bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment Efficacy Differences of Sorafenib for Advanced Hepatocellular Carcinoma: A Meta-Analysis of Randomized Clinical Trials
Authors: Shao Yu-Yun , Shau Wen-Yi , Chan Soa-Yu , Lu Li-Chun , Hsu Chih-Hung , Cheng Ann-Lii
Published: January 2015

Objectives: Hepatocellular carcinoma (HCC) is a heterogeneous disease. We explored whether any specific subgroups of patients may gain more survival benefits from sorafenib as the first-line therapy for advanced HCC. Methods: PubMed and the Cochrane library were searched for phase III clinical trials that compared sorafenib with other treatments as first-line therapy for advanced HCC. We retrieved data from the published articles and then calculated synthesized hazard ratios (HRs) of overall mortality for patients of different subgroups, using patients who received other treatments as the reference. Results: Four phase III clinical trials comparing sorafenib with other treatments were included in this study. The HRs were not significantly different between patients from various geographic regions (p = 0.183), patients with different Eastern Cooperative Oncology Group performance statuses (p = 0.699), or patients with different tumor involvement (p = 0.221). By contrast, the synthesized HR for hepatitis C virus (HCV)+ patients was 0.65 [95% confidence interval (CI) 0.53-0.80], which was significantly lower than that for HCV- patients (0.87, 95% CI 0.79-0.96, p = 0.013). Conclusions: As the first-line therapy for advanced HCC, sorafenib might provide more survival benefits to HCV+ patients than to HCV- patients.
Comprehensive DNA Methylation and Extensive Mutation Analyses of HER2-Positive Breast Cancer
Authors: Yamaguchi Takeshi , Mukai Hirofumi , Yamashita Satoshi , Fujii Satoshi , Ushijima Toshikazu
Published: January 2015

Objective: Resistance to trastuzumab is a problem that remains to be solved in HER2-positive breast cancer. We aimed to characterize profiles of genetic and epigenetic alterations in cancer-related pathways in HER2-positive breast cancers, using biopsy tissue samples obtained from patients enrolled in a prospective neoadjuvant clinical trial. Methods: HER2-positive breast cancer tissue samples were collected and processed with the PAXgene Tissue System. A total of 24 breast cancers were analyzed. Genetic alterations of 409 cancer-related genes were analyzed by a bench-top next-generation sequencer. DNA methylation statuses were analyzed by a bead array with 485,512 probes. Results: The WNT pathway was potentially activated by aberrant methylation of its negative regulators, such as DKK3 and SFRP1, in 9 breast cancers. The AKT/mTOR pathway was activated by mutations of PIK3CA in 5 breast cancers. The Notch pathway was potentially activated by mutations of NOTCH1 and NOTCH2 in 4 breast cancers. The p53 pathway was inactivated by mutations of TP53 in 13 breast cancers and potentially by aberrant methylation of its downstream genes in 10 breast cancers. Cell adhesion was affected by mutations of CDH1 in 1 breast cancer. Conclusion: Genes involved in cancer-related pathways were frequently affected not only by genetic but also by epigenetic alterations in HER2-positive breast cancer.
Augmented Pentose Phosphate Pathway Plays Critical Roles in Colorectal Carcinomas
Authors: Shibuya Norisuke , Inoue Ken-ichi , Tanaka Genki , Akimoto Kazumi , Kubota Keiichi
Published: January 2015

Glycolysis and the pentose phosphate pathway (PPP) are preferentially activated in cancer cells. Accumulating evidence indicated the significance of the altered glucose metabolism in cancer, but the implication for oncotherapy remains unclear. Here we report that the synthesis of glycolytic and PPP enzymes is almost ubiquitously augmented in colorectal carcinoma (CRC) specimens. The mammalian target of rapamycin (mTOR) inhibitor INK128 (300 nM) and phytochemical Avemar (1 mg/ml) inhibited the synthesis of PPP enzymes in CRC cell lines. INK128 (150-600 nM) and resveratrol (75-300 μM) inhibited aerobic glycolysis in the cell lines. INK128 (300 nM) and Avemar (1 mg/ml) decreased the NADPH/NADP+ ratio as well as the GSH/GSSG ratio in the cell lines. Finally, per os administration of INK128 (0.8 mg/kg) or Avemar (1 g/kg) suppressed tumor growth and delayed tumor formation by transplantable CRC specimens derived from patients. Taken together, pharmacological inhibition of the mTOR-PPP axis is a promising therapeutic strategy against CRCs.
Inhibition of Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 Protects against Plasma/Hypoxia-Mediated Trophoblast Dysfunction Associated with Preeclampsia
Authors: Zhang Yan , Ye Yuanhua , Wang Yufang , Chen Weiping
Published: January 2015

Background: Preeclampsia (PE) is associated with oxidative stress in the maternal circulation and placenta. This study aimed to determine if inhibition of lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) gives protection against oxidative stress-mediated trophoblast dysfunction. Methods: Plasma and placenta samples were obtained from 106 women with PE and 106 women with normal pregnancy (NP). Oxidized low-density lipoprotein (oxLDL) and soluble LOX-1 levels were determined by enzyme-linked immunoassay. Placental LOX-1 expression was determined by western blotting. Trophoblasts were subjected to hypoxia and treated with pooled plasma from patients with PE. Expression levels of placenta growth factor (PIGF) and the soluble form of the PIGF receptor (sFlt-1) in trophoblasts were determined. Results: Plasma concentrations of oxLDL and sLOX-1 were significantly over-expressed and LOX-1 protein expression in the placenta was significantly increased in PE patients compared with matched NP controls (both p < 0.05). Exposure of trophoblasts to hypoxia and pooled PE plasma induced overexpression of sFlt-1 and downregulation of PIGF. These effects were inhibited by the LOX-1 inhibitor TS20. Conclusion: LOX-1 accumulation may contribute to the pathogenesis of PE by promoting sFlt-1 production in trophoblasts, suggesting that oxidative stress may be an important mediator regulating angiogenic pathways in trophoblasts.
The Preoperative Neutrophil/Lymphocyte Ratio Does not Correlate with the 21-Gene Recurrence Score in Estrogen Receptor-Positive Breast Cancer Patients
Authors: Grenader Tal , Plotkin Yevgeni , Geffen David B.
Published: January 2015

