bluuebunny/crossref_metadata_2025 huggingface dataset:
TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis
Authors: Principe Daniel R. , DeCant Brian , Mascariñas Emman , Wayne Elizabeth A. , Diaz Andrew M. , Akagi Naomi , Hwang Rosa , Pasche Boris , Dawson David W. , Fang Deyu , Bentrem David J. , Munshi Hidayatullah G. , Jung Barbara , Grippo Paul J.
Published: March 2016

In early pancreatic carcinogenesis, TGFβ acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFβ appears to promote tumor progression. Therefore, to better understand the contributions of TGFβ signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGFβ signals facilitated pancreatic tumorigenesis, whereas global loss of TGFβ signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGFβ1 production, and the resultant restoration of antitumor immune function. Similarly, TGFBR-deficient T cells resisted TGFβ-induced inactivation ex vivo, and adoptive transfer of TGFBR-deficient CD8+ T cells led to enhanced infiltration and granzyme B–mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGFβ expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGFβ may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have already lost tumor-suppressive TGFβ signals in the epithelium. Cancer Res; 76(9); 2525–39. ©2016 AACR.
The Prosurvival IKK-Related Kinase IKKϵ Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine
Authors: Göktuna Serkan Ismail , Shostak Kateryna , Chau Tieu-Lan , Heukamp Lukas C. , Hennuy Benoit , Duong Hong-Quan , Ladang Aurélie , Close Pierre , Klevernic Iva , Olivier Fabrice , Florin Alexandra , Ehx Grégory , Baron Frédéric , Vandereyken Maud , Rahmouni Souad , Vereecke Lars , van Loo Geert , Büttner Reinhard , Greten Florian R. , Chariot Alain
Published: March 2016

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikkϵ in Wnt-driven tumor development. We found that Ikkϵ was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikkϵ in β-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkϵ to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkϵ was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding pro-inflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkϵ-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkϵ phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikkϵ to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. Cancer Res; 76(9); 2587–99. ©2016 AACR.
Oncoprotein HBXIP Modulates Abnormal Lipid Metabolism and Growth of Breast Cancer Cells by Activating the LXRs/SREBP-1c/FAS Signaling Cascade
Authors: Zhao Yu , Li Hang , Zhang Yingyi , Li Leilei , Fang Runping , Li Yinghui , Liu Qian , Zhang Weiying , Qiu Liyan , Liu Fabao , Zhang Xiaodong , Ye Lihong
Published: March 2016

Abnormal lipid metabolism is a hallmark of tumorigenesis. Accumulating evidence demonstrates that fatty acid synthase (FAS, FASN) is a metabolic oncogene that supports the growth and survival of tumor cells and is highly expressed in many cancers. Here, we report that the oncoprotein, hepatitis B X-interacting protein (HBXIP, LAMTOR5) contributes to abnormal lipid metabolism. We show that high expression of HBXIP in 236 breast cancer patients was significantly associated with decreased overall survival and progression-free survival. Interestingly, the expression of HBXIP was positively related to that of FAS in clinical breast cancer tissues, and HBXIP overexpression in breast cancer cells resulted in FAS upregulation. Mechanistically, HBXIP upregulated SREBP-1c (SREBF1), which activates the transcription of FAS, by directly interacting with and coactivating nuclear receptor (NR) liver X receptors (LXR). Physiologically, LXRs are activated via a coactivator containing NR motif in a ligand-dependent manner. However, in breast cancer cells, HBXIP containing the corepressor/nuclear receptor motif with special flanking sequence could coactivate LXRs independent of ligand. Moreover, overexpressed SREBP-1c was able to activate the transcription of HBXIP, forming a positive-feedback loop. Functionally, HBXIP enhanced lipogenesis, resulting in the growth of breast cancer cells in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP contributes to the abnormal lipid metabolism in breast cancer through LXRs/SREBP-1c/FAS signaling, providing new insights into the mechanisms by which cancer cells reprogram lipid metabolism in their favor. Cancer Res; 76(16); 4696–707. ©2016 AACR.
IL15 Agonists Overcome the Immunosuppressive Effects of MEK Inhibitors
Authors: Allegrezza Michael J. , Rutkowski Melanie R. , Stephen Tom L. , Svoronos Nikolaos , Tesone Amelia J. , Perales-Puchalt Alfredo , Nguyen Jenny M. , Sarmin Fahmida , Sheen Mee R. , Jeng Emily K. , Tchou Julia , Wong Hing C. , Fiering Steven N. , Conejo-Garcia Jose R.
Published: March 2016

