bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245409 (XL765), a Novel, Orally Administered PI3K/mTOR Inhibitor in Patients with Advanced Solid Tumors
Authors: Papadopoulos Kyriakos P. , Tabernero Josep , Markman Ben , Patnaik Amita , Tolcher Anthony W. , Baselga José , Shi Weiliang , Egile Coumaran , Ruiz-Soto Rodrigo , Laird A. Douglas , Miles Dale , LoRusso Patricia M.
Published: March 2014

Purpose: This phase I, first-in-human study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SAR245409, an inhibitor of pan-Class I phosphoinositide 3-kinase (PI3K) and mTOR, administered orally once or twice daily in patients with advanced solid tumors.

Experimental Design: Eighty-three patients received SAR245409. Doses ranged from 15 to 120 mg twice daily, and 70 to 100 mg once daily. A 3+3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events and response. Assessments included pharmacokinetic, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations.

Results: The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related adverse events were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%), and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 adverse events were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96–7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin, and tumor samples. Best response was stable disease in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with stable disease were treated for ≥16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity.

Conclusion: SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/mTORC2 pathway signaling and was associated with clinically relevant stable disease. Clin Cancer Res; 20(9); 2445–56. ©2014 AACR.
Phase I Dendritic Cell p53 Peptide Vaccine for Head and Neck Cancer
Authors: Schuler Patrick J. , Harasymczuk Malgorzata , Visus Carmen , DeLeo Albert , Trivedi Sumita , Lei Yu , Argiris Athanassios , Gooding William , Butterfield Lisa H. , Whiteside Theresa L. , Ferris Robert L.
Published: March 2014

Background: p53 accumulation in head and neck squamous cell carcinoma (HNSCC) cells creates a targetable tumor antigen. Adjuvant dendritic cell (DC)–based vaccination against p53 was tested in a phase I clinical trial.

Experimental Methods: Monocyte-derived DC from 16 patients were loaded with two modified HLA-class I p53 peptides (Arm 1), additional Th tetanus toxoid peptide (Arm 2), or additional Th wild-type (wt) p53-specific peptide (Arm 3). Vaccine DCs (vDC) were delivered to inguinal lymph nodes at three time points. vDC phenotype, circulating p53-specific T cells, and regulatory T cells (Treg) were serially monitored by flow cytometry and cytokine production by Luminex. vDC properties were compared with those of DC1 generated with an alternative maturation regimen.

Results: No grade II–IV adverse events were observed. Two-year disease-free survival of 88% was favorable. p53-specific T-cell frequencies were increased postvaccination in 11 of 16 patients (69%), with IFN-γ secretion detected in four of 16 patients. Treg frequencies were consistently decreased (P = 0.006) relative to prevaccination values. The phenotype and function of DC1 were improved relative to vDC.

Conclusion: Adjuvant p53-specific vaccination of patients with HNSCC was safe and associated with promising clinical outcome, decreased Treg levels, and modest vaccine-specific immunity. HNSCC patients' DC required stronger maturation stimuli to reverse immune suppression and improve vaccine efficacy. Clin Cancer Res; 20(9); 2433–44. ©2014 AACR.
Increased KIT Inhibition Enhances Therapeutic Efficacy in Gastrointestinal Stromal Tumor
Authors: Kim Teresa S. , Cavnar Michael J. , Cohen Noah A. , Sorenson Eric C. , Greer Jonathan B. , Seifert Adrian M. , Crawley Megan H. , Green Benjamin L. , Popow Rachel , Pillarsetty Nagavarakishore , Veach Darren R. , Ku Anson T. , Rossi Ferdinand , Besmer Peter , Antonescu Cristina R. , Zeng Shan , DeMatteo Ronald P.
Published: March 2014

Purpose: Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and a model of targeted molecular therapy. GIST depends on oncogenic KIT signaling and responds to the tyrosine kinase inhibitor imatinib. However, imatinib is rarely curative. We hypothesized that PLX3397, which inhibits KIT and colony-stimulating-factor-1 receptor (CSF1R), would be more efficacious than imatinib in GIST by also depleting tumor-associated macrophages, which are generally thought to support tumor growth.

Experimental Design: We treated KitV558del/+ mice that develop GIST or mice with subcutaneous human GIST xenografts with imatinib or PLX3397 and analyzed tumor weight, cellular composition, histology, molecular signaling, and fibrosis. In vitro assays on human GIST cell lines were also performed.

Results: PLX3397 was more effective than imatinib in reducing tumor weight and cellularity in both KitV558del/+ murine GIST and human GIST xenografts. The superiority of PLX3397 did not depend on depletion of tumor-associated macrophages, because adding CSF1R inhibition did not improve the effects of imatinib. Instead, PLX3397 was a more potent KIT inhibitor than imatinib in vitro. PLX3397 therapy also induced substantial intratumoral fibrosis, which impaired the subsequent delivery of small molecules.

