bluuebunny/crossref_metadata_2025 huggingface dataset:
ERK5 Is a Critical Mediator of Inflammation-Driven Cancer
Authors: Finegan Katherine G. , Perez-Madrigal Diana , Hitchin James R. , Davies Clare C. , Jordan Allan M. , Tournier Cathy
Published: February 2015

Chronic inflammation is a hallmark of many cancers, yet the pathogenic mechanisms that distinguish cancer-associated inflammation from benign persistent inflammation are still mainly unclear. Here, we report that the protein kinase ERK5 controls the expression of a specific subset of inflammatory mediators in the mouse epidermis, which triggers the recruitment of inflammatory cells needed to support skin carcinogenesis. Accordingly, inactivation of ERK5 in keratinocytes prevents inflammation-driven tumorigenesis in this model. In addition, we found that anti-ERK5 therapy cooperates synergistically with existing antimitotic regimens, enabling efficacy of subtherapeutic doses. Collectively, our findings identified ERK5 as a mediator of cancer-associated inflammation in the setting of epidermal carcinogenesis. Considering that ERK5 is expressed in almost all tumor types, our findings suggest that targeting tumor-associated inflammation via anti-ERK5 therapy may have broad implications for the treatment of human tumors. Cancer Res; 75(4); 742–53. ©2015 AACR.
BMX Negatively Regulates BAK Function, Thereby Increasing Apoptotic Resistance to Chemotherapeutic Drugs
Authors: Fox Joanna L. , Storey Alan
Published: February 2015

The ability of chemotherapeutic agents to induce apoptosis, predominantly via the mitochondrial (intrinsic) apoptotic pathway, is thought to be a major determinant of the sensitivity of a given cancer to treatment. Intrinsic apoptosis, regulated by the BCL2 family, integrates diverse apoptotic signals to determine cell death commitment and then activates the nodal effector protein BAK to initiate the apoptotic cascade. In this study, we identified the tyrosine kinase BMX as a direct negative regulator of BAK function. BMX associates with BAK in viable cells and is the first kinase to phosphorylate the key tyrosine residue needed to maintain BAK in an inactive conformation. Importantly, elevated BMX expression prevents BAK activation in tumor cells treated with chemotherapeutic agents and is associated with increased resistance to apoptosis and decreased patient survival. Accordingly, BMX expression was elevated in prostate, breast, and colon cancers compared with normal tissue, including in aggressive triple-negative breast cancers where BMX overexpression may be a novel biomarker. Furthermore, BMX silencing potentiated BAK activation, rendering tumor cells hypersensitive to otherwise sublethal doses of clinically relevant chemotherapeutic agents. Our finding that BMX directly inhibits a core component of the intrinsic apoptosis machinery opens opportunities to improve the efficacy of existing chemotherapy by potentiating BAK-driven cell death in cancer cells. Cancer Res; 75(7); 1345–55. ©2015 AACR.
Associations between Environmental Exposures and Incident Colorectal Cancer by ESR2 Protein Expression Level in a Population-Based Cohort of Older Women
Authors: Tillmans Lori S. , Vierkant Robert A. , Wang Alice H. , Samadder Niloy Jewel , Lynch Charles F. , Anderson Kristin E. , French Amy J. , Haile Robert W. , Harnack Lisa J. , Potter John D. , Slager Susan L. , Smyrk Thomas C. , Thibodeau Stephen N. , Cerhan James R. , Limburg Paul J.
Published: February 2015

Background: Cigarette smoking (smoking), hormone therapy (MHT), and folate intake (folate) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. Expression of estrogen receptor β (ESR2) has been associated with colorectal cancer stage and survival.

Methods: In this prospective cohort study, we examined smoking, MHT, and folate-associated colorectal cancer risks by ESR2 protein expression level among participants in the Iowa Women's Health Study (IWHS). Self-reported exposure variables were assessed at baseline. Archived, paraffin-embedded colorectal cancer tissue specimens were collected and evaluated for ESR2 protein expression by IHC. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between smoking, MHT, or folate and ESR2-defined colorectal cancer subtypes.

Results: Informative environmental exposure and protein expression data were available for 491 incident colorectal cancer cases. Positive associations between ESR2-low and -high tumors and several smoking-related variables were noted, most prominently with average number of cigarettes per day (RR, 4.24; 95% CI, 1.81–9.91 for ESR2-low and RR, 2.15; 95% CI, 1.05–4.41 for ESR2-high for ≥40 cigarettes compared with nonsmokers). For MHT, a statistically significant association with ESR2-low tumors was observed with longer duration of exposure (RR, 0.54; 95% CI, 0.26–1.13 for >5 years compared with never use). No associations were found for folate.

Conclusions: In this study, smoking and MHT were associated with ESR2 expression patterns.

Impact: These data support possible heterogeneous effects from smoking and MHT on ERβ-related pathways of colorectal carcinogenesis in older women. Cancer Epidemiol Biomarkers Prev; 24(4); 713–9. ©2015 AACR.
The Association between Fatalistic Beliefs and Late Stage at Diagnosis of Lung and Colorectal Cancer
Authors: Lyratzopoulos Georgios , Liu Michael Pang-Hsiang , Abel Gary A. , Wardle Jane , Keating Nancy L.
Published: February 2015

Background: Fatalistic beliefs may be implicated in longer help-seeking intervals, and consequently, greater risk of advanced stage at cancer diagnosis.

Methods: We examined associations between fatalism and stage at diagnosis in a population-based cohort of 4,319 U.S. patients with newly diagnosed lung or colorectal cancer participating in the Cancer Care Outcomes and Research Surveillance (CanCORS) study. Fatalistic beliefs were assessed with an established measure. A fatalism score (range, 4–16) was created by summing Likert scale responses to four items. Cancer stage at diagnosis was abstracted from medical records by trained staff. Logistic regression was used to assess the association between fatalism score and advanced stage at diagnosis (IV vs. I–III), adjusting for sociodemographic and clinical characteristics.

