bluuebunny/crossref_metadata_2025 huggingface dataset:
Preclinical Anticancer Efficacy of BET Bromodomain Inhibitors Is Determined by the Apoptotic Response
Authors: Conery Andrew R. , Centore Richard C. , Spillane Kerry L. , Follmer Nicole E. , Bommi-Reddy Archana , Hatton Charlie , Bryant Barbara M. , Greninger Patricia , Amzallag Arnaud , Benes Cyril H. , Mertz Jennifer A. , Sims Robert J.
Published: January 2016

Small-molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are being tested in clinical trials for a variety of cancers, but patient selection strategies remain limited. This challenge is partly attributed to the heterogeneous responses elicited by BET inhibition (BETi), including cellular differentiation, senescence, and death. In this study, we performed phenotypic and gene-expression analyses of treatment-naive and engineered tolerant cell lines representing human melanoma and leukemia to elucidate the dominant features defining response to BETi. We found that de novo and acquired tolerance to BETi is driven by the robustness of the apoptotic response, and that genetic or pharmacologic manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further reveal that the expression signatures of the apoptotic genes BCL2, BCL2L1, and BAD significantly predict response to BETi. Taken together, our findings highlight the apoptotic program as a determinant of response to BETi, and provide a molecular basis for patient stratification and combination therapy development. Cancer Res; 76(6); 1313–9. ©2016 AACR.
Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin–GUCY2C Paracrine Signaling Axis
Authors: Lin Jieru E. , Colon-Gonzalez Francheska , Blomain Erik , Kim Gilbert W. , Aing Amanda , Stoecker Brian , Rock Justin , Snook Adam E. , Zhan Tingting , Hyslop Terry M. , Tomczak Michal , Blumberg Richard S. , Waldman Scott A.
Published: January 2016

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin–GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide. Cancer Res; 76(2); 339–46. ©2016 AACR.
Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110β
Authors: Nakanishi Yoshito , Walter Kimberly , Spoerke Jill M. , O'Brien Carol , Huw Ling Y. , Hampton Garret M. , Lackner Mark R.
Published: January 2016

Activation of the PI3K pathway occurs commonly in a wide variety of cancers. Experience with other successful targeted agents suggests that clinical resistance is likely to arise and may reduce the durability of clinical benefit. Here, we sought to understand mechanisms underlying resistance to PI3K inhibition in PTEN-deficient cancers. We generated cell lines resistant to the pan-PI3K inhibitor GDC-0941 from parental PTEN-null breast cancer cell lines and identified a novel PIK3CB D1067Y mutation in both cell lines that was recurrent in cancer patients. Stable expression of mutant PIK3CB variants conferred resistance to PI3K inhibition that could be overcome by downstream AKT or mTORC1/2 inhibitors. Furthermore, we show that the p110β D1067Y mutant was highly activated and induced PIP3 levels at the cell membrane, subsequently promoting the localization and activation of AKT and PDK1 at the membrane and driving PI3K signaling to a level that could withstand treatment with proximal inhibitors. Finally, we demonstrate that the PIK3CB D1067Y mutant behaved as an oncogene and transformed normal cells, an activity that was enhanced by PTEN depletion. Collectively, these novel preclinical and clinical findings implicate the acquisition of activating PIK3CB D1067 mutations as an important event underlying the resistance of cancer cells to selective PI3K inhibitors. Cancer Res; 76(5); 1193–203. ©2016 AACR.
Integrated Analysis of PTEN and p4EBP1 Protein Expression as Predictors for pCR in HER2-Positive Breast Cancer
Authors: Loibl Sibylle , Darb-Esfahani Silvia , Huober Jens , Klimowicz Alexander , Furlanetto Jenny , Lederer Bianca , Hartmann Arndt , Eidtmann Holger , Pfitzner Berit , Fasching Peter A. , Tiemann Katharina , Jackisch Christian , Mehta Keyur , von Minckwitz Gunter , Untch Michael , Denkert Carsten
Published: January 2016

Background: The PI3K/AKT pathway and phosphatase and tensin homolog (PTEN) aberrations are common in breast cancer. We investigated the correlation between phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), PTEN, p4EBP1 (phosphorylated E4 binding protein 1), and pathologic complete response (pCR) in patients receiving neoadjuvant therapy.

Experimental Design: We retrospectively evaluated PIK3CA, PTEN, and p4EBP1 protein expression in centrally HER2-positive patients (n = 181) who received epirubicin cyclophosphamide/trastuzumab followed by docetaxel/trastuzumab alone or concomitant/followed by capecitabine within the GeparQuattro study. PTEN was assessed using the automated quantitative immunofluorescence analysis and was analyzed as a dichotomic variable. p4EBP1 was assessed by immunohistochemistry and used as a continuous and dichotomic variable.

Results: p4EBP1 was available from 137, PTEN from 108, and PIK3CA genotype from 83 patients. Overall, the pCR rate in PTEN-low tumors was 27.6%, and in PTEN-high tumors, it was 57.1% (P = 0.010). pCR rates were not statistically different between PIK3CA wild-type and mutant (35% vs. 22%) or p4EBP1 IRS ≤ 4 and IRS > 4 (39% vs. 33%). pCR rate was 57.1% (8/14) in PTEN-high/PIK3CA wild-type and decreased to 15.4% in PTEN-low/PIK3CA-mutant tumors (P = 0.023). In multivariable analysis adjusted for baseline parameters, PTEN independently predicted pCR in the following cohorts: overall [OR, 7.54; 95% confidence interval (CI), 2.03–28.06; P = 0.003], PIK3CA wild-type (OR, 23.81; 95% CI, 1.75–324.05; P = 0.017), p4EBP1 IRS > 4 (OR, 11.53; 95% CI, 1.84–72.24; P = 0.009), and hormone receptor–positive (OR, 40.91; 95% CI, 2.93–570.44; P = 0.006). p4EBP1 was independently predictive for pCR in PIK3CA wild-type tumors (OR, 0.14; 95% CI, 0.03–0.78; P = 0.025).