Conclusions: PLX3397 therapy has greater efficacy than imatinib in preclinical GIST models and warrants study in patients with GIST. The resultant intratumoral fibrosis may represent one of the barriers to achieving complete tumor eradication. Clin Cancer Res; 20(9); 2350–62. ©2014 AACR.
Prevalence and Clinical Implications of Epstein–Barr Virus Infection in De Novo Diffuse Large B-Cell Lymphoma in Western Countries
Authors: Ok Chi Young , Li Ling , Xu-Monette Zijun Y. , Visco Carlo , Tzankov Alexander , Manyam Ganiraju C. , Montes-Moreno Santiago , Dybaer Karen , Chiu April , Orazi Attilio , Zu Youli , Bhagat Govind , Chen Jiayu , Richards Kristy L. , Hsi Eric D. , Choi William W. L. , van Krieken J. Han , Huh Jooryung , Ai Weiyun , Ponzoni Maurilio , Ferreri Andrés J.M. , Farnen John P. , Møller Michael B. , Bueso-Ramos Carlo E. , Miranda Roberto N. , Winter Jane N. , Piris Miguel A. , Medeiros L. Jeffrey , Young Ken H.
Published: March 2014

Purpose: Epstein–Barr virus–positive (EBV+) diffuse large B-cell lymphoma (DLBCL) of the elderly is a variant of DLBCL with worse outcome that occurs most often in East-Asian countries and is uncommon in the Western hemisphere. We studied the largest cohort of EBV+ DLBCL, independent of age, treated with rituximab combined with CHOP (R-CHOP) in developed Western countries.

Experimental design: A large cohort (n = 732) of patients with DLBCL treated with R-CHOP chemotherapy is included from the multicenter consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by FISH and mutation analysis, genomic information by gene expression profiling (GEP), and gene set enrichment analysis (GSEA).

Results: Twenty-eight patients (4.0%) were positive for EBV with a median age of 60.5 years. No clinical characteristics distinguished patients with EBV+ DLBCL from patients with EBV-negative (EBV−) DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3, and CD30 were more commonly expressed in EBV+ DLBCLs (P < 0.05). Significant differences in survival were not observed in patients with EBV+ DLBCL versus EBV− DLBCL. However, CD30 expression combined with EBV conferred an inferior outcome. GEP showed a unique expression signature in EBV+ DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways independent of molecular subtype.

Conclusions: The clinical characteristics of patients with EBV+ versus EBV− DLBCL are similar and EBV infection does not predict a worse outcome. EBV+ DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBV+ DLBCL and, consistent CD30 and EBV is associated with an adverse outcome. Clin Cancer Res; 20(9); 2338–49. ©2014 AACR.
Is There Clinical Value to Prognostic Signatures in Early-Stage NSCLC?
Authors: Bunn Paul A. , Hirsch Fred R. , Aisner Dara L.
Published: March 2014

pAMPK and pmTOR favorably predicted outcome in early non–small cell lung cancer (NSCLC). The differences were small. Phosphoprotein lability makes routine clinical use and validation difficult. Protein immunohistochemistry is unlikely to be clinically useful, and numerous efforts to create predictive models to select resected patients for therapy have been unsuccessful. Clin Cancer Res; 20(7); 1727–9. ©2014 AACR.
Estrogen Receptor Mutations in Breast Cancer—New Focus on an Old Target
Authors: Segal Corrinne V. , Dowsett Mitch
Published: March 2014

Recent studies have provided strong evidence for the emergence of substantial numbers of constitutively active ESR1 mutations in estrogen receptor–positive metastatic breast cancer that are undetected in primary disease. Some of these mutants remain partially sensitive to current anti-estrogen therapies but effective therapeutics targeted at them may require new approaches. Clin Cancer Res; 20(7); 1724–6. ©2014 AACR.
New Approaches but the Same Flaws in the Search for Prognostic Signatures
Authors: Salazar Ramon , Tabernero Josep
Published: March 2014

A six-gene prognostic colorectal cancer hypoxia score was generated from expression data from in vitro experiments and microarray datasets and was validated in two distinct patient cohorts. The approach followed by the authors is original and biologically sound but could be limited by potential biases and other methodologic limitations. Clin Cancer Res; 20(8); 2019–22. ©2014 AACR.
Desensitization of Myofilaments to Ca
2+
as a Therapeutic Target for Hypertrophic Cardiomyopathy With Mutations in Thin Filament Proteins
Authors: Alves Marco L. , Dias Fernando A.L. , Gaffin Robert D. , Simon Jillian N. , Montminy Eric M. , Biesiadecki Brandon J. , Hinken Aaron C. , Warren Chad M. , Utter Megan S. , Davis Robert T. , Sadayappan Sakthivel , Robbins Jeffrey , Wieczorek David F. , Solaro R. John , Wolska Beata M.
Published: March 2014

Background—

Hypertrophic cardiomyopathy (HCM) is a common genetic disorder caused mainly by mutations in sarcomeric proteins and is characterized by maladaptive myocardial hypertrophy, diastolic heart failure, increased myofilament Ca
2+
sensitivity, and high susceptibility to sudden death. We tested the following hypothesis: correction of the increased myofilament sensitivity can delay or prevent the development of the HCM phenotype.

Methods and Results—

We used an HCM mouse model with an E180G mutation in α-tropomyosin (Tm180) that demonstrates increased myofilament Ca
2+
sensitivity, severe hypertrophy, and diastolic dysfunction. To test our hypothesis, we reduced myofilament Ca
2+
sensitivity in Tm180 mice by generating a double transgenic mouse line. We crossed Tm180 mice with mice expressing a pseudophosphorylated cardiac troponin I (S23D and S24D; TnI-PP). TnI-PP mice demonstrated a reduced myofilament Ca
2+
sensitivity compared with wild-type mice. The development of pathological hypertrophy did not occur in mice expressing both Tm180 and TnI-PP. Left ventricle performance was improved in double transgenic compared with their Tm180 littermates, which express wild-type cardiac troponin I. Hearts of double transgenic mice demonstrated no changes in expression of phospholamban and sarcoplasmic reticulum Ca
2+
ATPase, increased levels of phospholamban and troponin T phosphorylation, and reduced phosphorylation of TnI compared with Tm180 mice. Moreover, expression of TnI-PP in Tm180 hearts inhibited modifications in the activity of extracellular signal-regulated kinase and zinc finger-containing transcription factor GATA in Tm180 hearts.