Results: Overall, 917 (21%) patients had stage IV cancers (lung: 28%, colorectal: 16%). The mean fatalism score was 10.7 (median = 11; interquartile range, 9–12). In adjusted analyses, a higher fatalism score was associated with greater odds of stage IV diagnosis (OR per unit increase in fatalism = 1.05; 95% confidence interval 1.02–1.08; P = 0.003). Patients with the highest fatalism score had an adjusted 8.9% higher frequency of stage IV diagnosis compared with patients with the lowest score (25.4% vs. 16.5%).

Discussion: In this large and socioeconomically, geographically, and ethnically diverse population of patients with lung and colorectal cancer, fatalistic beliefs were associated with higher risk of advanced stage at diagnosis. Longitudinal studies are needed to confirm causation.

Impact: These findings support the value of incorporating information about the curability of early-stage cancers in public education campaigns. Cancer Epidemiol Biomarkers Prev; 24(4); 720–6. ©2015 AACR.
PTEN Loss Is Associated with Worse Outcome in HER2-Amplified Breast Cancer Patients but Is Not Associated with Trastuzumab Resistance
Authors: Stern Howard M. , Gardner Humphrey , Burzykowski Tomasz , Elatre Wafaa , O'Brien Carol , Lackner Mark R. , Pestano Gary A. , Santiago Angela , Villalobos Ivonne , Eiermann Wolfgang , Pienkowski Tadeusz , Martin Miguel , Robert Nicholas , Crown John , Nuciforo Paolo , Bee Valerie , Mackey John , Slamon Dennis J. , Press Michael F.
Published: February 2015

Purpose: To investigate the clinical relevance of PTEN in HER2-amplified and HER2-nonamplified disease.

Experimental Design: We assessed PTEN status in two large adjuvant breast cancer trials (BCIRG-006 and BCIRG-005) using a PTEN immunohistochemical (IHC) assay that was previously validated in a panel of 33 breast cancer cell lines and prostate cancer tissues with known PTEN gene deletion.

Results: In the HER2-positive patient population, absence of tumor cell PTEN staining occurred at a rate of 5.4% and was independent of ER/PR status. In contrast, 15.9% of HER2-negative patients exhibited absence of PTEN staining with the highest frequency seen in triple-negative breast cancer (TNBC) subgroup versus ER/PR-positive patients (35.1% vs. 10.9%). Complete absence of PTEN staining in tumor cells was associated with poor clinical outcome in HER2-positive disease. Those patients whose cancers demonstrated absent PTEN staining had a significant decrease in disease-free survival (DFS) and overall survival (OS) compared with patients with tumors exhibiting any PTEN staining patterns (low, moderate, or high). Trastuzumab appeared to provide clinical benefit even for patients lacking PTEN staining. In the HER2-negative population, there were no statistically significant differences in clinical outcome based on PTEN status.

Conclusions: This study is the largest to date examining PTEN status in breast cancer and the data suggest that the rate and significance of PTEN status differ between HER2-positive and HER2-negative disease. Furthermore, the data clearly suggest that HER2-positive patients with PTEN loss still benefit from trastuzumab. Clin Cancer Res; 21(9); 2065–74. ©2015 AACR.
Thyroid Cancer in Black Thyroid Glands: The Effect of Age and Race
Authors: Ibrahim Yasin , Crawford Byron E. , Murci Mohammad , Masoodi Hammad , Khan Amna N. , Hu Tian , Kandil Emad , Friedlander Paul
Published: February 2015

Background: Black thyroid pigmentation is a rare entity. The risk of malignancy is higher in black thyroid compared to non-black thyroid glands. We aimed to examine the effect of age and race on the risk of malignancy in black thyroid glands. Methods: We identified a series of consecutive patients who underwent thyroidectomy at an academic institution between January 1998 and May 2013. Patient demographics, clinical characteristics, and histopathology data were reviewed. Results: Among 925 patients who underwent thyroidectomy, 112 (12.1%) patients with black thyroid glands were identified. The incidence of thyroid cancer was 55.4% in black thyroid glands compared to 32.8% in non-black thyroid glands (p < 0.0001). The incidence of papillary thyroid cancer among the black and non-black thyroid glands was 34.8 and 20%, respectively (p < 0.001). The mean age (±SD) for patients with black thyroid glands and those with non-black thyroid was 54.3 ± 12.8 and 51.2 ± 15.7 years, respectively (p = 0.05). Black thyroid glands were also associated with a higher incidence of microcarcinomas (76 vs. 59%, p = 0.02). Among patients with black thyroid glands, Caucasians had a higher malignancy rate (63.4%) than African-Americans (37%; p = 0.03). Conclusion: The incidence of malignancy is higher in black thyroid compared to non-black thyroid glands, specifically in Caucasians.
Total Laparoscopic Hysterectomy in Obese and Morbidly Obese Women
Authors: Guraslan Hakan , Senturk Mehmet Baki , Dogan Keziban , Guraslan Birgul , Babaoglu Bulent , Yasar Levent
Published: February 2015