Many signal transduction inhibitors are being developed for cancer therapy target pathways that are also important for the proper function of antitumor lymphocytes, possibly weakening their therapeutic effects. Here we show that most inhibitors targeting multiple signaling pathways have especially strong negative effects on T-cell activation at their active doses on cancer cells. In particular, we found that recently approved MEK inhibitors displayed potent suppressive effects on T cells in vitro. However, these effects could be attenuated by certain cytokines that can be administered to cancer patients. Among them, clinically available IL15 superagonists, which can activate PI3K selectively in T lymphocytes, synergized with MEK inhibitors in vivo to elicit potent and durable antitumor responses, including by a vaccine-like effect that generated resistance to tumor rechallenge. Our work identifies a clinically actionable approach to overcome the T-cell–suppressive effects of MEK inhibitors and illustrates how to reconcile the deficiencies of signal transduction inhibitors, which impede desired immunologic effects in vivo. Cancer Res; 76(9); 2561–72. ©2016 AACR.
Analysis of Liver Tumor-Prone Mouse Models of the Hippo Kinase Scaffold Proteins RASSF1A and SAV1
Authors: Zhang Xiaoying , Guo Cai , Wu Xiwei , Li Arthur X. , Liu Limin , Tsark Walter , Dammann Reinhard , Shen Hui , Vonderfecht Steven L. , Pfeifer Gerd P.
Published: March 2016

The tumor suppressor gene RASSF1A is epigenetically silenced in most human cancers. As a binding partner of the kinases MST1 and MST2, the mammalian orthologs of the Drosophila Hippo kinase, RASSF1A is a potential regulator of the Hippo tumor suppressor pathway. RASSF1A shares these properties with the scaffold protein SAV1. The role of this pathway in human cancer has remained enigmatic inasmuch as Hippo pathway components are rarely mutated in tumors. Here we show that Rassf1a homozygous knockout mice develop liver tumors. However, heterozygous deletion of Sav1 or codeletion of Rassf1a and Sav1 produced liver tumors with much higher efficiency than single deletion of Rassf1a. Analysis of RASSF1A-binding partners by mass spectrometry identified the Hippo kinases MST1, MST2, and the oncogenic IκB kinase TBK1 as the most enriched RASSF1A-interacting proteins. The transcriptome of Rassf1a−/− livers was more deregulated than that of Sav1+/− livers, and the transcriptome of Rassf1a−/−, Sav1+/− livers was similar to that of Rassf1a−/− mice. We found that the levels of TBK1 protein were substantially upregulated in livers lacking Rassf1a. Furthermore, transcripts of several β-tubulin isoforms were increased in the Rassf1a-deficient livers presumably reflecting a role of RASSF1A as a microtubule-stabilizing protein. In human liver cancer, RASSF1A frequently undergoes methylation at the promoter but this was not observed for MST1, MST2, or SAV1. Our results suggest a multifactorial role of RASSF1A in suppression of liver carcinogenesis. Cancer Res; 76(9); 2824–35. ©2016 AACR.
Dietary Patterns and Plasma Sex Hormones, Prolactin, and Sex Hormone–Binding Globulin in Premenopausal Women
Authors: Hirko Kelly A. , Spiegelman Donna , Barnett Junaidah B. , Cho Eunyoung , Willett Walter C. , Hankinson Susan E. , Eliassen A. Heather
Published: March 2016

Background: Sex hormones are important for breast cancer, but it is unclear whether dietary patterns influence hormone concentrations.

Methods: Dietary pattern adherence scores for the alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), and Alternative Healthy Eating Index (AHEI) were calculated from semiquantitative food frequency questionnaires administered in 1995 and 1999. Premenopausal plasma concentrations of sex hormones were measured in samples collected in 1996 to 1999. We used generalized linear models to calculate geometric mean hormone concentrations across quartiles of dietary pattern scores among 1,990 women in the Nurses' Health Study II.