Conclusions—

Our data strongly indicate that reduction of myofilament sensitivity to Ca
2+
and associated correction of abnormal relaxation can delay or prevent development of HCM and should be considered as a therapeutic target for HCM.
Protein Kinase A–Phosphorylated K
V
1 Channels in PSD95 Signaling Complex Contribute to the Resting Membrane Potential and Diameter of Cerebral Arteries
Authors: Moore Christopher L. , Nelson Piper L. , Parelkar Nikhil K. , Rusch Nancy J. , Rhee Sung W.
Published: March 2014

Rationale:

Postsynaptic density-95 (PSD95) is a scaffolding protein that associates with voltage-gated,
Shaker
-type K
+
(K
V
1) channels and promotes the expression of K
V
1 channels in vascular smooth muscle cells of the cerebral (cVSMCs) circulation. However, the physiological role of PSD95 in mediating molecular signaling in cVSMCs is unknown.

Objective:

We explored whether a specific interaction between PSD95 and K
V
1 channels enables protein kinase A phosphorylation of K
V
1 channels in cVSMCs to promote vasodilation.

Methods and Results:

Rat cerebral arteries were used for analyses. A membrane-permeable peptide (K
V
1-C peptide) corresponding to the postsynaptic density-95, discs large, zonula occludens-1 binding motif in the C terminus of K
V
1.2α was designed as a dominant-negative peptide to disrupt the association of K
V
1 channels with PSD95. Application of K
V
1-C peptide to cannulated, pressurized cerebral arteries rapidly induced vasoconstriction and depolarized cVSMCs. These events corresponded to reduced coimmunoprecipitation of the PSD95 and K
V
1 proteins without altering surface expression. Middle cerebral arterioles imaged in situ through cranial window also constricted rapidly in response to local application of K
V
1-C peptide. Patch-clamp recordings confirmed that K
V
1-C peptide attenuates K
V
1 channel blocker (5-(4-phenylalkoxypsoralen))–sensitive current in cVSMCs. Western blots using a phospho-protein kinase A substrate antibody revealed that cerebral arteries exposed to K
V
1-C peptide showed markedly less phosphorylation of K
V
1.2α subunits. Finally, phosphatase inhibitors blunted both K
V
1-C peptide–mediated and protein kinase A inhibitor peptide–mediated vasoconstriction.

Conclusions:

These findings provide initial evidence that protein kinase A phosphorylation of K
V
1 channels is enabled by a dynamic association with PSD95 in cerebral arteries and suggest that a disruption of such association may compromise cerebral vasodilation and blood flow.
Risk Prediction Model for Heart Failure and Cardiomyopathy After Adjuvant Trastuzumab Therapy for Breast Cancer
Authors: Ezaz Ghideon , Long Jessica B. , Gross Cary P. , Chen Jersey
Published: March 2014

Background

Adjuvant trastuzumab improves survival for women with human epidermal growth factor receptor 2‐positive breast cancer, but increases risk for heart failure (
HF
) and cardiomyopathy (
CM
). However, clinical trials may underestimate
HF
/
CM
risk because they enroll younger subjects with fewer cardiac risk factors. We sought to develop a clinical risk score that identifies older women with breast cancer who are at higher risk of
HF
or
CM
after trastuzumab.

Methods and Results

Using the Surveillance, Epidemiology and End Results (
SEER
)‐Medicare database, we identified women with breast cancer who received adjuvant trastuzumab. Using a split‐sample design, we used a proportional hazards model to identify candidate predictors of
HF
/
CM
in a derivation cohort. A risk score was constructed using regression coefficients, and
HF
/
CM
rates were calculated in the validation cohort. The sample consisted of 1664 older women (mean age 73.6 years) with 3‐year
HF
/
CM
rate of 19.1%. A risk score consisting of age, adjuvant chemotherapy, coronary artery disease, atrial fibrillation or flutter, diabetes mellitus, hypertension, and renal failure was able to classify
HF
/
CM
risk into low (0 to 3 points), medium (4 to 5 points), and high (≥6 points) risk strata with 3‐year rates of 16.2%, 26.0%, and 39.5%, respectively.

Conclusions

A 7‐factor risk score was able to stratify 3‐year risk of
HF
/
CM
after trastuzumab between the lowest and highest risk groups by more than 2‐fold in a Medicare population. These findings will inform future research aimed at further developing a clinical risk score for
HF
/
CM
for breast cancer patients of all ages.
Acute Intravenous Injection of Serelaxin (Recombinant Human Relaxin‐2) Causes Rapid and Sustained Bradykinin‐Mediated Vasorelaxation
Authors: Leo Chen Huei , Jelinic Maria , Parkington Helena C. , Tare Marianne , Parry Laura J.
Published: March 2014

Background

A recent clinical trial (
RELAX
in in Acute Heart Failure [
RELAX
‐
AHF
]) demonstrated that 48 hours of continuous intravenous infusion of the vasorelaxant peptide serelaxin (recombinant human relaxin‐2) to patients with acute heart failure reduced cardiovascular mortality at 180 days. The persistence of a vasorelaxant response as a potential mechanism for this long‐term benefit and the vascular effects of a bolus intravenous injection of serelaxin have not been examined. This study investigates changes in resistance artery reactivity and passive mechanical wall properties following an intravenous serelaxin injection and whether these vascular effects persist in the absence of detectable circulating serelaxin.