Background: The study aimed at estimating the effect of body mass index (BMI), used to classify non-obese, obese, and morbidly obese patients, on clinical outcomes in total laparoscopic hysterectomy (TLH) cases. Methods: This retrospective cohort study included 153 patients who underwent TLH for benign, premalignant, or malignant conditions between August 2010 and June 2013. Patients were divided into 3 groups according to BMI, and the following variables were analyzed: operation time, conversion rate, blood loss, total complications, and length of hospital stay. Results: The mean BMI was 33.5 kg/m2 (range, 22-61). Forty-four patients were non-obese (BMI <30), 73 were obese (30≤ BMI <40), and 36 were morbidly obese (BMI ≥40). In 138 patients (90.2%), hysterectomy was performed using an endoscopic technique. The rate of conversion to laparotomy (9.8%; 95% confidence interval (CI), 5.1-14.5), blood loss (70.5 ml; range, 10-700), total complications (5.9%), and length of hospital stay (2.9 d; range, 1-8) did not vary according to BMI. Operation time was longer in obese (p = 0.003) and morbidly obese (0.002) patients than in non-obese patients. Conclusion: TLH could be considered a safe and feasible alternative to abdominal hysterectomy in obese and morbidly obese patients.
Expression of SIRT2 and SIRT6 in Retinoblastoma
Authors: Orellana Maria Eugenia , Quezada Carlos , Maloney Shawn C. , Antecka Emilia , Balazsi Matthew , Burnier Jr. Miguel N.
Published: February 2015

Purpose: SIRT2 and SIRT6 are members of the sirtuin family and are associated with cancer development and progression in certain tumours, but their expression in retinoblastoma has not been studied. The primary objective of our study was to determine the expression of SIRT2 and SIRT6 in human retinoblastoma cases. Methods: Eighteen formalin-fixed paraffin-embedded blocks of retinoblastoma cases from the Ocular Pathology Registry at the Henry C. Witelson Ocular Pathology Laboratory were obtained, classified and immunostained for SIRT2 and SIRT6 using mouse monoclonal antibodies. Results: Sixteen cases were poorly differentiated retinoblastoma cases. SIRT2 and SIRT6 were expressed in all cases of retinoblastoma although differences in the staining intensity were found between cases. SIRT2 and SIRT6 expression was also observed in various normal structures of the remaining ocular tissue. Conclusions: SIRT2 and SIRT6 are expressed in retinoblastoma, as well as in some normal ocular structures. While precise roles of these proteins must still be determined in retinoblastoma, their expression profiles suggest that further functional studies of both SIRT2 and SIRT6 should be pursued in this cancer.
A Comparison of Adenosquamous Carcinoma and Adenocarcinoma of the Cervix after Radical Hysterectomy
Authors: Lee Jung-Yun , Lee Chulmin , Hahn Seo Kyung , Kim Hee Seung , Chung Hyun Hoon , Kim Jae Weon , Park Noh Hyun , Song Yong-Sang
Published: February 2015

Background/Aims: The aim of this study was to compare the survival outcomes of adenocarcinoma and adenosquamous carcinoma in early-stage cervical cancer patients after radical hysterectomy. Methods: A retrospective analysis was performed of stage IB-IIA cervical cancer patients with adenocarcinoma or adenosquamous carcinoma who underwent radical hysterectomy at Seoul National University Hospital between 1998 and 2008. Results: A total of 166 patients with adenosquamous carcinoma (ASC) (n = 38) and adenocarcinoma (AC) (n = 128) were identified. In terms of baseline characteristics, the ASC group had higher rates of lymph node metastasis, deep stromal invasion, and lymphovascular space invasion than the AC group. However, there was no significant difference between the two histological subtypes in terms of recurrence-free survival (p = 0.396) and overall survival (p = 0.223). Patients with ASC showed similar outcomes to those with AC when limiting to either an intermediate/high-risk group or patients who underwent adjuvant concurrent chemoradiotherapy. Conclusion: Although the ASC group presented poorer pathologic findings after radical hysterectomy compared with the AC group, there was no significant difference in survival outcomes. This suggests that intermediate/high-risk patients with ASC may be successfully treated with postoperative concurrent chemoradiotherapy.
A Giant Ovarian Tumor Causing Anasarca and Dyspnea Successfully Managed after Preoperative Drainage
Authors: Yamaguchi Munekage , Tashiro Hironori , Takaishi Kiyomi , Honda Ritsuo , Katabuchi Hidetaka
Published: February 2015

Serious complications are likely to accompany the treatment of giant ovarian tumors, and resection with or without preoperative drainage has been previously reported. Here, we report the case of a 27-year-old Japanese woman with a significant weight gain of 50 kg, who was referred to the Kumamoto University Hospital because of gait impairment and dyspnea. Imaging tests revealed an ovarian tumor, 37 cm in diameter, with two solid components. The patient's condition improved after the removal of 31.5 l tumor fluid by using a suprapubic urinary catheter for 3 days. The tumor was subsequently resected without complications, and was diagnosed as a left mucinous ovarian tumor with malignant components, weighing 37 kg (81.5 lb). The patient was discharged after her anasarca improved, and her body weight decreased from 100 to 50 kg with accompanying considerable urination within two weeks. She was in good condition with no evidence of recurrence at 15 months after surgery. Tumor resection after preoperative drainage was effective in the management of a patient with dyspnea induced by a giant ovarian tumor. We suggest the use of a suprapubic urinary catheter for preoperative drainage because of its ease of use in preventing fluid leakage from the possibly malignant tumor.
Long-Term Response of Classic Kaposi's Sarcoma to Intralesional Doxorubicin: A Case Report
Authors: Mirza Yasir Azim , Altamura Davide , Hirbod Torkan , Verdolini Roberto
Published: February 2015

Classic Kaposi's sarcoma (KS) is a disease with low mortality but high morbidity. The optimum treatment of KS depends upon several factors, including location of lesions, disease progression, severity of symptoms and patient preference. We report the long-term response to the use of intralesional doxorubicin to successfully treat a large cutaneous lesion of KS on a patient refractory to traditional treatments.
The Prevalence of Depressive Symptoms in Frontotemporal Dementia: A Meta-Analysis
Authors: Chakrabarty Trisha , Sepehry Amir A. , Jacova Claudia , Hsiung Ging-Yuek Robin
Published: February 2015