Aims: The aim of this study was to examine the correlation, if any, between the preoperative neutrophil/lymphocyte ratio (NLR) and the OncotypeDX™ 21-gene recurrence score (RS) in patients with early-stage estrogen receptor (ER)-positive breast cancer (BC). Materials and Methods: We retrospectively reviewed the medical records of patients diagnosed with primary ER-positive BC who were referred for the RS assay. The correlation between the preoperative NLR and the RS was analyzed. Results: For the 242 patients with sufficient data for analysis, the median age at diagnosis was 59.5 years. The tumor size ranged from 0.50 to 5.50 cm, with a mean size of 1.8 cm; 73.2% of the tumors were < 2 cm in size. Most of the tumors (66.3%) were of grade 2; the rest was nearly equally divided between grades 1 and 3. The test results for the progesterone receptor (PR) were positive in 86.6% of the cases. Lymph node metastases were present in 22.3% of the patients. The median RS was 18 (range 0-60) and the mean NLR value was 2.11 (range 0.49-7.49). We found no significant correlation between the NLR and the RS. Conclusion: Our data suggest that the preoperative NLR does not predict the 21-gene RS in patients with early-stage hormone-sensitive BC.
A Prospective Multicentric Study of Pulmonary Rehabilitation in Patients with Chronic Obstructive Pulmonary Disease and Different Clinical Phenotypes
Authors: Ambrosino Nicolino , Venturelli Elena , de Blasio Francesco , Paggiaro Pierluigi , Pasqua Franco , Vitacca Michele , Vagheggini Guido , Clini Enrico M.
Published: January 2015

Background: Recently, it has been proposed that different clinical phenotypes can be recognized in patients with chronic obstructive disease (COPD), namely predominant airway disease or parenchymal destructive changes. Objectives: The aim of this prospective multicenter study was to evaluate whether these two phenotypes may influence outcomes following a pulmonary rehabilitation program (PRP). Methods: We have prospectively evaluated 364 consecutive COPD patients (70 ± 8 years, 76.3% males) admitted to a standard hospital-based PRP in 6 Italian centers. According to their phenotype, the study cohort was divided into two groups: patients with airway obstructive (group 1, n = 208) or parenchymal destructive COPD (group 2, n = 156). Before and after PRP, values of 6-min walking distance, perceived breathlessness (Medical Research Council), health-related quality of life (St. George's Respiratory Questionnaire) and respiratory muscle function (maximal inspiratory and expiratory pressure) were recorded. Results: PRP resulted in significant improvements in all outcome measures without any significant differences between groups. Conclusions: Our study confirms that COPD patients may benefit from pulmonary rehabilitation independent of their clinical phenotype.
Single-Agent versus Combination Doxorubicin-Based Transarterial Chemoembolization in the Treatment of Hepatocellular Carcinoma: A Single-Blind, Randomized, Phase II Trial
Authors: Liu Bing , Huang Jian-wen , Li Yong , Hu Bao-shan , He Xu , Zhao Wei , Zheng You-bing , Lu Li-gong
Published: January 2015

Objectives: It was the aim of this study to find an optimal therapeutic regimen of transarterial chemoembolization (TACE) by comparing the efficacy of chemoembolization with different anticancer agents in hepatocellular carcinoma (HCC) patients. Methods: A single-blind, three-group parallel, randomized trial was conducted in Guangdong General Hospital, Guangzhou, China, with patients with biopsy-confirmed HCC. Group 1 received single-drug (doxorubicin) chemoembolization, while group 2 received double-drug (doxorubicin and mitomycin C) chemoembolization. Patients in group 3 were treated with triple-drug (doxorubicin, mitomycin C, and gemcitabine) chemoembolization. Lipiodol was used as embolization agent in all protocols. We compared the overall survival (OS), time to progression (TTP), and objective response rate (ORR) between groups. Response assessment was performed according to modified RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Results: Between January 2008 and January 2011, 162 patients (group 1, n = 50; group 2, n = 59; group 3, n = 53) were recruited. The OS and TTP in groups 1, 2, and 3 were 14.9 and 6.4, 13.2 and 6.4, and 20.5 and 6.8 months, respectively. OS and TTP were statistically significant among groups (p = 0.002 and p = 0.037). The ORR was 22.0, 40.7, and 56.6%, respectively. The ORR was significantly different across the three groups (p < 0.002). Conclusions: TACE with multiple chemotherapeutic agents might significantly increase survival and tumor response; additionally, gemcitabine was likely to have an advantage in improving the prognosis of HCC patients.
Complete Androgen Insensitivity Syndrome Associated with Male Gender Identity or Female Precocious Puberty in the Same Family
Authors: Bermúdez de la Vega José A. , Fernández-Cancio Mónica , Bernal Susana , Audí Laura
Published: January 2015