Results: We did not observe significant associations between sex hormone concentrations and the DASH pattern and only one suggestive association between follicular estrone concentrations and the aMED pattern [top vs. bottom quartile −4.4%, 95% confidence interval (CI), −10.6% to 2.1%; Ptrend = 0.06]. However, women in the top versus bottom quartile of AHEI score had lower concentrations of follicular (−9.1%; 95% CI, −16.1% to −1.4%; Ptrend = 0.04) and luteal (−7.5%; 95% CI, −13.6% to −0.9%; Ptrend = 0.01) estrone, luteal-free (−9.3%; 95% CI, −16.8% to −1.1%; Ptrend = 0.01) and total (−6.7 %; 95% CI, −14.3% to 1.5%; Ptrend = 0.04) estradiol, follicular estradiol (−14.2%; 95% CI, −24.6% to −2.4%; Ptrend = 0.05), and androstenedione (−7.8%; 95% CI, −15.4% to 0.4%; Ptrend = 0.03).

Conclusion: Diet quality measured by the AHEI is inversely associated with premenopausal estrogen concentrations. Given that we did not observe similar associations with the aMED or DASH patterns, our findings should be interpreted with caution.

Impact: Given the role of estrogens in breast cancer etiology, our findings add to the substantial evidence on the benefits of adhering to a healthy diet. Cancer Epidemiol Biomarkers Prev; 25(5); 791–8. ©2016 AACR.
Lack of Immunomodulatory Interleukin-27 Enhances Oncogenic Properties of Mutant p53 In Vivo
Authors: Dibra Denada , Mitra Abhisek , Newman Melisa , Xia Xueqing , Cutrera Jeffry J. , Gagea Mihai , Kleinerman Eugenie S. , Lozano Guillermina , Li Shulin
Published: March 2016

Purpose: p53 is mutated in about 50% of human cancers, mostly through missense mutations. Expression of mutant p53 is associated with poor clinical outcomes or metastasis. Although mutant p53 is inherently instable, various stressors such as DNA damage or expression of the oncogenic Kras or c-myc affect the oncogenic properties of mutant p53. However, the effects of inflammation on mutant p53 are largely unknown. IL27 is an important immunomodulatory cytokine, but its impact on mutant p53-driven tumorigenesis has not been reported.

Experimental Design: IL27RA−/− mice were bred with mutant p53 heterozygous (p53R172H/+) mice to obtain IL27RA−/−p53H/+ and IL27RA−/−p53H/H mice. Mouse survival and tumor spectra for the cohort were analyzed. Stability of p53 protein was analyzed via IHC and Western blot analysis.

Results: This study unraveled that lack of IL27 signaling significantly shortened the survival duration of mice with tumors expressing both copies of the mutant p53 gene (Li-Fraumeni mouse model). Interestingly, in mice that were heterozygous for mutant p53, lack of IL27 signaling not only significantly shortened survival time but also doubled the incidence of osteosarcomas. Furthermore, lack of IL27 signaling is closely associated with increased mutant p53 stability in vivo from early age.

Conclusions: These results suggest that IL27 signaling modulates the oncogenic properties of mutant p53 in vivo. Clin Cancer Res; 22(15); 3876–83. ©2016 AACR.
Poly (ADP-Ribose) Polymerase Inhibitor Hypersensitivity in Aggressive Myeloproliferative Neoplasms
Authors: Pratz Keith W. , Koh Brian D. , Patel Anand G. , Flatten Karen S. , Poh Weijie , Herman James G. , Dilley Robert , Harrell Maria I. , Smith B. Douglas , Karp Judith E. , Swisher Elizabeth M. , McDevitt Michael A. , Kaufmann Scott H.
Published: March 2016

Purpose: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo.

Experimental Design: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays.

Results: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage–induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes.

Conclusions: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894–902. ©2016 AACR.
Unplugging JAK/STAT in Chronic Myelomonocytic Leukemia
Authors: Solary Eric
Published: March 2016

The proliferative component of chronic myelomonocytic leukemia, related to an increased sensitivity of myeloid progenitors to granulocyte macrophage–colony stimulating factor, suggests dedicated therapeutic approaches. In this issue, ruxolitinib, a JAK1 and -2 inhibitory drug, is shown to induce objective responses in chronic myelomonocytic leukemia patients. Clin Cancer Res; 22(15); 3707–9. ©2016 AACR.