Background: Depression is common in Alzheimer's and vascular dementia and is associated with poorer outcomes; however, less is known about the impact of depression on frontotemporal dementia (FTD). Here, we conducted a meta-analysis of diagnostic methods and the prevalence of depressive symptoms in FTD. Methods: PubMed, EMBASE and PsychINFO were queried for ‘depression' and/or ‘depressive mood' in behavioral- and language-variant FTD. The prevalence and diagnosis of depressive symptoms were extracted from relevant studies and the results pooled using a random-effects model. Results: We included 29 studies in this meta-analysis, with sample sizes ranging from 3 to 73 (n = 870). The omnibus estimated event rate of depressed mood was 0.334 (33%; 95% CI: 0.268-0.407). Symptoms were most commonly assessed via standardized neuropsychiatric rating scales, with other methods including subjective caregiver reports and chart reviews. The study results were heterogeneous due to the variability in diagnostic methods. Conclusions: Depressive symptoms similar to those in other dementias are commonly detected in FTD. However, the diagnostic methods are heterogeneous, and symptoms of depression often overlap with manifestations of FTD. Having a standardized diagnostic approach to depression in FTD will greatly facilitate future research in this area.
Lipid Levels and Renal Function Decline in Pre-Dialysis Patients
Authors: de Goeij Moniek C.M. , Rotmans Joris I. , Matthijssen Xanthe , de Jager Dinanda J. , Dekker Friedo W. , Halbesma Nynke ,   for the PREPARE-2 Study Group
Published: February 2015

Background: Little is known about the effect of low-density lipoprotein (LDL) cholesterol, triglyceride (TG), and high-density lipoprotein (HDL) cholesterol levels on renal function decline in patients receiving specialized pre-dialysis care. Methods: In the prospective PREPARE-2 study, incident patients starting pre-dialysis care were included when referred to one of the 25 participating Dutch specialized pre-dialysis outpatient clinics (2004-2011). Clinical and laboratory data were collected every 6 months. A linear mixed model was used to compare renal function decline between patients with LDL cholesterol, TG, or HDL cholesterol levels above and below the target goals (LDL cholesterol: <2.50 mmol/l, TG: <2.25 mmol/l, and HDL cholesterol: ≥1.00 mmol/l). Additionally the HDL/LDL cholesterol ratio was investigated (≥0.4). Results: In our study population (n = 306), the median age was 69 years and 70% were male. Patients with LDL cholesterol levels above the target of 2.50 mmol/l experienced an accelerated renal function decline compared to patients with levels below the target (crude additional decline: 0.10 ml/min/1.73 m2/month, 95% CI 0.00-0.20; p < 0.05). A similar trend was found for TG levels above the target of 2.25 mmol/l (0.05 ml/min/1.73 m2/month, 95% CI -0.06 to 0.16) and for a HDL/LDL cholesterol ratio below 0.4 (0.06 ml/min/1.73 m2/month, 95% CI -0.05 to 0.18). Adjustment for potential confounders resulted in similar results, and the exclusion of patients who were prescribed lipid-lowering medication (statin, fibrate, or cholesterol absorption inhibitor) resulted in a slightly larger estimated effect. Conclusion: High levels of LDL cholesterol were associated with an accelerated renal function decline, independent of the prescription of lipid-lowering medication.
Static Image Analysis as New Approach for the Characterization of Tumor Cell Lysate Used in Dendritic Cell Vaccine Preparation
Authors: Müller Isabelle , Hartmann Dorothee , Oertel Joachim , Keck Cornelia M. , Eichler Hermann
Published: February 2015

Background: Safety is an important consideration for the clinical application of dendritic cells (DC) loaded with autologous tumor lysate (TL). Thus, avitalization of TL from living autologous tumor tissue has to be guaranteed. Methods: Composition of TL was investigated by static image analysis (SIA) with the Morphologi G3 device, which simultaneously measures size and shape of up to 100,000 particles within one sample run. This approach was compared with sample characterization by high-resolution automated cell counting, trypan blue staining, and ATP quantification. Results: Using SIA, we only detected fragmented, non-cellular structures in completely avitalized TL, indicating complete destruction of living cells. Analysis of particle size distribution by SIA as well as CASY cell counter showed that 95% of particles had a diameter of <10 µm as a sign of cell fragmentation. Complete avitalization of TL was confirmed with trypan blue staining and ATP analysis. Conclusion: Regarding generation of DC vaccines, the proof of avitality of TL from living tumor tissue can clearly be achieved by SIA alone or in combination with standard assays. Our data show that SIA is a highly precise method for TL characterization. The SIA device complies with FDA regulation and, therefore, might be suitable for characterization of cellular therapy medicinal products.
Assessing Fetal Cardiac Function by Measuring Myocardial Radial Velocity Using the Phased-Tracking Method
Authors: Ozawa Katsusuke , Murotsuki Jun , Miyashita Susumu , Muromoto Jin , Hasegawa Hideyuki , Kanai Hiroshi , Yaegashi Nobuo
Published: February 2015