In 4 complete androgen insensitivity syndrome (CAIS) members of one family, 2 presented extreme and unusual clinical features: male gender identity disorder (case 1) and female precocious central puberty (case 2). The AR gene carried the mutation c.1752C>G, p.Phe584Leu. Gender dysphoria in CAIS may be considered as a true transgender and has been described in 3 other cases. Central precocious puberty has only been described in 1 case; Müllerian ducts in case 2 permitted menarche. Despite the common CAIS phenotype, there was a familial disparity for gender identity adequacy and timing and type of puberty.
Changes in Prognostic and Therapeutic Parameters in Prostate Cancer from an Epidemiological View over 20 Years
Authors: Dörr Martin , Hölzel Dieter , Schubert-Fritschle Gabriele , Engel Jutta , Schlesinger-Raab Anne
Published: January 2015

Background: The study objective was to examine changes in prognosis and treatment of prostate cancer patients over 20 years and to evaluate their impact on survival. Patients and Methods: 38,861 prostate cancer patients diagnosed between 1990 and 2010 and living in the catchment area of the Munich Cancer Registry were analysed. Results: Pre-therapeutic prostate-specific antigen (PSA) testing increased substantially in the early 1990s. A shift from capsule-exceeding tumours to capsule-limited tumours also took place especially in the 1990s. The proportion of radical prostatectomy increased continuously over the last 20 years from 20% to almost 50% whereas hormone therapy decreased from 55% to 18%. Radiation therapy and transurethral resection of the prostate increased slightly from about 5% to 10%. The 5- and 10-year relative survival rates increased from 92% to 97% and from 86% to 92%, respectively. Conclusions: 2 reasons may account for the rise in survival rates over 20 years: First, the establishment of widely used PSA testing resulted in a shift towards more favourable T categories due to the detection of many additional small tumours as well as the noticeable change in initial treatment strategy towards more radical prostatectomies. The second factor that likely increased survival was improvements in the therapies themselves.
Association of Peripheral Total and Differential Leukocyte Counts with Obesity-Related Complications in Young Adults
Authors: Yoshimura Aya , Ohnishi Shunsuke , Orito Chieko , Kawahara Yukako , Takasaki Hiroyo , Takeda Hiroshi , Sakamoto Naoya , Hashino Satoshi
Published: January 2015

Objective: Obesity has been demonstrated to be associated with elevated leukocytes in adults and children. This study assessed the associations between peripheral total and differential leukocyte counts and obesity-related complications in young adults. Methods: 12 obese (median age 21.5 (range 19-28) years, median BMI 35.7 (range 32.0-44.9) kg/m2) and 11 normal (median age 23 (range 18-27) years, median BMI 19.5 (range 18.1-21.7) kg/m2) adults were enrolled. Complete blood count and serum levels of liver enzymes, fasting blood glucose, insulin and lipids were measured, and the homeostasis model assessment of insulin resistance was calculated. Fat mass was calculated using a bioimpedance analysis device, and ultrasonography was performed to measure fat thickness and to detect fatty change of the liver. Results: Total leukocyte and monocyte counts were significantly increased in obese young adults. Total leukocyte count was associated with liver enzyme levels, insulin resistance as well as visceral and subcutaneous fat thickness. Neutrophil count was associated with insulin resistance. Lymphocyte count was associated with serum liver enzymes, insulin resistance, and dyslipidemia. Monocyte count was associated with serum liver enzyme, insulin resistance, visceral and subcutaneous fat thickness, body fat mass, and percentage body fat. Conclusion: The results of this study suggest that chronic low-grade systemic inflammation is associated with obesity-related complications such as nonalcoholic fatty liver disease, insulin resistance, and dyslipidemia in young adults.
Assessment of Processes of Change for Weight Management in a UK Sample
Authors: Andrés Ana , Saldaña Carmina , Beeken Rebecca J.
Published: January 2015

Objective: The present study aimed to validate the English version of the Processes of Change questionnaire in weight management (P-Weight). Methods: Participants were 1,087 UK adults, including people enrolled in a behavioural weight management programme, university students and an opportunistic sample. The mean age of the sample was 34.80 (SD = 13.56) years, and 83% were women. BMI ranged from 18.51 to 55.36 (mean = 25.92, SD = 6.26) kg/m2. Participants completed both the stages and processes questionnaires in weight management (S-Weight and P-Weight), and subscales from the EDI-2 and EAT-40. A refined version of the P-Weight consisting of 32 items was obtained based on the item analysis. Results: The internal structure of the scale fitted a four-factor model, and statistically significant correlations with external measures supported the convergent validity of the scale. Conclusion: The adequate psychometric properties of the P-Weight English version suggest that it could be a useful tool to tailor weight management interventions.
Typical and Atypical Pituitary Adenomas: A Single-Center Analysis of Outcome and Prognosis
Authors: Chiloiro Sabrina , Doglietto Francesco , Trapasso Barbara , Iacovazzo Donato , Giampietro Antonella , Di Nardo Francesco , de Waure Chiara , Lauriola Libero , Mangiola Annunziato , Anile Carmelo , Maira Giulio , De Marinis Laura , Bianchi Antonio
Published: January 2015