Conclusions: The study showed the potential role of PIK3CA genotype, PTEN, and p4EBP in predicting pCR after anthracycline–taxane-based chemotherapy and anti-HER2 treatment. Clin Cancer Res; 22(11); 2675–83. ©2016 AACR.
Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial
Authors: Jovelet Cécile , Ileana Ecaterina , Le Deley Marie-Cécile , Motté Nelly , Rosellini Silvia , Romero Alfredo , Lefebvre Celine , Pedrero Marion , Pata-Merci Noémie , Droin Nathalie , Deloger Marc , Massard Christophe , Hollebecque Antoine , Ferté Charles , Boichard Amélie , Postel-Vinay Sophie , Ngo-Camus Maud , De Baere Thierry , Vielh Philippe , Scoazec Jean-Yves , Vassal Gilles , Eggermont Alexander , André Fabrice , Soria Jean-Charles , Lacroix Ludovic
Published: January 2016

Purpose: Liquid biopsies based on circulating cell-free DNA (cfDNA) analysis are described as surrogate samples for molecular analysis. We evaluated the concordance between tumor DNA (tDNA) and cfDNA analysis on a large cohort of patients with advanced or metastatic solid tumor, eligible for phase I trial and with good performance status, enrolled in MOSCATO 01 trial (clinical trial NCT01566019).

Experimental Design: Blood samples were collected at inclusion and cfDNA was extracted from plasma for 334 patients. Hotspot mutations were screened using next-generation sequencing for 50 cancer genes.

Results: Among the 283 patients with tDNA–cfDNA pairs, 121 had mutation in both, 99 in tumor only, 5 in cfDNA only, and for 58 patients no mutation was detected, leading to a 55.0% estimated sensitivity [95% confidence interval (CI), 48.4%–61.6%] at the patient level. Among the 220 patients with mutations in tDNA, the sensitivity of cfDNA analysis was significantly linked to the number of metastatic sites, albumin level, tumor type, and number of lines of treatment. A sensitivity prediction score could be derived from clinical parameters. Sensitivity is 83% in patients with a high score (≥8). In addition, we analyzed cfDNA for 51 patients without available tissue sample. Mutations were detected for 22 patients, including 19 oncogenic variants and 8 actionable mutations.

Conclusions: Detection of somatic mutations in cfDNA is feasible for prescreening phase I candidates with a satisfactory specificity; overall sensitivity can be improved by a sensitivity score allowing to select patients for whom cfDNA constitutes a reliable noninvasive surrogate to screen mutations. Clin Cancer Res; 22(12); 2960–8. ©2016 AACR.
Social Information Processing and Cluster B Personality Pathology among Clinic-Referred Adolescents
Authors: Hessels Christel , van Aken Marcel A.G. , Orobio de Castro Bram , Laceulle Odilia M. , van Voorst Guus
Published: January 2016

Background: This study investigated relations between personality pathology and mentalizing capacities reflected in social information processing (SIP) of adolescents. Sampling and Methods: 96 adolescent outpatients completed a structured interview regarding SIP. Their clinicians completed a checklist based on DSM-IV, assessing severity of personality pathology. Results: Significant relations were found between the severity of personality pathology and SIP: the more severe the personality pathology, the higher the intensity of reported emotions, the more likely adolescents were to choose inadequate coping strategies and aggressive reactions in social situations, and the more positively they evaluated aggressive reactions. Severity of traits of antisocial (ASPD) and borderline personality disorder (BPD) had unique associations with distinctive SIP variables: ASPD being more related to inadequate coping strategies, less reflection on other's motives and aggressive responses, and BPD being more related to avoidant or prosocial responses and in particular to memories of frustrating events. Conclusions: This study provides evidence for difficulties in SIP among adolescents with more severe personality pathology, suggesting that the steps in the SIP model can be used to operationalize mentalizing problems. The results seem to paint a picture of ASPD and BPD having a shared background, but their own specific problems concerning SIP.
Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease: Efficacy and Safety
Authors: Bomback Andrew S.
Published: January 2016

Mineralocorticoid receptor antagonists (MRAs) that block aldosterone's effects on both epithelial and non-epithelial receptors have become a mainstay of therapy for chronic heart failure. Given that cardiovascular events remain the leading cause of death for patients with end-stage renal disease (ESRD), the question of whether these MRAs can be employed in dialysis patients arises. This review summarizes the rationale for blocking aldosterone in patients with chronic and end-stage kidney disease and surveys the data on both the efficacy and safety of using MRAs in the ESRD population. A small but growing body of literature suggests that use of MRAs by ESRD patients is associated with lower blood pressure, reduced left ventricular (LV) mass, and improved LV ejection fraction. Recently, a large randomized trial found an overall 3-year mortality rate of 6.4% in ESRD patients on spironolactone 25 mg daily vs. 19.7% in ESRD patients on no MRA therapy (p = 0.002), without a significantly increased risk of hyperkalemia.
Mesoamerican Nephropathy or Global Warming Nephropathy?
Authors: Roncal-Jimenez Carlos A. , García-Trabanino Ramon , Wesseling Catharina , Johnson Richard J.
Published: January 2016