Objective: This study aimed to assess the cardiac function of healthy and pathological fetuses by measuring radial velocity using phased tracking (PT). Based on phase differences, PT allows the displacement of a specified point to be detected with improved spatial and temporal resolution. Methods: PT was used to assess cardiac radial velocity in the basal free wall of the left and right ventricles in 134 healthy fetuses, 10 second-trimester intrauterine growth-restricted (IUGR) fetuses, and 10 recipient twins with twin-to-twin transfusion syndrome (TTTS). Maximum velocities were measured in systole and early diastole. Results: Maximum radial velocity was successfully measured in 126 healthy fetuses (94%) at gestational ages of 16-40 weeks. Systolic and early diastolic maximum velocities increased with gestational age in both ventricles. As compared with controls, IUGR fetuses had significantly lower early diastolic maximum velocities in the right ventricle, and recipient twins with TTTS had significantly lower systolic and early diastolic maximum velocities in both ventricles. Conclusions: PT demonstrated right ventricular diastolic dysfunction in second-trimester IUGR fetuses as well as systolic and diastolic dysfunctions in both ventricles in recipient twins with TTTS. PT could be useful for evaluating fetal cardiac radial function.
Influence of Pre-Storage Irradiation on the Oxidative Stress Markers, Membrane Integrity, Size and Shape of the Cold Stored Red Blood Cells
Authors: Antosik Adam , Czubak Kamila , Gajek Arkadiusz , Marczak Agnieszka , Glowacki Rafal , Borowczyk Kamila , Zbikowska Halina Malgorzata
Published: February 2015

Background: To investigate the extent of oxidative damage and changes in morphology of manually isolated red blood cells (RBCs) from whole blood, cold stored (up to 20 days) in polystyrene tubes and subjected to pre-storage irradiation (50 Gy) and to compare the properties of SAGM-preserved RBCs stored under experimental conditions (polystyrene tubes) with RBCs from standard blood bag storage. Methods: The percentage of hemolysis as well as the extracellular activity of LDH, thiobarbituric acid-reactive substances, reduced glutathione (GSH), and total antioxidant capacity (TAC) were measured. Changes in the topology of RBC membrane, shape, and size were evaluated by flow cytometry and judged against microscopy images. Results: Irradiation caused significant LDH release as well as increased hemolysis and lipid peroxidation, GSH depletion, and reduction of TAC. Prolonged storage of irradiated RBCs resulted in phosphatidylserine exposure on the cell surface. By day 20, approximately 60% of RBCs displayed non-discoid shape. We did not notice significant differences in percentage of altered cells and cell volume between RBCs exposed to irradiation and those not exposed. Conclusion: Irradiation of RBC transfusion units with a dose of 50 Gy should be avoided. For research purposes such as studying the role of antioxidants, storage of small volumes of RBCs derived from the same donor would be more useful, cheaper, and blood-saving.
Role of Mutation and Pharmacologic Block of Human KCNH2 in Vasculogenesis and Fetal Mortality
Authors: Teng Guoqi , Zhao Xiang , Lees-Miller James P. , Belke Darrell , Shi Chunhua , Chen Yongxiang , O’Brien Edward R. , Fedak Paul W. , Bracey Nathan , Cross James C. , Duff Henry J.
Published: February 2015

Background—

N629D
KCNH2
is a human missense long-QT2 mutation. Previously, we reported that the N629D/N629D mutation embryos disrupted cardiac looping, right ventricle development, and ablated I
Kr
activity at E9.5. The present study evaluates the role of KCNH2 in vasculogenesis.

Methods and Results—

N629D/N629D yolk sac vessels and aorta consist of sinusoids without normal arborization. Isolated E9.5 +/+ first branchial arches showed normal outgrowth of mouse ERG–positive/α-smooth muscle actin coimmunolocalized cells; however, outgrowth was grossly reduced in N629D/N629D. N629D/N629D aortas showed fewer α-smooth muscle actin positive cells that were not coimmunolocalized with mouse ERG cells. Transforming growth factor-β treatment of isolated N629D/N629D embryoid bodies partially rescued this phenotype. Cultured N629D/N629D embryos recapitulate the same cardiovascular phenotypes as seen in vivo. Transforming growth factor-β treatment significantly rescued these embryonic phenotypes. Both in vivo and in vitro, dofetilide treatment, over a narrow window of time, entirely recapitulated the N629D/N629D fetal phenotypes. Exogenous transforming growth factor-β treatment also rescued the dofetilide-induced phenotype toward normal.

Conclusions—

Loss of function of KCNH2 mutations results in defects in cardiogenesis and vasculogenesis. Because many medications inadvertently block the KCNH2 potassium current, these novel findings seem to have clinical relevance.
The Cardiovascular Health in Ambulatory Care Research Team (CANHEART)
Authors: Tu Jack V. , Chu Anna , Donovan Linda R. , Ko Dennis T. , Booth Gillian L. , Tu Karen , Maclagan Laura C. , Guo Helen , Austin Peter C. , Hogg William , Kapral Moira K. , Wijeysundera Harindra C. , Atzema Clare L. , Gershon Andrea S. , Alter David A. , Lee Douglas S. , Jackevicius Cynthia A. , Bhatia R. Sacha , Udell Jacob A. , Rezai Mohammad R. , Stukel Thérèse A.
Published: February 2015

Background—

The CArdiovascular HEalth in Ambulatory care Research Team (CANHEART) is conducting a unique, population-based observational research initiative aimed at measuring and improving cardiovascular health and the quality of ambulatory cardiovascular care provided in Ontario, Canada. A particular focus will be on identifying opportunities to improve the primary and secondary prevention of cardiovascular events in Ontario’s diverse multiethnic population.

Methods and Results—

A population-based cohort comprising 9.8 million Ontario adults ≥20 years in 2008 was assembled by linking multiple electronic survey, health administrative, clinical, laboratory, drug, and electronic medical record databases using encoded personal identifiers. The cohort includes ≈9.4 million primary prevention patients and ≈400 000 secondary prevention patients. Follow-up on clinical events is achieved through record linkage to comprehensive hospitalization, emergency department, and vital statistics administrative databases. Profiles of cardiovascular health and preventive care will be developed at the health region level, and the cohort will be used to study the causes of regional variation in the incidence of major cardiovascular events and other important research questions.