Methods and Results

Male rats were injected with 13.3 μg/kg serelaxin into the tail vein; mesenteric arteries were assessed 3 and 24 hours after treatment by using wire‐myography. Serelaxin increased basal nitric oxide synthase activity and reduced maximal contraction to endothelin‐1 at 3 hours after administration. Serelaxin treatment also selectively enhanced bradykinin‐mediated endothelium‐dependent relaxation. This effect was sustained for 24 hours in the absence of circulating serelaxin. Serelaxin‐mediated augmentation of bradykinin‐evoked relaxation involved endothelium‐derived hyperpolarization after 3 hours and prostacyclin‐mediated relaxation after 24 hours. Furthermore, upregulation of inducible nitric oxide synthase, phosphorylation of protein kinase B at Ser473 and endothelial nitric oxide synthase at Ser1177 was observed at 24 hours after serelaxin injection. There were no effects of serelaxin on passive arterial wall stiffness.

Conclusion

Our data show that a bolus intravenous injection of serelaxin modulates endothelial vasodilator function 3 hours after administration, an effect that was sustained for 24 hours. The prolonged bradykinin‐mediated vasorelaxation is principally mediated through prostacyclin.
The Importance of Purkinje Activation in Long Duration Ventricular Fibrillation
Authors: Huang Jian , Dosdall Derek J. , Cheng Kang‐An , Li Li , Rogers Jack M. , Ideker Raymond E.
Published: March 2014

Background

The mechanisms that maintain long duration ventricular fibrillation (
LDVF
) are unclear. The difference in distribution of the Purkinje system in dogs and pigs was explored to determine if Purkinje activation propagates to stimulate working myocardium (
WM
) during
LDVF
and
WM
pacing.

Methods and Results

In‐vivo extracellular recordings were made from 1044 intramural plunge and epicardial plaque electrodes in 6 pig and 6 dog hearts. Sinus activation propagated sequentially from the endocardium to the epicardium in dogs but not pigs. During epicardial pacing, activation propagated along the endocardium and traversed the
LV
wall almost parallel to the epicardium in dogs, but in pigs propagated away from the pacing site approximately perpendicular to the epicardium. After 1 minute of
VF
, activation rate near the endocardium was significantly faster than near the epicardium in dogs (
P
<0.01) but not pigs (
P
>0.05). From 2 to 10 minutes of
LDVF
, recordings exhibiting Purkinje activations were near the endocardium in dogs (
P
<0.01) but were scattered transmurally in pigs, and the
WM
activation rate in recordings in which Purkinje activations were present was significantly faster than the
WM
activation rate in recordings in which Purkinje activations were absent (
P
<0.01). In 10 isolated perfused dog hearts, the
LV
endocardium was exposed and 2 microelectrodes were inserted into Purkinje and adjacent myocardial cells. After 5 minutes of
LDVF
, mean Purkinje activation rate was significantly faster than mean
WM
activation rate (
P
<0.01).

Conclusion

These extracellular and intracellular findings about activation support the hypothesis that Purkinje activation propagates to stimulate
WM
during sinus rhythm, pacing, and
LDVF
.
Endothelial Cell‐, Platelet‐, and Monocyte/Macrophage‐Derived Microparticles are Elevated in Psoriasis Beyond Cardiometabolic Risk Factors
Authors: Takeshita Junko , Mohler Emile R. , Krishnamoorthy Parasuram , Moore Jonni , Rogers Wade T. , Zhang Lifeng , Gelfand Joel M. , Mehta Nehal N.
Published: March 2014

Background

Psoriasis, especially when severe, is a risk factor for cardiometabolic disease beyond traditional risk factors. The mechanism of atherogenesis in psoriasis remains unknown. Cell membrane vesicles (ie, microparticles), released upon cell activation or apoptosis, have recently been associated with cardiometabolic disease and may play a pathogenic role. Microparticle levels, particularly from endothelial cells and platelets, are elevated in patients with cardiovascular disorders, metabolic syndrome, other inflammatory diseases, autoimmune conditions, and have been shown to be predictive of cardiovascular outcomes.

Methods and Results

Concentrations of microparticles with positive expression for any of 7 cell surface markers (Annexin V,
CD
3,
CD
31,
CD
41a,
CD
64,
CD
105, and
CD
144) were measured in blood samples from psoriasis patients (n=53) and control subjects without psoriasis (n=41). Platelet‐free plasma was separated from whole blood by one‐step centrifugation for microparticle analysis. Microparticles were fluorescently labeled and characterized by flow cytometry. Higher concentrations of
CD
105 (5.5/μL versus 2.5/μL,
P
<0.001),
CD
31 (31/μL versus 18/μL,
P
=0.002),
CD
41a (50/μL versus 22/μL,
P
<0.001), and
CD
64 (5.0/μL versus 4.1/μL,
P
=0.02) singly positive microparticles corresponding to endothelial cell‐, platelet‐, and monocyte/macrophage‐derived microparticles, respectively, were found in psoriasis patients compared with controls. These differences persisted after adjustment for traditional cardiometabolic risk factors including body mass index.