See related article by Padron et al., p. 3746
Neoantigen Load, Antigen Presentation Machinery, and Immune Signatures Determine Prognosis in Clear Cell Renal Cell Carcinoma
Authors: Matsushita Hirokazu , Sato Yusuke , Karasaki Takahiro , Nakagawa Tohru , Kume Haruki , Ogawa Seishi , Homma Yukio , Kakimi Kazuhiro
Published: March 2016

Tumors commonly harbor multiple genetic alterations, some of which initiate tumorigenesis. Among these, some tumor-specific somatic mutations resulting in mutated protein have the potential to induce antitumor immune responses. To examine the relevance of the latter to immune responses in the tumor and to patient outcomes, we used datasets of whole-exome and RNA sequencing from 97 clear cell renal cell carcinoma (ccRCC) patients to identify neoepitopes predicted to be presented by each patient's autologous HLA molecules. We found that the number of nonsilent or missense mutations did not correlate with patient prognosis. However, combining the number of HLA-restricted neoepitopes with the cell surface expression of HLA or β2-microglobulin(β2M) revealed that an A-neohi/HLA-Ahi or ABC-neohi/β2Mhi phenotype correlated with better clinical outcomes. Higher expression of immune-related genes from CD8 T cells and their effector molecules [CD8A, perforin (PRF1) and granzyme A (GZMA)], however, did not correlate with prognosis. This may have been due to the observed correlation of these genes with the expression of other genes that were associated with immunosuppression in the tumor microenvironment (CTLA-4, PD-1, LAG-3, PD-L1, PD-L2, IDO1, and IL10). This suggested that abundant neoepitopes associated with greater antitumor effector immune responses were counterbalanced by a strongly immunosuppressive microenvironment. Therefore, immunosuppressive molecules should be considered high-priority targets for modulating immune responses in patients with ccRCC. Blockade of these molecular pathways could be combined with immunotherapies targeting neoantigens to achieve synergistic antitumor activity. Cancer Immunol Res; 4(5); 463–71. ©2016 AACR.
Atypical Teratoid Rhabdoid Tumor Diagnosis after Partial Resection of Dysembryoplastic Neuroepithelial Tumor: Case Report and Review of the Literature
Authors: Nadi Mustafa , Ahmad Tahani , Huang Annie , Hawkins Cynthia , Bouffet Eric , Kulkarni Abhaya V.
Published: March 2016

Dysembryoplastic neuroepithelial tumors (DNETs) are generally considered benign, slow-growing epilepsy-associated lesions. While rare cases of malignant transformation of DNET to high-grade glial tumors have been reported, to our knowledge there have been no reports of transformation/emergence of DNET to atypical teratoid rhabdoid tumor (AT/RT), a highly aggressive embryonal brain tumor. Here, we report the case of an 8-year-old boy who presented with an incidental finding of a small right insular lesion which grew slowly over 3 years. The patient first underwent surgery with subtotal tumor resection at age 11. Pathology was consistent with DNET. Following surgery, further tumor growth was evident, requiring fractionated radiotherapy and eventually chemotherapy, but continued tumor growth was witnessed. Three years after radiation, imaging showed dramatic further tumor growth, and the patient underwent a second debulking surgery. The pathology revealed a malignant tumor with BAF47-negative cells, suggestive of AT/RT. This report adds to our knowledge about the poorly understood behavior and natural history of DNETs and emphasizes the importance of lifelong clinical and neuroimaging follow-up of these lesions.
X-Linked Candidate Genes for a Ciliopathy-Like Disorder
Authors: Pavey Ashleigh R. , Vilboux Thierry , Babcock Holly E. , Ahronovich Margot , Solomon Benjamin D.
Published: March 2016