Conclusions—

Linkage of multiple databases will enable the CANHEART study cohort to serve as a powerful big data resource for scientific research aimed at improving cardiovascular health and health services delivery. Study findings will be shared with clinicians, policy makers, and the public to facilitate population health interventions and quality improvement initiatives.
Calpastatin Counteracts Pathological Angiogenesis by Inhibiting Suppressor of Cytokine Signaling 3 Degradation in Vascular Endothelial Cells
Authors: Miyazaki Takuro , Taketomi Yoshitaka , Saito Yuta , Hosono Tomohiko , Lei Xiao-Feng , Kim-Kaneyama Joo-ri , Arata Satoru , Takahashi Haruo , Murakami Makoto , Miyazaki Akira
Published: February 2015

Rationale:

Janus kinase/signal transducer and activator of transcription (JAK/STAT) signals and their endogenous inhibitor, suppressor of cytokine signaling 3 (SOCS3), in vascular endothelial cells (ECs) reportedly dominate the pathological angiogenesis. However, how these inflammatory signals are potentiated during pathological angiogenesis has not been fully elucidated. We suspected that an intracellular protease calpain, which composes the multifunctional proteolytic systems together with its endogenous inhibitor calpastatin (CAST), contributes to the JAK/STAT regulations.

Objective:

To specify the effect of EC calpain/CAST systems on JAK/STAT signals and their relationship with pathological angiogenesis.

Methods and Results:

The loss of CAST, which is ensured by several growth factor classes, was detectable in neovessels in murine allograft tumors, some human malignant tissues, and oxygen-induced retinopathy lesions in mice. EC-specific transgenic introduction of
CAST
caused downregulation of JAK/STAT signals, upregulation of SOCS3 expression, and depletion of vascular endothelial growth factor (VEGF)-C, thereby counteracting unstable pathological neovessels and disease progression in tumors and oxygen-induced retinopathy lesions in mice. Neutralizing antibody against VEGF-C ameliorated pathological angiogenesis in oxygen-induced retinopathy lesions. Small interfering RNA–based silencing of endogenous
CAST
in cultured ECs facilitated μ-calpain–induced proteolytic degradation of SOCS3, leading to VEGF-C production through amplified interleukin-6–driven STAT3 signals. Interleukin-6–induced angiogenic tube formation in cultured ECs was accelerated by
CAST
silencing, which is suppressible by pharmacological inhibition of JAK/STAT signals, antibody-based blockage of VEGF-C, and transfection of calpain-resistant SOCS3, whereas transfection of wild-type SOCS3 exhibited modest angiostatic effects.

Conclusions:

Loss of CAST in angiogenic ECs facilitates μ-calpain–induced SOCS3 degradation, which amplifies pathological angiogenesis through interleukin-6/STAT3/VEGF-C axis.
Interleukin 23 Levels Are Increased in Carotid Atherosclerosis
Authors: Abbas Azhar , Gregersen Ida , Holm Sverre , Daissormont Isabelle , Bjerkeli Vigdis , Krohg-Sørensen Kirsten , Skagen Karolina R. , Dahl Tuva B. , Russell David , Almås Trine , Bundgaard Dorte , Alteheld Lars Holger , Rashidi Azita , Dahl Christen P. , Michelsen Annika E. , Biessen Erik A. , Aukrust Pål , Halvorsen Bente , Skjelland Mona
Published: February 2015

Background and Purpose—

Interleukin (IL)-23 is a cytokine in the IL-12 family, mainly produced by antigen-presenting cells with a central role in inflammation. We hypothesize that IL-23 is also important in atherogenesis and investigate this in a population with carotid atherosclerosis.

Methods—

Plasma levels of IL-23 were measured in patients with carotid artery stenosis and in healthy controls. The mRNA levels of IL-23 and its receptor, IL-23R, were measured in atherosclerotic plaques, nonatherosclerotic vessels, peripheral blood mononuclear cells, and plasmacytoid dendritic cells.

Results—

Our findings were as follows: (1) patients with carotid atherosclerosis (n=177) had significantly raised plasma levels of IL-23 when compared with healthy controls (n=24) with particularly high levels in those with the most recent symptoms. (2) mRNA levels of IL-23 and IL-23R were markedly increased in carotid plaques (n=68) when compared with nonatherosclerotic vessels (n=8–10). Immunostaining showed colocalization to plaque macrophages. (3) Patients with carotid atherosclerosis had increased mRNA levels of both IL-23 and IL-23R in plasmacytoid dendritic cells, but not in peripheral blood mononuclear cells. (4) IL-23 increased IL-17 release in monocytes and particularly in peripheral blood mononuclear cells from patients with carotid atherosclerosis, but not in cells from healthy controls. (5) IL-23 gave a prominent tumor necrosis factor release in monocytes from patients with carotid atherosclerosis but not in cells from healthy controls. (6) High plasma levels of IL-23 were associated with increased mortality during follow-up.

Conclusions—

We have shown an association between IL-23 and disease progression in patients with carotid atherosclerosis, potentially involving IL-17-related mechanisms.
Genetic Study of Intracranial Aneurysms
Authors: Yan Junxia , Hitomi Toshiaki , Takenaka Katsunobu , Kato Masayasu , Kobayashi Hatasu , Okuda Hiroko , Harada Kouji H. , Koizumi Akio
Published: February 2015

Background and Purpose—

Rupture of intracranial aneurysms (IAs) causes subarachnoid hemorrhage, leading to immediate death or severe disability. Identification of the genetic factors involved is critical for disease prevention and treatment. We aimed to identify the susceptibility genes for IAs.