Conclusions

Increased microparticle concentrations, independent of cardiometabolic risk factors, in patients with psoriasis suggest that the presence of increased endothelial cell, platelet, and monocyte/macrophage activation with cell turnover may contribute to the heightened atherogenesis associated with psoriasis.
Cardiovascular and Mortality Risk of Apparent Resistant Hypertension in Women With Suspected Myocardial Ischemia: A Report From the NHLBI‐Sponsored WISE Study
Authors: Smith Steven M. , Huo Tianyao , Delia Johnson B. , Bittner Vera , Kelsey Sheryl F. , Vido Thompson Diane , Noel Bairey Merz C. , Pepine Carl J. , Cooper‐DeHoff Rhonda M.
Published: March 2014

Background

Women are more likely than men to develop resistant hypertension, which is associated with excess risk of major adverse outcomes; however, the impact of resistant hypertension in women with ischemia has not been explicitly studied. In this Women's Ischemia Syndrome Evaluation (
WISE
) analysis, we assessed long‐term adverse outcomes associated with apparent treatment‐resistant hypertension (
aTRH
) among women with suspected myocardial ischemia referred for coronary angiography.

Methods and Results

Women (n=927) were grouped according to baseline blood pressure (
BP
): normotensive (no hypertension history,
BP
<140/90 mm Hg, no antihypertensive drugs); controlled (
BP
<140/90 mm Hg and a hypertension diagnosis or on 1 to 3 drugs); uncontrolled (
BP
≥140/90 mm Hg on ≤2 drugs); or
aTRH
(
BP
≥140/90 mm Hg on 3 drugs or anyone on ≥4 drugs). Adverse outcomes (first occurrence of death [any cause], nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure or angina) were collected over 10 years of follow‐up. Apparent treatment‐resistant hypertension prevalence was 10.4% among those with hypertension. Women with
aTRH
had a greater incidence of adverse outcomes, compared with normotensive women (adjusted hazard ratio [
HR],
3.25; 95% confidence interval [
CI],
1.94 to 5.43), and women with controlled (
HR,
1.77; 95%
CI,
1.26 to 2.49) and uncontrolled (
HR,
1.62; 95%
CI,
1.15 to 2.27) hypertension; outcome differences were evident early in follow‐up. Risk of all‐cause death was greater in the
aTRH
group, compared to the normotensive women and women with controlled and uncontrolled hypertension.

Conclusions

In this cohort of women with evidence of ischemia,
aTRH
was associated with a profoundly increased long‐term risk of major adverse events, including death, that emerged early during follow‐up.
Splenectomy Is Modifying the Vascular Remodeling of Thrombosis
Authors: Frey Maria K. , Alias Sherin , Winter Max P. , Redwan Bassam , Stübiger Gerald , Panzenboeck Adelheid , Alimohammadi Arman , Bonderman Diana , Jakowitsch Johannes , Bergmeister Helga , Bochkov Valery , Preissner Klaus T. , Lang Irene M.
Published: March 2014

Background

Splenectomy is a clinical risk factor for complicated thrombosis. We hypothesized that the loss of the mechanical filtering function of the spleen may enrich for thrombogenic phospholipids in the circulation, thereby affecting the vascular remodeling of thrombosis.

Methods and Results

We investigated the effects of splenectomy both in chronic thromboembolic pulmonary hypertension (
CTEPH
), a human model disease for thrombus nonresolution, and in a mouse model of stagnant flow venous thrombosis mimicking deep vein thrombosis. Surgically excised thrombi from rare cases of
CTEPH
patients who had undergone previous splenectomy were enriched for anionic phospholipids like phosphatidylserine. Similar to human thrombi, phosphatidylserine accumulated in thrombi after splenectomy in the mouse model. A postsplenectomy state was associated with larger and more persistent thrombi. Higher counts of procoagulant platelet microparticles and increased leukocyte–platelet aggregates were observed in mice after splenectomy. Histological inspection revealed a decreased number of thrombus vessels. Phosphatidylserine‐enriched phospholipids specifically inhibited endothelial proliferation and sprouting.

Conclusions

After splenectomy, an increase in circulating microparticles and negatively charged phospholipids is enhanced by experimental thrombus induction. The initial increase in thrombus volume after splenectomy is due to platelet activation, and the subsequent delay of thrombus resolution is due to inhibition of thrombus angiogenesis. The data illustrate a potential mechanism of disease in
CTEPH
.
Never Good Enough
Authors: Alamillo-Martinez Laura
Published: March 2014

Abstract

In different schooling systems throughout the world children of socially advantaged groups experience a higher degree of academic success than children of minority or underprivileged groups. However, there is evidence that academic success comes at a cost. In this paper, based on the findings of an ethnographic research at a Spanish middle-upper class high school, it is argued that secondary school socialization has a strong focus on the future, and it fosters feelings of anxiety in the children of elites. Students believe that a good academic trajectory is the cornerstone to a successful career and they try to take individual control of their future lives without learning how to influence their competitive social context.
Beauty, the Beast, and the Baseball Bat: Ethnography of Self-Defense Training for Upper-Class Women in Revolutionary Cairo (Egypt)
Authors: Lachenal Perrine
Published: March 2014