The ability to interrogate the genome via chromosomal microarray and sequencing-based technologies has accelerated the ability to rapidly and accurately define etiologies as well as new candidate genes related to genetic conditions. We describe a male patient with a lethal presentation of a multiple congenital anomaly syndrome that appeared consistent with a ciliopathy phenotype. The patient was found to have a novel maternally inherited 1.9-Mb X chromosome deletion including 4 known genes. Presently, the biological functions of these genes are not well delineated. However, at least one of these genes may be a promising candidate gene for this pattern of anomalies based on the function of related genes and information from publicly available copy number variant databases of control and affected individuals. These genes would bear further scrutiny in larger cohorts of patients with similar phenotypes.
Stüve-Wiedemann Syndrome: Update on Clinical and Genetic Aspects
Authors: Romeo Bertola Débora , Honjo Rachel S. , Baratela Wagner A.R.
Published: March 2016

Stüve-Wiedemann syndrome is a rare autosomal recessive disorder characterized by bowed long bones, joint restrictions, dysautonomia, and respiratory and feeding difficulties, leading to death in the neonatal period and infancy in several occasions. Since the first cases in 1971, much has been learned about this condition, including its molecular basis - mutations in the leukemia inhibitory factor receptor gene (LIFR) -, natural history and management possibilities. This review aims to highlight the clinical aspects, radiological features, molecular findings, and management strategies in Stüve-Wiedemann syndrome.
Progressive Multifocal Leukoencephalopathy and Systemic Lupus Erythematosus: Focus on Etiology
Authors: Ghaderi Berntsson Shala , Katsarogiannis Evangelos , Lourenço Filipa , Moraes-Fontes Maria Francisca
Published: March 2016

Progressive multifocal leukoencephalopathy (PML) caused by reactivation of the JC virus (JCV), a human polyomavirus, occurs in autoimmune disorders, most frequently in systemic lupus erythematosus (SLE). We describe a HIV-negative 34-year-old female with SLE who had been treated with immunosuppressant therapy (IST; steroids and azathioprine) since 2004. In 2011, she developed decreased sensation and weakness of the right hand, followed by vertigo and gait instability. The diagnosis of PML was made on the basis of brain MRI findings (posterior fossa lesions) and JCV isolation from the cerebrospinal fluid (700 copies/ml). IST was immediately discontinued. Cidofovir, mirtazapine, mefloquine and cycles of cytarabine were sequentially added, but there was progressive deterioration with a fatal outcome 1 year after disease onset. This report discusses current therapeutic choices for PML and the importance of early infection screening when SLE patients present with neurological symptoms. In the light of recent reports of PML in SLE patients treated with rituximab or belimumab, we highlight that other IST may just as well be implicated. We conclude that severe lymphopenia was most likely responsible for JCV reactivation in this patient and discuss how effective management of lymphopenia in SLE and PML therapy remains an unmet need.
Metabolite Profiles Predict Acute Kidney Injury and Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Elmariah Sammy , Farrell Laurie A. , Daher Maureen , Shi Xu , Keyes Michelle J. , Cain Carolyn H. , Pomerantsev Eugene , Vlahakes Gus J. , Inglessis Ignacio , Passeri Jonathan J. , Palacios Igor F. , Fox Caroline S. , Rhee Eugene P. , Gerszten Robert E.
Published: March 2016

Background

Acute kidney injury (
AKI
) occurs commonly after transcatheter aortic valve replacement (
TAVR
) and is associated with markedly increased postoperative mortality. We previously identified plasma metabolites predictive of incident chronic kidney disease, but whether metabolite profiles can identify those at risk of
AKI
is unknown.

Methods and Results

We performed liquid chromatography–mass spectrometry–based metabolite profiling on plasma from patients undergoing
TAVR
and subjects from the community‐based Framingham Heart Study (N=2164).
AKI
was defined by using the Valve Academic Research Consortium‐2 criteria. Of 44 patients (mean age 82±9 years, 52% female) undergoing
TAVR
, 22 (50%) had chronic kidney disease and 9 (20%) developed
AKI
. Of 85 metabolites profiled, we detected markedly concordant cross‐sectional metabolic changes associated with chronic kidney disease in the hospital‐based
TAVR
and Framingham Heart Study cohorts. Baseline levels of 5‐adenosylhomocysteine predicted
AKI
after
TAVR
, despite adjustment for baseline glomerular filtration rate (odds ratio per 1‐
SD
increase 5.97, 95%
CI
1.62–22.0;
P
=0.007). Of the patients who had
AKI
, 6 (66.7%) subsequently died, compared with 3 (8.6%) deaths among those patients who did not develop
AKI
(
P
=0.0008) over a median follow‐up of 7.8 months. 5‐adenosylhomocysteine was predictive of all‐cause mortality after
TAVR
(hazard ratio per 1‐
SD
increase 2.96, 95%
CI
1.33–6.58;
P
=0.008), independent of baseline glomerular filtration rate.