Background: An epidemic of chronic kidney disease (CKD) of unknown cause has emerged along the Pacific Coast of Central America. The disease primarily affects men working manually outdoors, and the major group affected is sugarcane workers. The disease presents with an asymptomatic rise in serum creatinine that progresses to end-stage renal disease over several years. Renal biopsies show chronic tubulointerstitial disease. While the cause remains unknown, recent studies suggest that it is driven by recurrent dehydration in the hot climate. Potential mechanisms include the development of hyperosmolarity with the activation of the aldose reductase-fructokinase pathway in the proximal tubule leading to local injury and inflammation, and the possibility that renal injury may be the consequence of repeated uricosuria and urate crystal formation as a consequence of both increased generation and urinary concentration, similar to a chronic tumor lysis syndrome. The epidemic is postulated to be increasing due to the effects of global warming. Summary: An epidemic of CKD has led to the death of more than 20,000 lives in Central America. The cause is unknown, but appears to be due to recurrent dehydration. Potential mechanisms for injury are renal damage as a consequence of recurrent hyperosmolarity and/or injury to the tubules from repeated episodes of uricosuria. Key Messages: The epidemic of CKD in Mesoamerica may be due to chronic recurrent dehydration as a consequence of global warming and working conditions. This entity may be one of the first major diseases attributed to climate change and the greenhouse effect.
Increased Urinary Cystatin-C Levels Correlate with Reduced Renal Volumes in Neonates with Intrauterine Growth Restriction
Authors: Barbati Antonella , Cappuccini Benito , Aisa Maria Cristina , Grasselli Chiara , Zamarra Mariarosalba , Bini Vittorio , Bellomo Gianni , Orlacchio Aldo , Di Renzo Gian Carlo
Published: January 2016

Background: Exposure to intrauterine growth retardation (IUGR) can have a negative impact on nephrogenesis resulting in limited fetal kidney development and supporting the hypothesis that IUGR represents a risk for renal function and long-term renal disease. Cystatin-C (Cys-C), a strong inhibitor of cysteine proteinases, is freely filtered by the kidney glomerulus and is reabsorbed by the tubules, where it is almost totally catabolized; what remains is subsequently eliminated in urine. In tubular diseases and in hyperfiltration conditions, it seems reasonable to postulate that Cys-C degradation would decrease, and consequently an increase in its urinary elimination would be observed. Objectives: The aim of this study was to investigate the urinary excretion of Cys-C simultaneously with the assessment of renal volumes in adequate for gestational age (AGA) and IUGR neonates in order to identify its clinical value in IUGR. Methods: Urinary Cys-C levels were measured using the enzyme immunoassay DetectX® Human Cystatin C kit in IUGR and AGA neonates. Whole renal and renal cortex volumes were assessed with ultrasounds (Vocal II; Software, GE). Results: Urinary Cys-C levels in IUGR were significantly higher than those found in AGA and were negatively correlated to reduced whole renal and renal cortex volumes. Conclusions: The increased levels of Cys-C in the urine of neonates with IUGR were significantly associated with reduced renal/renal cortex volumes, suggesting that Cys-C could be taken as a surrogate of nephron mass. It also could be used as an early biochemical marker to identify IUGR neonates at high risk of developing long-term renal disease and to select patients for monitoring during childhood.
Investigating the Nature of the Left Periphery in Peninsular Spanish wh-Question Intonation
Authors: Henriksen Nicholas
Published: January 2016

Background/Aims: In this paper we aim to resolve the phonological status of utterance-initial rises in Spanish wh-questions. Methods/Analysis 1: In analysis 1 we examine the scaling and alignment properties of utterance-initial rises produced by 14 speakers of Peninsular Spanish. Results/Analysis 1: The results provide evidence for a single bitonal pitch accent at the left periphery (L + <H*) despite multiple options at the right periphery. Conclusion/Analysis 1: Our analysis, relying on the notion of sparse tonal specification, helps to explain Sp_ToBI transcribers' past inconsistencies in labeling wh-question initial rises. Methods/Analysis 2: In analysis 2 we tested whether there are scaling differences between the wh-question contours produced in analysis 1 and statement contours produced by the same 14 speakers. Results/Analysis 2: We showed that speakers scale utterance-initial peaks higher in statements, and that they scale utterancefinal peaks higher in wh-questions. Conclusion/Analysis 2: This finding is incompatible with the notion that speakers of Spanish use a higher F0 level from the start of the utterance to distinguish questions from statements.
Management of Intrapleural Sepsis with Once Daily Use of Tissue Plasminogen Activator and Deoxyribonuclease
Authors: Mehta Hiren J. , Biswas Abhishek , Penley Andrea M. , Cope Jessica , Barnes Matthew , Jantz Michael A.
Published: January 2016