Abstract

January 2011, Egypt: a huge revolutionary movement began. Since this moment, the perception of insecurity has clearly increased among the upper class. This feeling of vulnerability has opened the doors to new market opportunities related to personal security. In charming neighborhoods of Cairo, offers of self-defense training for women flourished. These training classes offer a valuable and fascinating ethnographic field for addressing the way emotional narratives shape social mobilizations. In class, self-defense participants confirm their shared social belonging while expressing feelings of anxiety in specific terms. Through the Egyptian case, I illustrate that anxiety constitutes a relevant analytical tool to better understand the social and emotional dynamics playing out in revolutionary societies.
Feeling Bad and Being Elite: A Comparative Analysis of the Anxieties and Uncertainties of Aspiring Barristers
Authors: Rogers Justine
Published: March 2014

Abstract

This paper examines the anxieties and uncertainties of aspiring barristers in order to understand the workings of elite professional status. The literature poses two diverging conceptions of negative feelings: as mechanisms for power and solidarity, concentrated at initiation, or else indicators of diminished control and breakdown. To allow for both potential meanings, this paper draws on an ethnographic study of two cohorts of trainee English barristers: one private, one public. The findings detail and compare the sources, nature, and consequences of bad feeling across the sectors. This innovative analysis detects the modes and blends of authority and cohesion, as well as differentiation, declining status, and even separation. This paper argues for intra-professional analyses as valuable groundwork for wider comparisons.
The Possible function of Buttresses in Caryocar Nuciferum (Caryocaraceae) in Guyana: Ecological and Wood Anatomical Observations
Authors: ter Steege Hans , ter Welle Ben J. H. , Laming Peter B.
Published: March 2014

This paper describes the microscopic structure and morphology of stern and buttresses of swamp-grown Caryocar nuciferum L. and discusses the function of buttresses. Buttresses are mainly found at the opposite side of the leaning direction of a tree and thus could function as tension members. In contrast to the stern wood, which exhibits a moderate amount of tension wood fibres with a gelatinous layer, the wood of the buttresses on the tension side and the compression side of the leaning tree is characterised by thick-walled tension wood fibres. In addition, the number of vessels in the buttresses is substantially higher than that in the stern wood. The preferential direction of the buttresses and the anatomical differences in the various parts of the tree are discussed.
Progress in Dendroclimatic Studies of Mountain Pine in Northern Thailand
Authors: D'Arrigo Rosanne , Barbett Michael , Watanasak Manas , Buckley Brendan , Krusic Paul , Boonchirdchoo Saran , Sarutanon Sakunyut
Published: March 2014

New data added to the existing tree-ring width chronologies of mountain pine (Pinus kesiya and Pinus merkusii) result in a total of seven chronologies for these species for Thailand. The oldest (1647-1993) is from a P. merkusii site at Phu Kradung, north central Thailand. An analysis of the three longest P. kesiya chronologies, from north central Thailand, with Phetchabun rainfall (1951-1992) reveals correspondence between years oflow growth and below average rainfall (drought) during the wet season (July-November). The lowest growth year averaged over these three sites during the period of rainfall data (1951-1992) occurred in 1979, coinciding with the lowest wet season rainfall on record. For the common period of tree-ring record prior to 1951 (1830-1950), the level of drought severity in 1979 appears to have been exceeded only twice previously, in 1832 and 1894. A P. merkusii record from Thung Salaeng Luang is most significantly correlated with temperatures during May-June, considered a critical period for the subsequent evolution of the Asian monsoon.
Who’s the Boss? Explaining Gender Inequality in Entrepreneurial Teams
Authors: Yang Tiantian , Aldrich Howard E.
Published: March 2014

Sociologists have examined gender inequalities across a wide array of social contexts. Yet, questions remain regarding how inequalities arise among autonomous groups pursuing economic goals. In this article, we investigate mixed-sex entrepreneurial teams to unpack the mechanisms by which gender inequality in leadership emerges, despite strong pressures toward merit-based organizing principles. We theorize the potentially competing relationships between merit and gender and explore the contingencies moderating their effects. Drawing on a unique, nationally representative dataset of entrepreneurial teams sampled from the U.S. population in 2005, we use conditional logistic regression to test our hypotheses. We demonstrate that merit’s effect becomes much larger when multiple merit-based criteria provide consistent predictions for which team member is superior to others, and when entrepreneurial founders adopt bureaucratic templates to construct new ventures. However, gender stereotypes of leaders pervasively constrain women’s access to power positions, and gender’s effect intensifies when spousal relationships are involved. Women have reduced chances to be in charge if they co-found new businesses with their husbands, and some family conditions further modify women’s chances, such as husbands’ employment and the presence of children.
Relationship Between Glycoprotein IIIa Platelet Receptor Gene Polymorphism and Coronary Artery Disease
Authors: Verdoia Monica , Cassetti Ettore , Schaffer Alon , Barbieri Lucia , Giovine Gabriella Di , Nardin Matteo , Marino Paolo , Sinigaglia Fabiola , Luca Giuseppe De
Published: March 2014

Glycoprotein IIb/IIIa (GP IIb/IIIa) is a key receptor for platelet aggregation and adhesion. We investigated whether a single-nucleotide polymorphism of GP IIIa subunit (Leu33Pro-PlA1/PlA2 allele) is associated with the extent of coronary artery disease (CAD) in a consecutive cohort of 1518 patients undergoing coronary angiography. Significant CAD was defined as at least a stenosis >50% and severe CAD as left main disease and/or trivessel disease. Additionally, carotid intima–media thickness (cIMT) was evaluated in 339 patients. The PlA2 allele was observed in 458 (30.2%) patients and associated with hypercholesterolemia ( P = .03). No difference was observed in the prevalence of CAD (72.6% vs 70.1%, P = .29; adjusted odds ratio, OR [95% confidence interval, CI] = 0.85 [0.67-1.08], P = .19) and severe CAD (27.5% vs 26.5%, adjusted OR [95% CI] = 0.93 [0.72-1.19], P = .55). Furthermore, Leu33Pro polymorphism did not affect cIMT and the prevalence of carotid plaques. Therefore, this polymorphism cannot be regarded as a risk factor for coronary or carotid atherosclerosis.
Phosphate homeostasis and disorders
Authors: Manghat P , Sodi R , Swaminathan R
Published: March 2014