Methods—

Exome sequencing was performed in 12 families with histories of multiple cases of IA (number of cases per family ≥3), with a total of 42 cases. Various filtering strategies were used to select the candidate variants. Replicate association studies of several candidate variants were performed in probands of 24 additional IA families and 426 sporadic IA cases. Functional analysis for the mutations was conducted.

Results—

After sequencing and filtering, 78 variants were selected for the following reasons: allele frequencies of variants in 42 patients was significantly (
P
<0.05) larger than expected; variants were completely shared by all patients with IA within ≥1 family; variants predicted damage to the structure or function of the protein by PolyPhen-2 (Polymorphism Phenotyping V2) and SIFT (Sorting Intolerance From Tolerant). We selected 10 variants from 9 genes (
GPR63
,
ADAMST15
,
MLL2
,
IL10RA
,
PAFAH2
,
THBD
,
IL11RA
,
FILIP1L
, and
ZNF222
) to form 78 candidate variants by considering commonness in families, known disease genes, or ontology association with angiogenesis. Replicate association studies revealed that only p.E133Q in
ADAMTS15
was aggregated in the familial IA cases (odds ratio, 5.96; 95% confidence interval, 2.40–14.82;
P
=0.0001; significant after the Bonferroni correction [
P
=0.05/78=0.0006]). Silencing
ADAMTS15
and overexpression of
ADAMTS15
p.E133Q accelerated endothelial cell migration, suggesting that
ADAMTS15
may have antiangiogenic activity.

Conclusions—

ADAMTS15
is a candidate gene for IAs.
The Selection of Situations by the ICC: An Empirically Based Evaluation of the otp’s Performance
Authors: Smeulers Alette , Weerdesteijn Maartje , Hola Barbora
Published: February 2015

The main aim of the International Criminal Court (icc) is to prosecute the most serious crimes of concern to the international community. One of the most valued features of the icc is the independent position of the Prosecutor in selecting situations and cases to investigate. The Prosecutor, however, has been heavily criticized for his selection policy and countries from the African Union even threatened to withdraw from the icc because of its alleged bias and unfair focus on African political leaders. In this article we present the results of our explorative study in which we empirically evaluate the situations selection policy of the icc Prosecutor. We conclude that given the icc’s limited jurisdictional reach, the Prosecutor is generally focusing on the gravest situations where international crimes are supposedly committed.
The Judgment of the German Bundesverfassungsgericht concerning Reparations for the Victims of the Varvarin Bombing
Authors: Mehring Sigrid
Published: February 2015

In August 2013, the German Federal Constitutional Court affirmed its stance against claims by individuals for reparations for violations of international humanitarian law that it had developed in previous case law. It denied reparation and compensation to be paid by the Federal Republic of Germany to the relatives of killed civilians and to civilians wounded as a consequence of the destruction of a bridge in the Serbian city of Varvarin. The bridge had been destroyed on 30 May 1999 in the course of the North Atlantic Treaty Organization’s (nato) aerial action “Allied Force” against the Federal Yugoslav Republic. The case concerned claims by survivors and family members of persons killed in the attacks. The Court rendered a joint decision on both constitutional claims and found no violation of constitutional rights.
A new species of the genus Mallomonas (Synurales, Chrysophyceae), Mallomonas fimbriata, sp. nov.
Authors: Gusev Evgeniy Sergeevich
Published: February 2015

Mallomonas fimbriata, sp. nov. is described from bog pool, located in Cam Ranh Peninsula, Khanh Hoa Province, Central Vietnam. The description is based on silica-scale morphology studied by means of transmission and scanning electron microscopy. New species has 3 types of scales: oval body scales, caudal ones with robust, long, forward pointing spines and elongated, widened to distal part apical scales. Scales are thick, 3-layered, with inner reticulation. Mallomonas fimbriata and the similar M. fenestrata form a special group with unique features of scales structure close to the sections Retrorsae and Quadratae.
Daustinia, a replacement name for Austinia (Convolvulaceae)
Authors: Buril Maria Teresa , Simões Ana Rita , Carine Mark , Alves Marccus
Published: February 2015

Buril et al. (2013) transferred a Brazilian species of Jacquemontia Choisy to the new genus Austinia Buril & A.R. Simões, named after Daniel F. Austin (1943–2015 ). However, the name Austinia was already occupied by a genus of a moss family, Fabroniaceae, described in 1875 by Johann Karl August Müller. The later homonym Austinia Buril & A.R. Simões is, therefore, not legitimate according to the Article 53.1 of the International Code of Nomenclature for Algae, Fungi and Plants (McNeill et al. 2012).
Two new species of the genus Anthroherpon Reitter, 1889 from northern Montenegro with notes on the “A. ganglbaueri” species group (Coleoptera: Leiodidae: Leptodirini)
Authors: NJUNJIĆ IVA , PERREAU MICHEL , PAVIĆEVIĆ DRAGAN
Published: February 2015

Two new species of Anthroherpon belonging to the “ganglbaueri” species group are described from northern Montenegro: Anthroherpon sinjajevina n. sp. and Anthroherpon cecai n. sp. Based on morphological investigations of other species of this group, we elevate A. udrzali Giachino & Vailati from subspecies to species rank, and suggest the synonymy of A. brckoensis Giachino & Guéorguiev with A ganglbaueri alticola Knirsch. An identification key of the ganglbaueri species group (sensu Guéorguiev, 1990) is given and the distributions of species and subspecies are mapped and discussed.
Cyathura odaliscae, a new species of anthurid isopod (Crustacea: Peracarida) from a brackish habitat on the Pacific coast of Costa Rica
Authors: HEARD RICHARD W. , VARGAS RITA
Published: February 2015