Background: Pleural infection remains a significant cause of morbidity, mortality, prolonged hospital stay, and increased healthcare costs, despite advances in therapy. Twice daily intrapleural tissue plasminogen activator (tPA)/deoxyribonuclease (DNase) initiated at the time of diagnosis has been shown to significantly improve radiological outcomes and decrease the need for surgery. Objectives: To analyze our experience with once daily tPA/DNase for intrapleural sepsis. Methods: Data derived from consecutive patients with empyema and complicated parapneumonic effusion who received once daily intrapleural tPA/DNase between January 2012 and August 2014 were reviewed. Measured outcomes included treatment success at 30 days, volume of pleural fluid drained, improvement in radiographic pleural opacity, length of hospital stay, need for surgery, and adverse events. Results: 55 consecutive patients (33 male; mean age ± SD, 54.6 ± 16.1 years) were treated with once daily intrapleural tPA/DNase for 3 days. The majority of the patients (n = 51; 92.7%) were successfully managed without the need for surgical intervention. The mean change in pleural opacity measured on chest radiograph at day 7 was -28.8 ±17.6%. The median amount of fluid drained was 2,195 ml. No serious adverse events requiring discontinuation of intrapleural medications were observed. The most common complication was pain requiring escalating doses of analgesics (n = 8; 15%). Compliance with the protocol was excellent. Conclusion: Early administration of once daily intrapleural tPA/DNase for 3 days is safe, effective, and represents a viable option for the management of empyema and complicated parapneumonic effusion.
Adult Presentation of Dyke-Davidoff-Masson Syndrome: A Case Report
Authors: Roy Ujjawal , Panwar Ajay , Mukherjee Adreesh , Biswas Debsadhan
Published: January 2016

Dyke-Davidoff-Masson syndrome (DDMS) is a rare disease which is clinically characterized by hemiparesis, seizures, facial asymmetry, and mental retardation. The classical radiological findings are cerebral hemiatrophy, calvarial thickening, and hyperpneumatization of the frontal sinuses. This disease is a rare entity, and it mainly presents in childhood. Adult presentation of DDMS is unusual and has been rarely reported in the medical literature. Key Messages: DDMS is a rare disease of childhood. However, it should be kept in mind as a diagnostic possibility in an adult who presents with a long duration of progressive hemiparesis with seizures and mental retardation. Cerebral hemiatrophy, calvarial thickening, and hyperpneumatization of the frontal sinuses are diagnostic for this illness on brain imaging.
Incidences of Feto-Fetal Transfusion Syndrome and Perinatal Outcomes in Triplet Gestations with Monochorionic Placentation
Authors: Sato Yuka , Ishii Keisuke , Yokouchi Tae , Murakoshi Takeshi , Kiyoshi Kenji , Nakayama Soichiro , Yonetani Naoto , Mitsuda Nobuaki
Published: January 2016

Introduction: This study aimed to determine the incidences of feto-fetal transfusion syndrome (FFTS) and perinatal outcomes in triplet gestations with monochorionic placentation. Materials and Methods: In this retrospective cohort study, we evaluated the incidences of FFTS and perinatal outcomes at 28 days of age in cases of triplet gestations with monochorionic placentation who visited our centers before 16 weeks of gestation and delivered over a period of 11 years. Results: In 41 triplet gestations (17 monochorionic triamniotic, 22 dichorionic triamniotic, 1 dichorionic diamniotic, and 1 monochorionic monoamniotic), the incidence of FFTS was 17.1%, and the median gestational age at FFTS diagnosis was 19 weeks. In 123 triplets, the incidences of fetal death and neonatal death at 28 days of age were 8.1 and 0.9%, respectively. None of the surviving infants had grade 3 or 4 intraventricular hemorrhage, while cystic periventricular leukomalacia occurred in 6 of 113 infants (5.3%). The incidence of poor outcomes (death or any major neurological complication at 28 days of age) was 13.8%. Discussion: Seventeen percent of triplet pregnancies with monochorionic placentation developed FFTS, and 14% had a poor outcome. Therefore, triplet gestations with monochorionic placentation should be followed carefully.
Impact of Mechanical Thrombectomy on the Organization of the Management of Acute Ischemic Stroke
Authors: Daubail Benoît , Ricolfi Frédéric , Thouant Pierre , Vogue Charlotte , Chavent Adrien , Osseby Guy-Victor , Hervieu-Begue Marie , Delpont Benoit , Mangola Bruno , Bejot Yannick , Giroud Maurice
Published: January 2016

Background: Several trials and meta-analyses have recently demonstrated the superiority of endovascular therapy over standard medical treatment in patients presenting with acute ischemic stroke. In order to offer the best possible treatment to a maximum number of patients, many stroke care networks probably have to be reorganized. After analyzing the reliability of data in the literature, an algorithm is suggested for a pre-hospital and in-hospital alert system to improve the timeliness of subsequent treatment: a drip-and-ship approach. Summary: Five recent well-designed randomized studies have demonstrated the benefit of endovascular therapy associated with intravenous fibrinolysis by recombinant tissue plasminogen activator (rt-PA) for acute ischemic stroke with confirmation by recent meta-analyses. The keys for success are a very short time to reperfusion, within 6 h, a moderate to severe pre-treatment deficit (National Institute of Health around 17), cerebral imaging able to identify proximal large vessel occlusion in the anterior circulation, a limited infarct core and a reversible penumbra, the use of the most recent devices (stent retriever) and a procedure that avoids general anesthesia, which reduces blood pressure. To meet these goals, every country must build a national stroke infrastructure plan to offer the best possible treatment to all patients eligible for intravenous fibrinolysis and endovascular therapy. The plan may include the following actions: inform the population about the first symptoms of stroke, provide the call number to improve the timeliness of treatment, increase the number of comprehensive stroke centers, link these to secondary and primary stroke centers by telemedicine, teach and train paramedics, emergency doctors and radiologists to identify the stroke infarct, proximal large vessel occlusion and the infarct core quickly, train a new generation of endovascular radiologists to improve access to this therapy. Key Message: After 20 years of rt-PA, this new evidence-based therapy is a revolution in stroke medicine that will benefit patients. However, a new robust and multi-disciplinary care strategy is necessary to transfer the scientific data into clinical practice. It will require reorganization of the stroke infrastructure, which will include comprehensive stroke centers and secondary and primary stroke centers. The winners will be patients with severe stroke.
Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice
Authors: Chu Yi , Lund Donald D. , Doshi Hardik , Keen Henry L. , Knudtson Kevin L. , Funk Nathan D. , Shao Jian Q. , Cheng Justine , Hajj Georges P. , Zimmerman Kathy A. , Davis Melissa K. , Brooks Robert M. , Chapleau Mark W. , Sigmund Curt D. , Weiss Robert M. , Heistad Donald D.
Published: January 2016