Recent studies of inherited disorders of phosphate metabolism have shed new light on the understanding of phosphate metabolism. Phosphate has important functions in the body and several mechanisms have evolved to regulate phosphate balance including vitamin D, parathyroid hormone and phosphatonins such as fibroblast growth factor-23 (FGF23). Disorders of phosphate homeostasis leading to hypo- and hyperphosphataemia are common and have clinical and biochemical consequences. Notably, recent studies have linked hyperphosphataemia with an increased risk of cardiovascular disease. This review outlines the recent advances in the understanding of phosphate homeostasis and describes the causes, investigation and management of hypo- and hyperphosphataemia.
Unrestricted Mixture Models for Class Identification in Growth Mixture Modeling
Authors: Liu Min , Hancock Gregory R.
Published: March 2014

Growth mixture modeling has gained much attention in applied and methodological social science research recently, but the selection of the number of latent classes for such models remains a challenging issue, especially when the assumption of proper model specification is violated. The current simulation study compared the performance of a linear growth mixture model (GMM) for determining the correct number of latent classes against a completely unrestricted multivariate normal mixture model. Results revealed that model convergence is a serious problem that has been underestimated by previous GMM studies. Based on two ways of dealing with model nonconvergence, the performance of the two types of mixture models and a number of model fit indices in class identification are examined and discussed. This article provides suggestions to practitioners who want to use GMM for their research.
Enhancing a Short Measure of Big Five Personality Traits With Bayesian Scaling
Authors: Jones W. Paul
Published: March 2014

A study in a university clinic/laboratory investigated adaptive Bayesian scaling as a supplement to interpretation of scores on the Mini-IPIP. A “probability of belonging” in categories of low, medium, or high on each of the Big Five traits was calculated after each item response and continued until all items had been used or until a predetermined criteria for the posterior probability has been obtained. The study found higher levels of correspondence with the IPIP-50 score categories using the adaptive Bayesian scaling than with the Mini-IPIP alone. The number of additional items ranged from a mean of 2.9 to 12.5 contingent on the level of certainty desired.
I ritorni della contemporaneità: Lettura di Millimetri di Milo De Angelis
Authors: Tassoni Luigi
Published: March 2014

La riedizione di un volumetto di 29 poesie di Milo De Angelis, avvenuta a trent’anni di distanza dalla prima apparizione, offre la possibilità di valutare criticamente il mutato scenario della ricezione del testo, e la differenza del contesto di lettura fra gli anni Ottanta del Novecento e l’epoca presente. La differenza si coglie a partire dallo sguardo d’insieme rivolto al complesso intreccio dei percorsi generazionali della poesia europea contemporanea osservati, attraverso la speciale lente di un libro decisivo, fino ai loro sviluppi recenti. E quel libro, Millimetri, dal titolo fortemente indicativo, può essere considerato una sorta di manifesto della difficoltà storica, della scrittura tragica, del nonsenso che esige la gratificazione del discorso. Allora la differenza si approfondisce attraverso l’irrinunciabile analisi diretta al testo, che è interrogato e discusso nelle sue risonanze fono-ritmiche, nelle costanti tematiche, nelle ripetute autocitazioni, nelle eccezioni sintattiche e nelle contraddizioni di fondo. Il discorso di De Angelis si comprende nel suo percorso di trasformazione delle allucinazioni, dallo stesso poeta spiegate in Lucrezio, in un orizzonte visivo che con una precisa scelta di oggetti, azioni e spazi, dà storia al presente, e considera presenti l’adolescenza e la memoria, così come la lotta, il tragico, la gioia e il gioco.
A potential bio-filler: The substitution effect of furfural modified clam shell for carbonate calcium in polypropylene
Authors: Xia Mei-sheng , Yao Zhi-tong , Ge Liu-qin , Chen Tao , Li Hai-yan
Published: March 2014

Shell waste has the potential to be used as a bio-filler. In this work, the commercial calcium carbonate and furfural modified clam shell were used as fillers in polypropylene. Both fillers were characterized and analyzed by X-ray diffraction, scanning electron microscopy equipped with an energy dispersive spectrometer, particle size analyzer, Fourier transformed infrared spectroscopy, and contact angle measurement. The mechanical and thermal properties of unfilled polypropylene and polypropylene composites were investigated as well. X-ray diffraction and energy dispersive spectrometer analysis indicated that the major phase of calcium carbonate was calcite; of modified clam shell, calcite and aragonite. The calcium carbonate displayed a cubic-like morphology with a smaller particle size as compared with that of modified clam shell. The contact angle measurements indicated that calcium carbonate was fully hydrophobic, while modified clam shell was amphiphilic. Thermal gravimetric analyses confirmed the reinforcement effects of both calcium carbonate and modified clam shell in polypropylene composites. Mechanical property studies showed that the inclusion of modified clam shell played the role mainly of toughening the polypropylene; of calcium carbonate, that of reinforcing, with a nonsignificant toughening effect. The optimal filler ratio of modified clam shell could reach 15 wt.%, as compared with 10 wt.% for calcium carbonate, making it possible for substituting calcium carbonate in polypropylene.
Governance and Conflict Relapse
Authors: Hegre Håvard , Nygård Håvard Mokleiv
Published: March 2014