Background and Objective: In 2004, the World Health Organization defined atypical pituitary adenomas as those with a Ki-67 expression >3%, an excessive p53 expression and increased mitotic activity. As the usefulness of this classification is controversial, we reviewed typical and atypical pituitary adenomas to compare the clinical and prognostic features. Patients and Methods: We retrospectively reviewed 343 consecutive pituitary adenomas. Atypical pituitary adenomas represented 18.7% of cases. All patients were operated on at the Department of Neurosurgery of our institution and were followed up at the Hypothalamic-Pituitary Disease Unit of the same institution. The median follow-up time was 75 months (range 7-345). Results: Younger age at diagnosis as well as immunohistochemical positivity for adrenocorticotropic hormone and prolactin correlated with a higher risk of atypical pituitary adenomas, whereas typical and atypical pituitary adenomas did not differ with regard to gender, tumor size, recurrence risk and disease-free survival time (DFST). Among the 219 patients who underwent radical surgery, a Ki-67 expression ≥1.5% was associated with a higher risk of recurrence and a worse DFST, even after correction for age at diagnosis, gender, immunohistochemical classification, tumor size, invasiveness and Knosp classification [p = 0.01; hazard ratio (HR) 2.572; 95% confidence interval (CI) 1.251-5.285). Pituitary adenomas with a Ki-67 expression ≥1.5% showed a worse DFST as compared to pituitary adenomas with a Ki-67 expression <1.5% (HR 2.166; 95% CI 1.154-4.064). Conclusion: In this series, atypical and typical pituitary adenomas did not differ with regard to recurrence and DFST. Pituitary adenomas with a Ki-67 expression ≥1.5% showed a higher recurrence risk and a worse DFST as compared to those with a Ki-67 expression <1.5%. We suggest that a Ki-67 expression ≥1.5% may be useful as a prognostic marker, though this will need to be confirmed by prospective, multicenter data.
Bone and Joint Disorders in Acromegaly
Authors: Claessen Kim M.J.A. , Mazziotti Gherardo , Biermasz Nienke R. , Giustina Andrea
Published: January 2015

Acromegaly is a chronic, progressive disease caused by a growth hormone (GH)-producing pituitary adenoma, resulting in elevated GH and insulin-like growth factor 1 concentrations. Following appropriate therapy (surgery, radiotherapy and/or medical treatment), many systemic GH-induced comorbid conditions improve considerably. Unfortunately, despite biochemical control, acromegaly patients suffer from a high prevalence of late manifestations of transient GH excess, significantly impairing their quality of life. In this overview article, we summarize the pathophysiology, diagnosis, clinical picture, disease course and management of skeletal complications of acromegaly, focusing on vertebral fractures and arthropathy.
Type and intensity of FVIII exposure on inhibitor development in PUPs with haemophilia A
Authors: Elisa Mancuso Maria , Santagostino Elena , Kenet Gili , Elalfy Mohssen , Holzhauer Susanne , Bidlingmaier Christoph , Escuriola Ettingshausen Carmen , Iorio Alfonso , Nowak-Göttl Ulrike , Marcucci Maura
Published: January 2015

The impact of treatment-related factors on inhibitor development in previously untreated patients (PUPs) with haemophilia A is still debated. We present the results of a collaborative, individual patient data meta-analytic project. Eligible data sources were published cohorts of PUPs for which patient-level data were available. The exposures of interest were factor (F)VIII type (recombinant [rFVIII] vs plasma-derived [pdFVIII]) and treatment intensity (≥ vs < 150 IU/kg/week) at first treatment. Family history of inhibitors, F8 mutations, age, treatment regimen (on-demand vs prophylaxis), secular trend and surgery were analysed as putative confounders using different statistical approaches (multivariable Cox regression, propensity score analyses, CART). Analyses accounted for the multi-centre origin of the data. We included 761 consecutive, unselected PUPs with moderate to severe haemophilia A from 10 centres in Egypt, Germany, Israel and Italy. A total of 27 % of patients developed inhibitors; 40 % and 22 % of patients treated with rFVIII and pdFVIII (unadjusted HR 2.2, 95 % CI 1.6–2.9), respectively; 51 % and 24 % of patients receiving high-and low-intensity treatment (unadjusted HR 2.9, 95 % CI 2.0–4.2), respectively. In adjusted analyses, only treatment intensity remained an independent predictor; the effect of FVIII type was largely due to confounding, but with a significant interaction between FVIII type and treatment intensity. This patient-level meta-analysis confirms, across different statistical approaches, that high-intensity treatment is a strong risk factor for inhibitor development. The possible role of FVIII type in subgroups is suggested by the test for interactions but could not be proven because of the limited subgroups sample sizes.
Hydrogels With Integrin-Binding Angiopoietin-1–Derived Peptide, QHREDGS, for Treatment of Acute Myocardial Infarction
Authors: Reis Lewis A. , Chiu Loraine L.Y. , Wu Jun , Feric Nicole , Laschinger Carol , Momen Abdul , Li Ren-Ke , Radisic Milica
Published: January 2015

Background—

Hydrogels are being actively investigated for direct delivery of cells or bioactive molecules to the heart after myocardial infarction (MI) to prevent cardiac functional loss. We postulate that immobilization of the prosurvival angiopoietin-1–derived peptide, QHREDGS, to a chitosan-collagen hydrogel could produce a clinically translatable thermoresponsive hydrogel to attenuate post-MI cardiac remodeling.

Methods and Results—

In a rat MI model, QHREDGS-conjugated hydrogel (QHG213H), control gel, or PBS was injected into the peri-infarct/MI zone. By in vivo tracking and chitosan staining, the hydrogel was demonstrated to remain in situ for 2 weeks and was cleared in ≈3 weeks. By echocardiography and pressure–volume analysis, the QHG213H hydrogel significantly improved cardiac function compared with the controls. Scar thickness and scar area fraction were also significantly improved with QHG213H gel injection compared with the controls. There were significantly more cardiomyocytes, determined by cardiac troponin-T staining, in the MI zone of the QHG213H hydrogel group; and hydrogel injection did not induce a significant inflammatory response as assessed by polymerase chain reaction and an inflammatory cytokine assay. The interaction of cardiomyocytes and cardiac fibroblasts with QHREDGS was found to be mediated by β
1
-integrins.