Conclusions

In an elderly population with severe aortic stenosis undergoing
TAVR
, metabolite profiling improves the prediction of AKI. Given the multifactorial nature of
AKI
after
TAVR
, metabolite profiles may identify those patients with reduced renal reserve.
Prospective Association Between the Dietary Inflammatory Index and Cardiovascular Diseases in the SUpplémentation en VItamines et Minéraux AntioXydants (SU.VI.MAX) Cohort
Authors: Neufcourt Lola , Assmann Karen E. , Fezeu Léopold K. , Touvier Mathilde , Graffouillère Laurie , Shivappa Nitin , Hébert James R. , Wirth Michael D. , Hercberg Serge , Galan Pilar , Julia Chantal , Kesse‐Guyot Emmanuelle
Published: March 2016

Background

Cardiovascular diseases (CVD) are the leading cause of death in the world, and diet plays a major role in CVD incidence, especially through lipid oxidation mechanisms. This, in turn, leads to tissue inflammation and formation of atheromatous plaques.

Methods and Results

Our objective was to evaluate the association between the inflammatory potential of the diet and the incidence of overall CVD or its subclasses. We included 7743 participants from the Supplémentation en Vitamines et Minéraux AntioXydants (SU.VI.MAX) cohort. All cardiovascular events were recorded using self‐reported information or clinical visits, and were validated. The dietary inflammatory index (DII) was computed using repeated 24‐hour dietary records (mean=9.5±3.4 records/subject). Hazard ratio and 95% CI for outcomes (CVD and subclasses) were estimated across sex‐specific quartiles of the DII using Cox proportional hazard models. A total of 292 cardiovascular events were recorded and validated during an average of 11.4 years of follow‐up: 93 myocardial infarctions, 58 strokes, 128 angina pectoris and revascularization interventions, and 13 sudden deaths. When considering CVD subclasses, a diet with pro‐inflammatory properties, as expressed by higher DII scores, was significantly associated with a higher risk of myocardial infarction (hazard ratio
Quartile 4 versus Quartile 1
=2.24, 95% CI: 1.08–4.67). No significant association was observed between the DII score and stroke or both angina pectoris and revascularization intervention.

Conclusions

A pro‐inflammatory diet, as measured by a higher DII score, was prospectively associated with a higher risk of myocardial infarction. Promotion of a diet exhibiting anti‐inflammatory properties may help prevent myocardial infarctions.
Incidence and In‐Hospital Mortality of Acute Kidney Injury (AKI) and Dialysis‐Requiring AKI (AKI‐D) After Cardiac Catheterization in the National Inpatient Sample
Authors: Brown Jeremiah R. , Rezaee Michael E. , Nichols Elizabeth L. , Marshall Emily J. , Siew Edward D. , Matheny Michael E.
Published: March 2016

Background

Acute kidney injury (
AKI
) and dialysis‐requiring
AKI
(
AKI
‐D) are common, serious complications of cardiac procedures.

Methods and Results

We evaluated 3 633 762 (17 765 214 weighted population) cardiac catheterization or percutaneous coronary intervention (
PCI
) hospital discharges from the nationally representative National Inpatient Sample to determine annual population incidence rates for
AKI
and
AKI
‐D in the United States from 2001 to 2011. Odds ratios for both conditions and associated in‐hospital mortality were calculated for each year in the study period using multiple logistic regression. The number of cardiac catheterization or
PCI
cases resulting in
AKI
rose almost 3‐fold from 2001 to 2011. The adjusted odds of
AKI
and
AKI
‐D per year among cardiac catheterization and
PCI
patients were 1.11 (95%
CI
: 1.10–1.12) and 1.01 (95%
CI
: 0.99–1.02), respectively. Most importantly, in‐hospital mortality significantly decreased from 2001 to 2011 for
AKI
(19.6–9.2%) and
AKI
‐D (28.3–19.9%), whereas odds of associated in‐hospital mortality were 0.50 (95%
CI
: 0.45–0.56) and 0.70 (95%
CI
: 0.55–0.93) in 2011 versus 2001, respectively. The population‐attributable risk of mortality for
AKI
and
AKI
‐D was 25.8% and 3.8% in 2001 and 41.1% and 6.5% in 2011, respectively. Males and females had similar patterns of
AKI
increase, although males outpaced females.

