism and discrimination are no longer salient issues in contemporary society, members of racially underrepresented groups continue to experience disparate treatment in everyday public interactions. The context of full-service restaurants is one such public setting wherein African Americans, in particular, encounter racial prejudices and discriminatory treatment. To further understand the pervasiveness of such anti-Black attitudes and actions within the restaurant context, this article analyzes primary survey data derived from a community sample of servers ( N = 200). Participants were asked a series of questions ascertaining information about the racial climate of their workplaces. Findings reveal substantial server negativity toward African Americans’ tipping and dining behaviors. Racialized discourse and discriminatory behaviors are also shown to be quite common in the restaurant context. The anti-Black attitudes and actions that the authors document in this research are illustrative of the continuing significance of race in contemporary society, and the authors encourage further research on this relatively neglected area of inquiry.
Who Knows Who Knows What in the Group? The Effects of Communication Network Centralities, Use of Digital Knowledge Repositories, and Work Remoteness on Organizational Members’ Accuracy in Expertise Recognition
Authors: Su Chunke
Published: January 2012

Organizational members vary in their ability to accurately recognize each other’s expertise. The goal of this study is to extend transactive memory theory to understand how organizational group members develop accurate perceptions of others’ knowledge through a multidimensional access to expertise cues. Specifically, this study examines how a group member’s accuracy in expertise recognition is influenced by one’s centralities in the communication network, use of digital knowledge repositories, and work remoteness. By analyzing data collected from 208 individuals from 17 organizational groups, this study found that a member’s accuracy in expertise recognition was positively influenced by one’s degree centrality in the communication network and negatively influenced by the extent to which one’s work was done remotely. Furthermore, there was an interaction effect between work remoteness and use of digital knowledge repositories such that the negative influence of work remoteness on expertise recognition was weaker when members used digital knowledge repositories.
The ageing behaviour of hydrogenated nitrile butadiene rubber/nanoclay nanocomposites in various mediums
Authors: Cadambi Rahul M , Ghassemieh Elaheh
Published: January 2012

Hydrogenated nitrile butadiene rubber (HNBR) nanocomposites were prepared using commercially available organoclays (Cloisite 15A). The main focus of the current investigation is to study the influence of the organoclay reinforced in HNBR after subjecting it to long-term oxidative ageing and immersion studies. All the different nanoclay nanocomposites were air aged for a period of 168 h and at 150°C. The changes in the mechanical properties such as tensile strength and elongation at break have been compared with respect to the control sample. For immersion tests, three different liquid mediums were considered for this current investigation. All the samples were immersed in different mediums for a period of 168 h at 150°C. The changes in the swelling index and the mechanical properties have been reported with respect to the control sample. After reinforcing nanoclays into HNBR there was good resistance to swelling in all the three different liquid mediums in comparison to control sample. Tensile testing was performed on the immersed nanocomposites to evaluate the mechanical behaviour after immersion studies. A probable mechanism behind the improved performance has been suggested.
Evaluation of Novel Urinary Renal Biomarkers with a Cisplatin Model of Kidney Injury: Effects of Collection Period
Authors: Pinches Mark D. , Betts Catherine J. , Bickerton Susan J. , Beattie Laura , Burdett Lisa D. , Thomas Helen T. , Derbyshire Nicola A. , Moores Michele
Published: January 2012

A number of novel urinary biomarkers have been identified and partially qualified for use as markers for renal injury in rats. To date, all evaluation studies have been made using 18 to 24 hour collection periods. However, shorter, more welfare friendly, urine collection periods are also used in industry. In this article, we quantify urinary biomarker concentration in serial paired sequential short and long urine collections from male rats administered varying concentrations of cisplatin. We calculate the rate of biomarker excretion in normal animals for both collection periods and the bias and correlation in urinary biomarker concentration between collection periods in dosed and control animals, and we estimate the level of agreement in biomarker concentration between both collection periods. We conclude that although there are minor differences in the concentration of some urinary biomarkers that are dependent upon the time and duration of collection, shorter collection protocols do not influence subsequent interpretation of normalized urinary biomarker data for most biomarkers.
Offenders’ Crime Narratives as Revealed by the Narrative Roles Questionnaire
Authors: Youngs Donna , Canter David V.
Published: January 2012

The study of narrative processes as part of the immediate factors that shape criminal action is limited by the lack of a methodology for differentiating the narrative themes that characterise specific crime events. The current study explores how the roles offenders see themselves as playing during an offence encapsulate their underlying crime narratives and thus provide the basis for a quantitative methodology. To test this possibility, a 33-item Narrative Roles Questionnaire (NRQ) was developed from intensive interviews with offenders about their experience of committing a recent offence. A multidimensional analysis of the NRQ completed by 71 convicted offenders revealed life narrative themes similar to those identified in fiction by Frye and with noncriminals by McAdams, labelled The Professional, Victim, Hero, and Revenger offence roles. The NRQ thus is a first step in opening up the possibility of empirical studies of the narrative aetiological perspective in criminology.
Fatigue crack growth “overload effect”: mechanistic insights from in-situ synchrotron measurements
Authors: Croft Mark , Jisrawi Najeh , Ignatov Alexander , Holtz Ronald L , Zhong Zhong
Published: January 2012

Synchrotron-based, high-energy X-ray diffraction measurements are used to study the local strain fields underlying the transient fatigue crack growth rate retardation produced by a single overload cycle known as the overload effect. Specifically, 4140 steel compact tension specimens fatigued for varying levels of crack growth after an overload cycle have been studied with in-situ diffraction under varying external loads. The load responses of the strain at the overload-position, versus at the crack tip, are focused upon in detail. The large compressive residual strain at the overload-point is observed to remain essentially unchanged even after the overload-point is left in the wake of the propagating crack tip. The differential strain-load response at the crack-tip/overload position before and immediately after the overload is seen to be unchanged. Once the overload point is behind the crack tip, a highly nonlinear behavior is observed in which the load response of the strain field transfers from the overload -point to the crack tip when the load exceeds a critical value. The results are discussed in terms of plasticity-induced crack face contact at the overload point as an important local mechanism contributing to the “overload effect” in this specific system.