Conclusions—

We demonstrated for the first time that the QHG213H peptide–modified hydrogel can be injected in the beating heart where it remains localized for a clinically effective period. Moreover, the QHG213H hydrogel induced significant cardiac functional and morphological improvements after MI relative to the controls.
Reference Values for Pulse Wave Doppler and Tissue Doppler Imaging in Pediatric Echocardiography
Authors: Dallaire Frederic , Slorach Cameron , Hui Wei , Sarkola Taisto , Friedberg Mark K. , Bradley Timothy J. , Jaeggi Edgar , Dragulescu Andreea , Har Ronnie L.H. , Cherney David Z.I. , Mertens Luc
Published: January 2015

Background—

In pediatric echocardiography, pulse wave Doppler, and tissue Doppler imaging velocities are widely used to assess cardiac function. Current reference values and
Z
scores, allowing adjustment for growth are limited by inconsistent methodologies and small sample size. Using a standardized approach for parametric modeling and
Z
score quality assessment, we propose new pediatric reference values and
Z
score equations for most left ventricular pulse wave Doppler and tissue Doppler imaging measurements.

Methods and Results—

Two hundred thirty-three healthy pediatric subjects 1 to 18 years of age were prospectively recruited. Thirteen pulse wave Doppler and 14 tissue Doppler imaging measurements were recorded. Normalization for growth was done via a complete and standardized approach for parametric nonlinear regression modeling. Several analyses were performed to ensure adequate
Z
score distribution and to detect potential residual associations with growth or residual heteroscedasticity. Most measurements adopted a nonlinear relationship with growth and displayed significant heteroscedasticity. Compared with age, height, and weight, normalization for body surface area was most efficient in removing the effect of growth. Generally, polynomial and allometric models yielded adequate goodness-of-fit. Residual values for several measurements had significant departure from the normal distribution, which could be corrected using logarithmic or reciprocal transformation. Overall, weighted parametric nonlinear models allowed us to compute
Z
score equations with adequate normal distribution and without residual association with growth.

Conclusions—

We present
Z
scores for normalized pulse wave Doppler and tissue Doppler imaging in pediatric echocardiography. Further studies are needed to define the threshold beyond which health becomes a disease by integrating other important factors such as ventricular morphology, loading conditions, and heart rate.
Molecular Mechanisms of Autophagy in the Cardiovascular System
Authors: Gatica Damián , Chiong Mario , Lavandero Sergio , Klionsky Daniel J.
Published: January 2015

Autophagy is a catabolic recycling pathway triggered by various intra- or extracellular stimuli that is conserved from yeast to mammals. During autophagy, diverse cytosolic constituents are enveloped by double-membrane vesicles, autophagosomes, which later fuse with lysosomes or the vacuole to degrade their cargo. Dysregulation in autophagy is associated with a diverse range of pathologies including cardiovascular disease, the leading cause of death in the world. Accordingly, there is tremendous interest in modulating autophagy for therapeutic purposes. One complexity with regard to cardiovascular homeostasis, however, is that the timing of autophagic activity appears to be critical; for example, cardiomyocyte autophagy during ischemia/reperfusion can be either beneficial or harmful. Here, we review the molecular mechanisms that govern autophagosome formation and analyze the link between autophagy and cardiovascular disease.
Regulation of Signal Transduction by Reactive Oxygen Species in the Cardiovascular System
Authors: Brown David I. , Griendling Kathy K.
Published: January 2015

Oxidative stress has long been implicated in cardiovascular disease, but more recently, the role of reactive oxygen species (ROS) in normal physiological signaling has been elucidated. Signaling pathways modulated by ROS are complex and compartmentalized, and we are only beginning to identify the molecular modifications of specific targets. Here, we review the current literature on ROS signaling in the cardiovascular system, focusing on the role of ROS in normal physiology and how dysregulation of signaling circuits contributes to cardiovascular diseases, including atherosclerosis, ischemia–reperfusion injury, cardiomyopathy, and heart failure. In particular, we consider how ROS modulate signaling pathways related to phenotypic modulation, migration and adhesion, contractility, proliferation and hypertrophy, angiogenesis, endoplasmic reticulum stress, apoptosis, and senescence. Understanding the specific targets of ROS may guide the development of the next generation of ROS-modifying therapies to reduce morbidity and mortality associated with oxidative stress.
Therapeutic Targeting of Autophagy
Authors: Orogo Amabel M. , Gustafsson Åsa B.
Published: January 2015

Autophagy is an evolutionarily conserved process by which long-lived proteins and organelles are sequestered by autophagosomes and subsequently degraded by lysosomes for recycling. Autophagy is important for maintaining cardiac homeostasis and is a survival mechanism that is upregulated during stress or starvation. Accumulating evidence suggests that dysregulated or reduced autophagy is associated with heart failure and aging. Thus, modulating autophagy represents an attractive future therapeutic target for treating cardiovascular disease. Activation of autophagy is generally considered to be cardioprotective, whereas excessive autophagy can lead to cell death and cardiac atrophy. It is important to understand how autophagy is regulated to identify ideal therapeutic targets for treating disease. Here, we discuss the key proteins in the core autophagy machinery and describe upstream regulators that respond to extracellular and intracellular signals to tightly coordinate autophagic activity. We review various genetic and pharmacological studies that demonstrate the important role of autophagy in the heart and consider the advantages and limitations of approaches that modulate autophagy.
Autophagy in Vascular Disease
Authors: De Meyer Guido R.Y. , Grootaert Mandy O.J. , Michiels Cédéric F. , Kurdi Ammar , Schrijvers Dorien M. , Martinet Wim
Published: January 2015