Objective—

Hypercholesterolemia and hypertension are associated with aortic valve stenosis (AVS) in humans. We have examined aortic valve function, structure, and gene expression in hypercholesterolemic/hypertensive mice.

Approach and Results—

Control, hypertensive, hypercholesterolemic (
Apoe

−/−

), and hypercholesterolemic/hypertensive mice were studied. Severe aortic stenosis (echocardiography) occurred only in hypercholesterolemic/hypertensive mice. There was minimal calcification of the aortic valve. Several structural changes were identified at the base of the valve. The intercusp raphe (or seam between leaflets) was longer in hypercholesterolemic/hypertensive mice than in other mice, and collagen fibers at the base of the leaflets were reoriented to form a mesh. In hypercholesterolemic/hypertensive mice, the cusps were asymmetrical, which may contribute to changes that produce AVS. RNA sequencing was used to identify molecular targets during the developmental phase of stenosis. Genes related to the structure of the valve were identified, which differentially expressed before fibrotic AVS developed. Both RNA and protein of a profibrotic molecule, plasminogen activator inhibitor 1, were increased greatly in hypercholesterolemic/hypertensive mice.

Conclusions—

Hypercholesterolemic/hypertensive mice are the first model of fibrotic AVS. Hypercholesterolemic/hypertensive mice develop severe AVS in the absence of significant calcification, a feature that resembles AVS in children and some adults. Structural changes at the base of the valve leaflets include lengthening of the raphe, remodeling of collagen, and asymmetry of the leaflets. Genes were identified that may contribute to the development of fibrotic AVS.
Induction of Angiogenesis by a Type III Phosphodiesterase Inhibitor, Cilostazol, Through Activation of Peroxisome Proliferator-Activated Receptor-γ and cAMP Pathways in Vascular Cells
Authors: Sanada Fumihiro , Kanbara Yasuhiro , Taniyama Yoshiaki , Otsu Rei , Carracedo Miguel , Ikeda-Iwabu Yuka , Muratsu Jun , Sugimoto Ken , Yamamoto Koichi , Rakugi Hiromi , Morishita Ryuichi
Published: January 2016

Objective—

Peripheral arterial disease is highly prevalent in the elderly and in the subjects with cardiovascular risk factors such as diabetes. Approximately 2% to 4% of those affected with peripheral arterial disease commonly complain of intermittent claudication. Cilostazol, a type III phosphodiesterase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of intermittent claudication. Cilostazol has been shown to be beneficial for the improvement of pain-free walking distance in patients with intermittent claudication in a series of randomized clinical trials. However, the underlying mechanism how cilostazol improved intermittent claudication symptoms is still unclear.

Approach and Results—

In this study, the effect of cilostazol on ischemic leg was investigated in mouse ischemic hindlimb model. Administration of cilostazol significantly increased the expression of hepatocyte growth factor (HGF), vascular endothelial growth factor, angiopoietin-1, and peroxisome proliferator-activated receptor-γ in vasculature. The capillary density in ischemic leg was also significantly increased in cilostazol treatment group when compared with control and aspirin treatment group. However, an increase in capillary density and the expression of growth factors was almost completely abolished by coadministration of HGF-neutralizing antibody, suggesting that cilostazol enhanced angiogenesis mainly through HGF. In vitro experiment revealed that cilostazol treatment increased HGF production in vascular smooth muscle cells via 2 major pathways: peroxisome proliferator-activated receptor-γ and cAMP pathways.

Conclusions—

Our data suggest that the favorable effects of cilostazol on ischemic leg might be through the angiogenesis through the induction of HGF via peroxisome proliferator-activated receptor-γ and cAMP pathways.
Sleep Fragmentation, Cerebral Arteriolosclerosis, and Brain Infarct Pathology in Community-Dwelling Older People
Authors: Lim Andrew S.P. , Yu Lei , Schneider Julie A. , Bennett David A. , Buchman Aron S.
Published: January 2016

Background and Purpose—

Although several forms of sleep disruption are associated with stroke, few studies have examined the relationship between sleep and histopathologic measures of cerebrovascular disease. We tested the hypothesis that greater sleep fragmentation is associated with a higher burden of cerebral vessel and infarct pathology at autopsy.