Conclusions

The Incidence of
AKI
among cardiac catheterization and
PCI
patients has increased sharply in the United States, and this should be addressed by implementing prevention strategies. However, mortality has significantly declined, suggesting that efforts to manage
AKI
and
AKI
‐D after cardiac catheterization and
PCI
have reduced mortality.
Ultrathin Strut Biodegradable Polymer Sirolimus‐Eluting Stent Versus Durable‐Polymer Everolimus‐Eluting Stent for Percutaneous Coronary Revascularization: 2‐Year Results of the BIOSCIENCE Trial
Authors: Zbinden Rainer , Piccolo Raffaele , Heg Dik , Roffi Marco , Kurz David J. , Muller Olivier , Vuilliomenet André , Cook Stéphane , Weilenmann Daniel , Kaiser Christoph , Jamshidi Peiman , Franzone Anna , Eberli Franz , Jüni Peter , Windecker Stephan , Pilgrim Thomas
Published: March 2016

Background

No data are available on the long‐term performance of ultrathin strut biodegradable polymer sirolimus‐eluting stents (
BP
‐
SES
). We reported 2‐year clinical outcomes of the
BIOSCIENCE
(Ultrathin Strut Biodegradable Polymer Sirolimus‐Eluting Stent Versus Durable Polymer Everolimus‐Eluting Stent for Percutaneous Coronary Revascularisation) trial, which compared
BP
‐
SES
with durable‐polymer everolimus‐eluting stents (
DP
‐
EES
) in patients undergoing percutaneous coronary intervention.

Methods and Results

A total of 2119 patients with minimal exclusion criteria were assigned to treatment with
BP
‐
SES
(n=1063) or
DP
‐
EES
(n=1056). Follow‐up at 2 years was available for 2048 patients (97%). The primary end point was target‐lesion failure, a composite of cardiac death, target‐vessel myocardial infarction, or clinically indicated target‐lesion revascularization. At 2 years,
target‐lesion failure
occurred in 107 patients (10.5%) in the
BP
‐
SES
arm and 107 patients (10.4%) in the
DP
‐
EES
arm (risk ratio [
RR
] 1.00, 95%
CI
0.77–1.31,
P
=0.979). There were no significant differences between
BP
‐
SES
and
DP
‐
EES
with respect to cardiac death (
RR
1.01, 95%
CI
0.62–1.63,
P
=0.984), target‐vessel myocardial infarction (
RR
0.91, 95%
CI
0.60–1.39,
P
=0.669),
target‐lesion revascularization
(
RR
1.17, 95%
CI
0.81–1.71,
P
=0.403), and definite stent thrombosis (
RR
1.38, 95%
CI
0.56–3.44,
P
=0.485). There were 2 cases (0.2%) of definite very late stent thrombosis in the
BP
‐
SES
arm and 4 cases (0.4%) in the
DP
‐
EES
arm (
P
=0.423). In the prespecified subgroup of patients with
ST
‐segment elevation myocardial infarction,
BP
‐
SES
was associated with a lower risk of
target‐lesion failure
compared with
DP
‐
EES
(
RR
0.48, 95%
CI
0.23–0.99,
P
=0.043,
P
interaction
=0.026).

Conclusions

Comparable safety and efficacy profiles of
BP
‐
SES
and
DP
‐
EES
were maintained throughout 2 years of follow‐up.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
01443104.
Sumoylation of LYS590 of NCX3 f-Loop by SUMO1 Participates in Brain Neuroprotection Induced by Ischemic Preconditioning
Authors: Cuomo Ornella , Pignataro Giuseppe , Sirabella Rossana , Molinaro Pasquale , Anzilotti Serenella , Scorziello Antonella , Sisalli Maria Josè , Di Renzo Gianfranco , Annunziato Lucio
Published: March 2016