Autophagy is a reparative, life-sustaining process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. Growing evidence reveals that basal autophagy is an essential in vivo process mediating proper vascular function. Moreover, autophagy is stimulated by many stress-related stimuli in the arterial wall to protect endothelial cells and smooth muscle cells against cell death and the initiation of vascular disease, in particular atherosclerosis. Basal autophagy is atheroprotective during early atherosclerosis but becomes dysfunctional in advanced atherosclerotic plaques. Little is known about autophagy in other vascular disorders, such as aneurysm formation, arterial aging, vascular stiffness, and chronic venous disease, even though autophagy is often impaired. This finding highlights the need for pharmacological interventions with compounds that stimulate the prosurvival effects of autophagy in the vasculature. A large number of animal studies and clinical trials have indicated that oral or stent-based delivery of the autophagy inducer rapamycin or derivatives thereof, collectively known as rapalogs, effectively inhibit the basic mechanisms that control growth and destabilization of atherosclerotic plaques. Other autophagy-inducing drugs, such as spermidine or add-on therapy with widely used antiatherogenic compounds, including statins and metformin, are potentially useful to prevent vascular disease with minimal adverse effects.
The Role of Autophagy in Vascular Biology
Authors: Nussenzweig Samuel C. , Verma Subodh , Finkel Toren
Published: January 2015

There is increasing interest in the role of autophagic flux in maintaining normal vessel wall biology and a growing suspicion that autophagic dysregulation may be a common pathway through which vascular aging and associated pathologies develop. Within endothelial and smooth muscle cells, diverse but important triggers that range from oxidized lipids to β-amyloid seem to stimulate autophagosome formation potently. In addition, emerging evidence links autophagy to a wide array of vascular processes ranging from angiogenesis to calcification of the vessel wall. Alterations in autophagic flux are also increasingly being implicated in disease processes that include both atherosclerosis and pulmonary hypertension. Finally, recent insights point toward an important role of autophagy in the paracrine regulation of vasoactive substances from the endothelium. Here, we review the progress in understanding how autophagy can contribute to vascular biology and the emerging strategies to target this process for therapeutic benefit.
Antiandrogenic Therapy With Finasteride Attenuates Cardiac Hypertrophy and Left Ventricular Dysfunction
Authors: Zwadlo Carolin , Schmidtmann Elisa , Szaroszyk Malgorzata , Kattih Badder , Froese Natali , Hinz Hebke , Schmitto Jan Dieter , Widder Julian , Batkai Sandor , Bähre Heike , Kaever Volkhard , Thum Thomas , Bauersachs Johann , Heineke Joerg
Published: January 2015

Background—

In comparison with men, women have a better prognosis when experiencing aortic valve stenosis, hypertrophic cardiomyopathy, or heart failure. Recent data suggest that androgens like testosterone or the more potent dihydrotestosterone contribute to the development of cardiac hypertrophy and failure. Therefore, we analyzed whether antiandrogenic therapy with finasteride, which inhibits the generation of dihydrotestosterone by the enzyme 5-α-reductase, improves pathological ventricular remodeling and heart failure.

Methods and Results—

We found a strongly induced expression of all 3 isoforms of the 5-α-reductase (Srd5a1 to Srd5a3) in human and mouse hearts with pathological hypertrophy, which was associated with increased myocardial accumulation of dihydrotestosterone. Starting 1 week after the induction of pressure overload by transaortic constriction, mice were treated with finasteride for 2 weeks. Cardiac function, hypertrophy, dilation, and fibrosis were markedly improved in response to finasteride treatment in not only male, but also in female mice. In addition, finasteride also very effectively improved cardiac function and mortality after long-term pressure overload and prevented disease progression in cardiomyopathic mice with myocardial Gαq overexpression. Mechanistically, finasteride, by decreasing dihydrotestosterone, potently inhibited hypertrophy and Akt-dependent prohypertrophic signaling in isolated cardiac myocytes, whereas the introduction of constitutively active Akt blunted these effects of finasteride.

Conclusions—

Finasteride, which is currently used in patients to treat prostate disease, potently reverses pathological cardiac hypertrophy and dysfunction in mice and might be a therapeutic option for heart failure.
Dysfunction in the βII Spectrin–Dependent Cytoskeleton Underlies Human Arrhythmia
Authors: Smith Sakima A. , Sturm Amy C. , Curran Jerry , Kline Crystal F. , Little Sean C. , Bonilla Ingrid M. , Long Victor P. , Makara Michael , Polina Iuliia , Hughes Langston D. , Webb Tyler R. , Wei Zhiyi , Wright Patrick , Voigt Niels , Bhakta Deepak , Spoonamore Katherine G. , Zhang Chuansheng , Weiss Raul , Binkley Philip F. , Janssen Paul M. , Kilic Ahmet , Higgins Robert S. , Sun Mingzhai , Ma Jianjie , Dobrev Dobromir , Zhang Mingjie , Carnes Cynthia A. , Vatta Matteo , Rasband Matthew N. , Hund Thomas J. , Mohler Peter J.
Published: January 2015

Background—

The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked to cardiac pathologies, including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction and cardiac electric activity is not well understood and often overlooked in the cardiac arrhythmia field.

Methods and Results—

Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the posttranslational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction, leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electric and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes, including the Na/Ca exchanger, ryanodine receptor 2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin–deficient mice.