Methods—

We used ordinal logistic regression models to relate sleep fragmentation measured by actigraphy to the severity of arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy, and the number of macroscopic and microscopic infarcts assessed by structured brain autopsy in 315 participants from the Rush Memory and Aging Project.

Results—

Greater sleep fragmentation was associated with more severe arteriolosclerosis (odds ratio, 1.27; 95% confidence interval, 1.02–1.59;
P
=0.03 per 1 SD greater sleep fragmentation) and more subcortical macroscopic infarcts (odds ratio, 1.31; 95% confidence interval, 1.01–1.68;
P
=0.04). These associations were independent of established cardiovascular risk factors and diseases, and several medical comorbidities.

Conclusions—

Sleep fragmentation is associated with arteriolosclerosis and subcortical infarcts in older adults.
No Nuts? No Problem!
Authors: Solevåg Anna Rebecca
Published: January 2016

This article applies a “crip reading” to the story of the Ethiopian eunuch in Acts 8:26–40. First, insights from disability studies theory and crip theory are used as a hermeneutical lens to scrutinize the socially constructed meanings of the eunuch’s bodily “stigma.” The eunuch, it is argued, is a disabled – a crip – character because his body is marked and he does not display the culturally valued ability to procreate. Second, this article shows how the meaning of bodily signs of castration and circumcision change from the Hebrew Bible to Acts and suggests that the story of the Ethiopian eunuch holds a special place in Luke’s renegotiation of bodily signs. Finally, this article explores the destabilizing potential of the story and argues that a crip Christ who defies both norms of masculinity and norms of ability emerges from the eunuch’s reading of Isaiah 53.
From Frunze to Bishkek: Soviet Territorial Youth Formations and Their Decline in the 1990s and 2000s
Authors: Nasritdinov Emil , Schröder Philipp
Published: January 2016

This article presents an “alternative urban history” of Bishkek (Frunze). We describe the history of Soviet streets and of the everyday life of young people, whose narratives fit neither the Soviet nor the post-Soviet history textbooks. Yet, these stories are extremely important, rich, and unique. They reveal the complex dynamics of the social organization of urban territories in cities of Soviet origin. The research has shown that the territorial youth culture of Frunze had much in common with similar developments in cities all across the Soviet Union. At the same time, it developed its own particular features, complexities, and diversities due to specific local conditions. The study also provides insights into the power of territory. It reveals how identities, everyday practices, and the socialization of young people were embedded in the specific geographies of the Kyrgyz capital.
First description of the male of Yaobinthrips yangtzei (Thysanoptera: Thripidae)
Authors: LI YAJIN , XIE YONG-HUI , ZHANG HONGRUI
Published: January 2016

The monobasic Thripinae genus Yaobinthrips has been known only from females, and the objective here is to provide a description of the male. A member of the Frankliniella genus-group, the type species, yangtzei Zhang et al. (2010) was described from specimens taken in Sichuan Province of Southwestern China from the flowers of Dalbergia yunnanensis [Fabaceae]. In April, 2015 a sample of both sexes of this thrips species was taken from the white flowers of the same plant species, but in Yunnan Province. This plant is actually widespread in southwestern China in Yunnan, Sichuan, Guizhou Provinces and Guangxi Zhuang Autonomous Region. Provinces, growing at an elevation ranging from 1400 to 2200 meters, and flowering from April to May (Li et al. 2007).
First records of Lithodes longispina Sakai, 1971 (Crustacea: Decapoda: Anomura: Lithodidae) from southwestern Taiwan, including a site in the vicinity of a cold seep
Authors: WANG TENG-WEI , AHYONG SHANE T. , CHAN TIN-YAM
Published: January 2016

Lithodid crabs (Lithodidae Samouelle, 1819), commonly known as king crabs, are frequent targets of commercial fishing worldwide with most of them living in deep water (Sakai 1971; Ahyong et al. 2010). Lithodes Latreille, 1806, is the second largest genus of lithodid crabs, currently including 29 species worldwide (Ahyong 2010). In Taiwanese waters, however, only two species, L. turritus Ortmann, 1892, and L. formosae Ahyong & Chan, 2010, have been reported (Wu et al. 1998; Ahyong & Chan 2010; Ahyong et al. 2010). We report herein the discovery of L. longispina Sakai, 1971, previously known reliably only from Japan (Sakai 1971; Ikeda 1998; Ahyong 2010), from off southwestern Taiwan, including a specimen collected in the vicinity of a cold seep.
Two new species of the genus Turbicellepora Ryland, 1963 (Bryozoa: Celleporidae) found on Lophelia coral from the Greenland slope
Authors: DENISENKO NINA V.
Published: January 2016

The genus Turbicellepora was established by Ryland (1963) in the course of his work on the Norwegian bryozoan fauna. At present, the genus includes 71 recent and fossil species, which have been reported from all continents and seas (Bock & Gordon 2014). The distinctive characteristics of the genus include a multiporous ooecium, proximal orificial sinus, an asymmetrically placed peristomial avicularium and enlarged or vicarious avicularia (Ryland 1963). Occasionally, an additional pre-oral avicularium is also present (Hayward 1978). Colonies have a changeable form. They can be massive and branching or have the form of a mound or flat crust. The most comprehensive comparative study of European species of the genus, with detailed descriptions of 13 taxa, was carried out by Hayward (1978), who noted that the genus seemed to be centred in the Atlanto–Mediterranean region.
Investigation of the Effects of Anthropogenic Pollution on Typhoon Precipitation and Microphysical Processes Using WRF-Chem
Authors: Jiang Baolin , Huang Bo , Lin Wenshi , Xu Suishan
Published: January 2016