Many conflict studies regard formal democratic institutions as states’ most important vehicle to reduce deprivation-motivated armed conflict against their governments. We argue that the wider concept of good governance—the extent to which policy making and implementation benefit the population at large—is better suited to analyze deprivation-based conflict. The article shows that the risk of conflict in countries characterized by good governance drops rapidly after a conflict has ended or after independence. In countries with poor governance, this process takes much longer. Hence, improving governance is important to reduce the incidence of conflict. We also decompose the effect of good governance into what can be explained by formal democratic institutions and less formal aspects of governance, and into what comes from economic development and what is due to how well countries are governed. We find that informal aspects of good governance to be at least as important as formal institutions in preventing conflict and that good governance has a clear effect over and beyond economic development.
YAP Overexpression Affects Tooth Morphogenesis and Enamel Knot Patterning
Authors: Liu M. , Zhao S. , Wang X.-P.
Published: March 2014

Teeth develop through distinct morphological stages. At the cap stage, a compactly clustered and concentrically arranged cell mass, the enamel knot, appears at the tip of the enamel organ. Cells in this knot express sets of key molecules, and as such have been proposed to act as a signaling center directing tooth morphogenesis and tooth cusp formation. YAP is a transcriptional co-activator of the Hippo signaling pathway that is essential for the proper regulation of organ growth. In this study, we analyzed the tooth phenotype in transgenic mice that overexpressed a constitutively active form of YAP in the dental epithelium. We found that overexpression of YAP resulted in deformed tooth morphogenesis with widened dental lamina. In addition, the enamel knot was mislocated to the upper portion of the enamel organ, where it remained devoid of proliferating cells and contained apoptotic cells with intense Edar transcripts and reduced E-cadherin expression. Interestingly, some signaling molecules, such as Shh, Fgf4, and Wnt10a, were not expressed in this mislocated enamel knot, but remained at the tip of the enamel organ. Analysis of these data suggests that the signaling center is induced by reciprocal epithelial-mesenchymal interactions, and its induction may be independent of the enamel knot.
Gender Differences in the Determinants of Prison Rule Violations
Authors: Celinska Katarzyna , Sung Hung-En
Published: March 2014

This article addresses gender differences in the extent and explanation of inmate misconduct. The study employs nationally representative prisoner survey data to assess gender-specific explanations of prison rule violations. The gender-specific factors include prior victimization, diagnosed mental disorders, and the amount of inmate contact with their families via visits and phone calls. Logistic regression models support gender-specific explanations of inmate misconduct but also identify other factors of general importance. The policy implications of gendered pathways in prison misconduct are discussed.
The neoliberal firm and nested subsumption: Labour process transformations in the NYC taxi industry
Authors: Mathew Biju
Published: March 2014

In this paper I use New York’s taxi industry and the struggle around GPS technologies to articulate some essential aspects of a new regime of labour subsumption that is taking shape, most evidently in cities. I argue that these new aspects of labour subsumption may be useful in understanding changes in labour regimes across industries in the neoliberal period. Finally, I attempt to demonstrate connections between theories of labour subsumption and practices of labour organising. I contend that labour subsumption theory and specific forms of labour organisation show a clear relationship in the past and thus, if we are able to discern significant developments in the modes by which capital subsumes labour in the present neoliberal period, this could offer new insights in the domain of labour organising strategies.
Managerial Practices, Trust in Leadership, and Performance
Authors: Cho Yoon Jik , Poister Theodore H.
Published: March 2014

This research explores relationships among managerial practices, trust in leadership, teamwork, and organizational performance. It seeks to contribute to the existing knowledge of trust research by exploring several antecedents and outcomes. Based on the social exchange theory, the research examines whether managerial practices are associated with trust in leadership. Trust in leadership, then, is expected to improve teamwork and organizational performance by several leadership theories. Using data from an employee survey conducted for the Georgia Department of Transportation (GDOT) in 2010, we test the ideas by structural equation model analysis. Three kinds of trust in leadership—trust in department leadership, trust in leadership team, and trust in supervisor—are investigated. The analysis confirms that several managerial practices are substantially associated with the three kinds of trust, which in turn affects teamwork and organizational performance. Trust in department leadership is directly related to performance, whereas trust in leadership team and trust in supervisor are more likely to affect performance through teamwork.
Exposure to Outgroup Members Criticizing Their Own Group Facilitates Intergroup Openness
Authors: Saguy Tamar , Halperin Eran
Published: March 2014

A major barrier to conflict resolution is group members’ tendency to hold on to the ingroup’s narrative of the conflict and reject the outgroup’s perspective. In the current research, we propose that voicing internal criticism to an outgroup crowd can undermine such orientations and foster intergroup openness. Across four experiments, Israeli Jews who were exposed to a Palestinian criticizing Palestinians were more open to the Palestinians’ perspective of the conflict, than those not exposed to the criticism. This effect was obtained when the criticism was related (Study 1) and unrelated (Study 2) to the conflict, and was consistently mediated by increased hope about the future relations between the groups. Study 3 showed that the effect is more pronounced among those who believe that groups can change. Study 4 established that perceptions about the outgroup as open-minded underlie the effect of ingroup criticism on hope, and further demonstrated downstream effects of openness.