Conclusions—

Our findings identify βII spectrin as critical for normal myocyte electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.
Reactive Oxygen Metabolites are Closely Associated With the Diagnosis and Prognosis of Coronary Artery Disease
Authors: Hirata Yoshihiro , Yamamoto Eiichiro , Tokitsu Takanori , Kusaka Hiroaki , Fujisue Koichiro , Kurokawa Hirofumi , Sugamura Koichi , Maeda Hirofumi , Tsujita Kenichi , Kaikita Koichi , Hokimoto Seiji , Sugiyama Seigo , Ogawa Hisao
Published: January 2015

Background

Reactive oxygen species (
ROS
) are associated with development of coronary artery disease (
CAD
). However, there's no useful biomarker of
ROS
in
CAD
.

Methods and Results

We recruited 395 consecutive
CAD
patients who were performed coronary angiography (262 male and 133 female, age 70.2±10), and we measured serum derivatives of reactive oxidative metabolites (
DROM
) were measured. Two hundred twenty‐seven non‐
CAD
patients were also enrolled. We performed follow‐up study in these 395
CAD
patients and case‐control study after risk factor and 1:1 pair matching (both, n=163). As subgroup analysis,
DROM
were also measured at the aortic root and the coronary sinus in 59
CAD
patients.
DROM
were significantly higher in
CAD
patients (n=163, median [inter‐quartile range,
IQR
]=338 [302 to 386]) than in risk factor‐matched non‐
CAD
patients (n=163, 311 [282 to 352.5], effect size=0.33,
P
<0.001). During a mean follow‐up period of 20 months of 395
CAD
patients, 83 cardiovascular events were recorded. Kaplan‐Meier analysis showed a higher probability of cardiovascular events in the high‐
DROM
group (>346 U.CARR) than in the low‐
DROM
group (≤346 U.CARR) (
P
=0.001 [log‐rank test]). Multivariate Cox hazard analysis identified ln‐
DROM
as an independent predictor for cardiovascular events (hazard ratio: 10.8, 95% confidence interval: 2.76 to 42.4,
P
=0.001). The transcardiac gradient of
DROM
was significantly higher in
CAD
patients than in non‐
CAD
patients (−2.0 [−9.0 to 9.0] versus 8 [−8.0 to 28.3], effect size=0.21,
P
=0.04), indicating that
DROM
production in coronary circulation is associated with development of
CAD
.

Conclusion

DROM
are increased in
CAD
patients and associated with future cardiovascular events.
DROM
might provide clinical benefits for risk stratification of
CAD
.

Clinical Trial Registration

URL:
http://www.umin.ac.jp/ctr/
. Unique identifier: UMIN000012990.
The Effects of Short-term and Long-term Learning on the Responses of Lateral Intraparietal Neurons to Visually Presented Objects
Authors: Sigurdardottir Heida M. , Sheinberg David L.
Published: January 2015

The lateral intraparietal area (LIP) is thought to play an important role in the guidance of where to look and pay attention. LIP can also respond selectively to differently shaped objects. We sought to understand to what extent short-term and long-term experience with visual orienting determines the responses of LIP to objects of different shapes. We taught monkeys to arbitrarily associate centrally presented objects of various shapes with orienting either toward or away from a preferred spatial location of a neuron. The training could last for less than a single day or for several months. We found that neural responses to objects are affected by such experience, but that the length of the learning period determines how this neural plasticity manifests. Short-term learning affects neural responses to objects, but these effects are only seen relatively late after visual onset; at this time, the responses to newly learned objects resemble those of familiar objects that share their meaning or arbitrary association. Long-term learning affects the earliest bottom–up responses to visual objects. These responses tend to be greater for objects that have been associated with looking toward, rather than away from, LIP neurons' preferred spatial locations. Responses to objects can nonetheless be distinct, although they have been similarly acted on in the past and will lead to the same orienting behavior in the future. Our results therefore indicate that a complete experience-driven override of LIP object responses may be difficult or impossible. We relate these results to behavioral work on visual attention.
Type studies on Archilejeunea (Lejeuneaceae, Marchantiophyta): five new synonyms and a new combination
Authors: Shi Xue-Qin , Gradstein S. Robbert , Zhu Rui-Liang
Published: January 2015

Archilejeunea (Spruce 1884: 88) Stephani (1888: 113) is a pantropical genus with about 28 species in two subgenera, subg. Archilejeunea with five species and the remaining ones in subg. Dibrachiella (Spruce 1884: 90) Schiffner (1893: 130) (Gradstein & Buskes 1985). The genus has been well-studied in the Neotropics and Australia (Gradstein & Buskes 1985; Thiers & Gradstein 1989; Gradstein 1994; Gradstein & Schäfer-Verwimp 2012) but the treatments of the African and Asiatic species are incomplete or outdated (e.g., Stephani 1911; Verdoorn 1934; Vanden Berghen 1951; Udar & Awasthi 1981a, 1982; Mizutani 1993; Gradstein et al. 2002). Several species have not been studied since their first publication. Moreover, recent molecular-phylogenetic studies indicate that Archilejeunea is not monophyletic (Wilson et al. 2007). Members of A. subg. Archilejeunea were resolved in a clade with Caudalejeunea (Stephani 1890: 18) Schiffner (1893: 129) and Schiffneriolejeunea Verdoorn (1933: 89), while those of A. subg. Dibrachiella resolved in a distant clade with species of Spruceanthus Verdoorn (1934: 151) and Ptychanthus Nees (1838: 211). As a result, the genus urgently needs revision.
Revision of the Genus Crioprosopus Audinet-Serville, and description of three new genera of Trachyderini (Coleoptera: Cerambycidae: Cerambycinae)
Authors: EYA BRYAN K.
Published: January 2015