Taking Typhoon Usagi (2013) as an example, this study used the Weather Research and Forecasting Model with Chemistry to investigate the influence of anthropogenic aerosols on typhoons. Three simulations (CTL, CLEAN, EXTREME) were designed according to the emission intensity of the anthropogenic pollution. The results showed that although anthropogenic pollution did not demonstrate clear influence on the track and strength of the typhoon, it clearly changed the precipitation, distribution of water hydrometeors, and microphysical processes. In the CLEAN experiment, the precipitation rate declined because cloud water collected by the rain decreased. Similarly, the precipitation rate decreased in the EXTREME experiment, because the autoconversion of cloud water to rain was restrained. Regarding precipitation type, the rate of stratiform precipitation in both the CLEAN and the EXTREME simulations was suppressed because the ice-phase microphysical processes weakened. Compared with the CTL run, the rate of stratiform precipitation at the periphery of the typhoon was reduced by about 28% in both the CLEAN and the EXTREME simulations. Moreover, the rate of convective precipitation within 140–160 km of the center of the typhoon in the EXTREME experiment was about 33% greater than in the CTL simulation. This increase was triggered by new convection at the periphery in the EXTREME simulation related to cloud water reevaporation. Finally, compared with the CTL experiment, the peaks of both convective and mixed precipitation in the CLEAN and EXTREME experiments shifted 10 km toward the typhoon periphery.
Composite Analysis of the Effects of ENSO Events on Antarctica
Authors: Welhouse Lee J. , Lazzara Matthew A. , Keller Linda M. , Tripoli Gregory J. , Hitchman Matthew H.
Published: January 2016

Previous investigations of the relationship between El Niño–Southern Oscillation (ENSO) and the Antarctic climate have focused on regions that are impacted by both El Niño and La Niña, which favors analysis over the Amundsen and Bellingshausen Seas (ABS). Here, 35 yr (1979–2013) of European Centre for Medium-Range Weather Forecasts interim reanalysis (ERA-Interim) data are analyzed to investigate the relationship between ENSO and Antarctica for each season using a compositing method that includes nine El Niño and nine La Niña periods. Composites of 2-m temperature (T2m), sea level pressure (SLP), 500-hPa geopotential height, sea surface temperatures (SST), and 300-hPa geopotential height anomalies were calculated separately for El Niño minus neutral and La Niña minus neutral conditions, to provide an analysis of features associated with each phase of ENSO. These anomaly patterns can differ in important ways from El Niño minus La Niña composites, which may be expected from the geographical shift in tropical deep convection and associated pattern of planetary wave propagation into the Southern Hemisphere. The primary new result is the robust signal, during La Niña, of cooling over East Antarctica. This cooling is found from December to August. The link between the southern annular mode (SAM) and this cooling is explored. Both El Niño and La Niña experience the weakest signal during austral autumn. The peak signal for La Niña occurs during austral summer, while El Niño is found to peak during austral spring.
The Global Warming–Induced South Asian High Change and Its Uncertainty
Authors: Qu Xia , Huang Gang
Published: January 2016

Based on models from phase 5 of the Coupled Model Intercomparison Project (CMIP5), the present study investigates the South Asian high (SAH) change in response to global warming. Under global warming, the selected 16 coupled general circulation models all feature an elevation of geopotential height at 100 hPa to the south of the SAH climatological position; an easterly response is found over the northern Indian Ocean in all the models, while a westerly response is found over subtropical Asia. The ridges of the SAH shift equatorward in 75% of models. Using the linear baroclinic model, it is found that the combined effects of latent heating and the mean advection of stratification change (MASC) are mainly responsible for those responses. The MASC mainly leads to the aforementioned easterly and westerly responses; the latent heating contributes to the geopotential height response and the easterly response over the northern Indian Ocean. The most important intermodel diversity is found in the 100-hPa circulation change under global warming, accounting for more than half of the total intermodel variance. The intermodel spread of latent heating and the MASC are important factors in driving the 100-hPa circulation diversity. Furthermore, analysis shows that the projected uncertainties in humidity, vertical velocity, and global mean temperature change are the three most important sources of intermodel diversity for the 100-hPa circulation change.
Indications for Protracted Groundwater Depletion after Drought over the Central Valley of California*,+
Authors: Simon Wang S.-Y. , Lin Yen-Heng , Gillies Robert R. , Hakala Kirsti
Published: January 2016

Ongoing (2014–16) drought in the state of California has played a major role in the depletion of groundwater. Within California’s Central Valley, home to one of the world’s most productive agricultural regions, drought and increased groundwater depletion occurs almost hand in hand, but this relationship appears to have changed over the last decade. Data derived from 497 wells have revealed a continued depletion of groundwater lasting a full year after drought, a phenomenon that was not observed in earlier records before the twenty-first century. Possible causes include 1) lengthening of drought associated with amplification in the 4–6-yr drought and El Niño frequency since the late 1990s and 2) intensification of drought and increased pumping that enhances depletion. Altogether, the implication is that current groundwater storage in the Central Valley will likely continue to diminish even further in 2016, regardless of the drought status.
Improving Large-Domain Convection-Allowing Forecasts with High-Resolution Analyses and Ensemble Data Assimilation
Authors: Schwartz Craig S.
Published: January 2016

Analyses with 20-km horizontal grid spacing were produced from continuously cycling three-dimensional variational (3DVAR), ensemble square root Kalman filter (EnSRF), and “hybrid” variational–ensemble data assimilation (DA) systems over a domain spanning the conterminous United States. These analyses initialized 36-h Weather Research and Forecasting Model forecasts containing a large convection-allowing 4-km nested domain, where downscaled 20-km 3DVAR, EnSRF, and hybrid analyses initialized the 4-km forecasts. Overall, hybrid analyses initialized the best 4-km precipitation forecasts.