During a preliminary survey of a brackish mangrove habitat in the Terraba River delta on the Pacific coast of Costa Rica, several adult and subadult specimens of a new anthurid isopod, Cyathura odaliscae n. sp. were discovered. The specimens were collected from decaying wood in low salinity conditions (<5‰). The unique shape and complexity of the male copulatory stylet of C. odaliscae distinguishes it from the other 22 species for which males have been described. A combination of other characters (e.g., morphology of the mouth parts, body setation, shape of telson and first pereopod) is used to distinguish the female from the others within the genus. Illustrations of the known male copulatory stylets for the genus and a table listing diagnostic information, depth ranges, and general distribution for the 32 currently recognized species of Cyathura are provided.
Pelocoris balius La Rivers (Hemiptera: Heteroptera: Naucoridae) in Florida: New Status of an Enigmatic Saucer Bug
Authors: SITES ROBERT W.
Published: February 2015

The saucer bug subspecies Pelocoris femoratus balius La Rivers was described from east-central Florida and differs from the nominate subspecies by pronounced dark spotting on the fore femora, head, and pronotum. This subspecies is much less commonly encountered than is P. f. femoratus (Palisot de Beauvois), which occurs throughout Florida. Although both subspecies occur in the area, uncertainty about the taxonomic status of P. f. balius has persisted. I here elevate P. f. balius to full species status based on collections of both taxa from the same bodies of water in multiple counties and additional morphological differences to those given in the original description. A supplemental description, distribution map, and illustrations to distinguish between the two species are provided.
An Analysis of a Barotropically Unstable, High–Rossby Number Vortex in Shear
Authors: Ryglicki David R.
Published: February 2015

The interactions of the barotropic instability found at low levels in tropical cyclones and a shear forcing are presented. Previous works have indicated that at low levels of tropical cyclones, the inner edge of the core may be barotropically unstable and thereby able to support counterpropagating vortex Rossby wave interactions. It has also been demonstrated that hurricanes and other barotropic vortices possess innate, dry abilities to maintain themselves when under the duress of vertical wind shear. This work will address how these two separate processes interact with each other.

In this study, the barotropic ring is given additional vorticity in the outer regions to mimic observations more closely. This allows for the outward propagation of energy and simultaneous reduction of the radius of maximum wind. When this vortex is sheared, it is found that the shear forcing, which acts as a de facto wavenumber-1 forcing, does not noticeably alter the growth of the most unstable mode, wavenumber 3. The tilt precession of the vortex is altered greatly, as the tilt becomes both larger and slower. Palinstrophy and deformation analysis indicates that overall peak mixing is also reduced, owing to changes in the axisymmetrization process. Energetics analyses show that the radial component of the shear forcing acts to generate eddies while the tangential component of the shear tends to destroy eddies. The calculations are carried out a second time with another center-finding method, which shows the tilt to be much smaller and more variable while imparting a large wavenumber-1 signal in Fourier analyses.
Stochastic and Perturbed Parameter Representations of Model Uncertainty in Convection Parameterization*
Authors: Christensen H. M. , Moroz I. M. , Palmer T. N.
Published: February 2015

It is now acknowledged that representing model uncertainty in atmospheric simulators is essential for the production of reliable probabilistic forecasts, and a number of different techniques have been proposed for this purpose. This paper presents new perturbed parameter schemes for use in the European Centre for Medium-Range Weather Forecasts (ECMWF) convection scheme. Two types of scheme are developed and implemented. Both schemes represent the joint uncertainty in four of the parameters in the convection parameterization scheme, which was estimated using the Ensemble Prediction and Parameter Estimation System (EPPES). The first scheme developed is a fixed perturbed parameter scheme, where the values of uncertain parameters are varied between ensemble members, but held constant over the duration of the forecast. The second is a stochastically varying perturbed parameter scheme. The performance of these schemes was compared to the ECMWF operational stochastic scheme, stochastically perturbed parameterization tendencies (SPPT), and to a model that does not represent uncertainty in convection. The skill of probabilistic forecasts made using the different models was evaluated. While the perturbed parameter schemes improve on the stochastic parameterization in some regards, the SPPT scheme outperforms the perturbed parameter approaches when considering forecast variables that are particularly sensitive to convection. Overall, SPPT schemes are the most skillful representations of model uncertainty owing to convection parameterization.
Marine Boundary Layer Heights and Their Longitudinal, Diurnal, and Interseasonal Variability in the Southeastern Pacific Using COSMIC, CALIOP, and Radiosonde Data
Authors: Ho Shu-peng , Peng Liang , Anthes Richard A. , Kuo Ying-Hwa , Lin Hsiao-Chun
Published: February 2015

The spatial and temporal variability of the marine boundary layer (MBL) over the southeastern Pacific is studied using high-resolution radiosonde data from the VAMOS Ocean–Cloud–Atmosphere–Land Study Regional Experiment (VOCALS-REx), lidar cloud measurements from the CALIOP instrument on the CALIPSO satellite, radio occultation (RO) data from the COSMIC satellites, and the ERA-Interim. The height of the MBL (MBLH) is estimated using three RO-derived parameters: the bending angle, refractivity, and water vapor pressure computed from the refractivity derived from a one-dimensional variational data inversion (1D-VAR) procedure. Two different diagnostic methods (minimum gradient and break point method) are compared. The results show that, although a negative bias in the refractivity exists as a result of superrefraction, the spatial and temporal variations of the MBLH determined from the RO observations are consistent with those from CALIOP and the radiosondes. The authors find that the minimum gradient in the RO bending angle gives the most accurate estimation of the MBL height.