The genera Callona Waterhouse, 1840 and Crioprosopus Audinet-Serville, 1834 (Coleoptera: Cerambycidae: Cerambycinae: Trachyderini) are revised. The genus Callona is synonymized with Crioprosopus, and new genera, Callistochroma gen. nov., Megapurpuricenus gen. nov. and Pilostenaspis gen. nov. are described. Five species, three previously included in Callona [C. flavofasciata Chemsak & Hovore, 2011, lampros (Bates, 1885), and rutilans (Bates 1869)], and two from Crioprosopus [C. cacicus (Bates, 1885) and viridipennis (Latreille, 1811)], are transferred to Callistochroma, with viridipennis designated as the type species. Two species, one previously described as Crioprosopus (C. lateralis LeConte, 1884) and another from Stenaspis Audinet-Serville (S. pilosella Bates, 1892), are transferred into Pilostenaspis, with lateralis designated as the type species. Crioprosopus magnificus (LeConte, 1875) is transferred into Megapurpuricenus, and designated as the type species. Keys to the above genera and species along with illustrations of the available species in color are included. New species described include: Pilostenaspis copei sp. nov. from Mexico; Crioprosopus wappesi sp. nov. from Guatemala; Crioprosopus hondurensis sp. nov. from Honduras; Callistochroma chrysiptera sp. nov. and Crioprosopus chiriquiensis sp. nov. from Panama, and Callistochroma viridipurpurea sp. nov. from Colombia.
Papuadocus blodiwai gen. nov., sp. nov. (Crustacea: Amphipoda: Maeridae), a new bathyal species associated with sunken wood in the Bismarck Sea (Papua New Guinea)
Authors: CORBARI LAURE , SORBE JEAN CLAUDE
Published: January 2015

A new species belonging to a new genus of Maeridae, Papuadocus blodiwai gen. nov., sp. nov., is described from bathyal bottoms of the Bismarck Sea (Papua New Guinea). This genus/species can be distinguished from most other known maerids by right and left maxillas 1 with asymmetrical palps and by gnathopod 2 not sexually dimorphic. Its closest relative is the genus Bathyceradocus also characterized by asymmetrical maxillas 1, but differing by the presence of gill on coxae 7. These observations lead to the conclusion that the diagnosis of the family Maeridae has to be amended to receive both             Bathyceradocus and Papuadocus genera. All the collected specimens lived in association with sunken wood, at 500–580 m depth.
Notes on some Indo-Pacific Caridean shrimps (Crustacea: Decapoda: Caridea: Palaemonidae and Gnathophyllidae) particularly from India
Authors: PRAKASH SANJEEVI , KUMAR THIPRAMALAI THANGAPPAN AJITH , SUBRAMONIAM THANUMALAYA
Published: January 2015

Although among the less conspicuous members of the tropical shallow reef fauna, the caridean shrimps are not less abundant. Much scope for further study on the marine carideans of Indian waters still exists and many species must certainly remain to be discovered. Although, the recent checklist on prawn fauna of Indian waters reports 285 species of caridean shrimps (including fresh water forms) (Radhakrishnan et al, 2012). With this, the present study also contributes another report on the documentation of six species of caridean shrimps from the Gulf of Mannar and Lakshadweep waters of Indian peninsula. Out of six species Ancylomenes magnificus (Bruce), Periclimenes soror Nobili, Stegopontonia commensalis Nobili, Gnathophyllum americanum Guerin Meneville and Gnathophylloides mineri Schmitt are new to the Indian fauna. In the present paper, detailed notes on species description, color pattern, distribution, habitat and hosts were discussed.
Larvae of Hydromanicus (Insecta: Trichoptera: Hydropsychidae) from Thailand
Authors: PROMMI TAENG ON , PERMKAM SURAKRAI
Published: January 2015

Larvae of only 2 of the 13 species of Hydromanicus known from Thailand have been described previously. In this research, the “metamorphotype method” was used to associate yet-unidentifiable larvae and pupae with their identifiable adults: Pupal identifications were based on genitalic features in common with described adults, and larvae were associated with the pupae. Herein, the final larval instar of Hydromanicus malayanus, H. abiud and H. inferior are described and illustrated.
A new Triodopsis juxtidens subspecies (Gastropoda: Pulmonata) from West Virginia, U.S.A.
Authors: HOTOPP KENNETH P.
Published: January 2015

The Appalachian Mountains of North America hold a unique diversity of land snails, including those within the family Polygyridae genus Triodopsis. West Virginia has ten or more representatives of the genus (Hubricht, 1985), displaying variations upon the conchological theme of a depressed heliciform shape with a reflected peristome bearing three lamellae. However, it remains unclear whether all of the recognized variants on this theme represent species as commonly defined. In the case of the Triodopsis juxtidens (Pilsbry, 1894) subgroup as defined by Emberton (1988)—T. juxtidens, T. discoidea (Pilsbry, 1904), T. neglecta (Pilsbry, 1899), and T. pendula Hubricht, 1952—no penial morphology or allozyme differences are known (Emberton, 1988). Conversely, mitochondrial DNA analysis that included five T. juxtidens specimens suggests this putative species is not monophyletic (Perez et al., 2014). Rampant variation in shell morphology among Triodopsis species creates further taxonomic and identification challenges. Without additional supporting evidence for species-level differences, such as anatomical and genetic analyses, a conservative taxonomic approach is to recognize regionally distinct forms as subspecies. A unique form from the upper Bluestone River watershed is described here as Triodopsis juxtidens robinae subsp. nov.