Furthermore, whether 4-km precipitation forecasts could be improved by initializing them with true 4-km analyses was assessed. As it was computationally infeasible to produce 4-km continuously cycling ensembles over the large 4-km domain, several “dual-resolution” hybrid DA configurations were adopted where 4-km backgrounds were combined with 20-km ensembles to produce 4-km hybrid analyses. Additionally, 4-km 3DVAR analyses were produced.

In both hybrid and 3DVAR frameworks, initializing 4-km forecasts with true 4-km analyses, rather than downscaled 20-km analyses, yielded superior precipitation forecasts over the first 12 h. Differences between forecasts initialized from 4-km and downscaled 20-km hybrid analyses were smaller for 18–36-h forecasts, but there were occasionally meaningful differences. Continuously cycling the 4-km backgrounds and using static background error covariances with larger horizontal length scales in the hybrid led to better forecasts. All hybrid-initialized forecasts, including those initialized from downscaled 20-km analyses, were more skillful than forecasts initialized from 4-km 3DVAR analyses, suggesting the analysis method was more important than analysis resolution.
Re-framing ‘counterfeit from a public health perspective’: A case for fraudulent medicine
Authors: Bandiera Rhiannon , Marmo Marinella
Published: January 2016

‘Black market’ counterfeiters operating outside of authorised industry are often framed as the perpetrators of dangerous and defective medicines within legal pharmaceutical markets. However, the assumption that all medicines which deliberately violate regulatory standards and quality specifications have black market origins is ill conceived, as poor medicine quality can occur regardless of who the manufacturer of the medicine may be. This paper proposes a reframing of all pharmaceutical products which intentionally, or negligently, fail to comply with regulatory standards and which are then fraudulently depicted as being of standard, from ‘counterfeit’ to ‘fraudulent medicines’. This proposal is reinforced with examples from Australian law, where Australian pharmaceutical companies, who deliberately violated regulatory standards and produced defective and dangerous medicines, have been prosecuted using legislation designed to capture poor-quality counterfeit drugs. The paper argues that these corporate crimes should not be framed as ‘counterfeiting’ but as ‘frauds’, thus containing acts of ‘counterfeiting’ to existing intellectual property law and providing due recognition for all acts which defraud and cause harm to the consumer.
Patriarchy, gender, infantilisation: A cultural account of police intelligence work in Scotland
Authors: Atkinson Colin
Published: January 2016

Drawing upon qualitative research undertaken in Scotland, this paper provides new insights into police culture by exploring the interactions between sworn police officers and civilian intelligence analysts engaged in intelligence work. The claim is made that by exploring the cultural impact of intelligence analysis, it is possible to identify patriarchal dispositions within police culture and the emergence of a gender order in policing that subordinates femininity, youth and other masculinities that run counter to police culture's form of hegemonic masculinity. This gender order is interwoven with processes of infantilisation that inhibit the integration of intelligence analysts into police intelligence work. This article concludes by discussing the prospects for cultural change in policing from the inter-related perspectives of both social theory and professional practice.
Brain gray matter alterations and associated demographic profiles in adults with autism spectrum disorder: A meta-analysis of voxel-based morphometry studies
Authors: Yang Xun , Si Tianjing , Gong Qiyong , Qiu Lihua , Jia Zhiyun , Zhou Mi , Zhao Youjin , Hu Xinyu , Wu Min , Zhu Hongyan
Published: January 2016

Background:

There is increasing evidence that children with autism spectrum disorder are accompanied by specific anatomical alterations. However, the anatomical abnormalities in adults with autism spectrum disorder are poorly understood. This study was aimed to identify the neuroanatomical substrates underlying the pathophysiology of adults with autism spectrum disorder. We also investigated the relationship between neuroanatomical alterations and clinical and demographic characteristics.

Methods:

A total of 13 datasets were enrolled, of which 12 studies compared whole-brain differences of 382 adult patients with autism and 393 healthy control subjects. We conducted a meta-analysis to quantitatively estimate regional gray matter volume abnormalities in individuals with autism using the effect-size signed differential mapping.

Results:

The voxel-wise meta-analysis revealed that relative to controls, adults with autism spectrum disorder had significantly increased gray matter volume in the middle temporal gyrus, superior temporal gyrus, postcentral gyrus and parahippocampal gyrus, and reduced gray matter volume in the anterior cingulate cortex and cerebellum. Variations in gray matter volume were significantly associated with the mean age and mean total IQ score of the patients, as well as with the percentage of male patients with autism.

Conclusion:

These findings confirmed that the neuroanatomical alterations in the fronto-temporal cortices, limbic system and cerebellum in adult individuals with autism were different from the children and young adolescent’s autism. The effects of demographic characteristics on the brain morphological changes allow us to further clarify the neurobiological mechanisms and developmental trajectory in adult population with autism spectrum disorder.