Background and Purpose—

The small ubiquitin-like modifier (SUMO), a ubiquitin-like protein involved in posttranslational protein modifications, is activated by several conditions, such as heat stress, hypoxia, and hibernation and confers neuroprotection. Sumoylation enzymes and substrates are expressed also at the plasma membrane level. Among the numerous plasma membrane proteins controlling ionic homeostasis during cerebral ischemia, 1 of the 3 brain sodium/calcium exchangers (NCX3), exerts a protective role during ischemic preconditioning. In this study, we evaluated whether NCX3 is a target for sumoylation and whether this posttranslational modification participates in ischemic preconditioning-induced neuroprotection. To test these hypotheses, we analyzed (1) SUMO1 conjugation pattern after ischemic preconditioning; (2) the effect of SUMO1 knockdown on the ischemic damage after transient middle cerebral artery occlusion and ischemic preconditioning, (3) the possible interaction between SUMO1 and NCX3 and (4) the molecular determinants of NCX3 sequence responsible for sumoylation.

Methods—

Focal brain ischemia and ischemic preconditioning were induced in rats by middle cerebral artery occlusion. SUMOylation was evaluated by western blot and immunohistochemistry. SUMO1 and NCX3 interaction was analyzed by site-directed mutagenesis and immunoprecipitation assay.

Results—

We found that (1) SUMO1 knockdown worsened ischemic damage and reduced the protective effect of preconditioning; (2) SUMO1 bound to NCX3 at lysine residue 590, and its silencing increased NCX3 degradation; and (3) NCX3 sumoylation participates in SUMO1 protective role during ischemic preconditioning. Thus, our results demonstrate that NCX3 sumoylation confers additional neuroprotection in ischemic preconditioning.

Conclusions—

Finally, this study suggests that NCX3 sumoylation might be a new target to enhance ischemic preconditioning-induced neuroprotection.
Exendin-4 Inhibits Matrix Metalloproteinase-9 Activation and Reduces Infarct Growth After Focal Cerebral Ischemia in Hyperglycemic Mice
Authors: Kuroki Takuma , Tanaka Ryota , Shimada Yoshiaki , Yamashiro Kazuo , Ueno Yuji , Shimura Hideki , Urabe Takao , Hattori Nobutaka
Published: March 2016

Background and Purpose—

Admission hyperglycemia is an independent risk factor for poor outcome of ischemic stroke. Amelioration of hyperglycemia by insulin has not been shown to improve the poststroke outcome. Glucagon-like peptide 1 receptor agonists, which modulate glucose levels by stimulating insulin secretion, have been shown to exert cytoprotective effects by inhibiting inflammation and oxidative stress. This study aimed to evaluate whether the glucagon-like peptide 1 receptor agonist exendin-4 could reduce glucose levels and exert protective effects after acute focal ischemia in hyperglycemic mice.

Methods—

Hyperglycemia was induced by intraperitoneal injection of dextrose 15 minutes before transient middle cerebral artery occlusion was performed for 60 minutes using an intraluminal thread. We assessed 4 groups: (1) normal glucose (vehicle control), (2) induced hyperglycemia, (3) induced hyperglycemia with insulin treatment, and (4) induced hyperglycemia with exendin-4 treatment. Neurovascular injuries in brains from each group were evaluated 24 hours and 7 days post ischemia.

Results—

Hyperglycemia significantly increased infarct volume (36.3±1.20 versus 26.9±1.28;
P
<0.001), brain edema (
P
<0.05), and hemorrhagic transformation compared with control (
P
<0.001). This increase in infarct volume was associated with increased blood–brain barrier disruption and matrix metalloproteinase-9 activation. Exendin-4, but not insulin, attenuated matrix metalloproteinase-9 activation, proinflammatory cytokine (tumor necrosis factor-α) release, and biomarkers of oxidative stress and showed significant inhibition of infarct growth at 24 hours (23.6±0.97 versus 36.3±1.20;
P
<0.001) and at 7 days after ischemia (21.0±0.92 versus 29.3±1.41;
P
<0.001).

Conclusions—

Treatment with exendin-4 could be a potentially useful therapeutic option for treatment of acute ischemic stroke with transient hyperglycemia.
UN EMPLOI PARTICULIER DE LA PARTICULE ZHE DANS LE PARLER DE HONGTONG (SHANXI)
Authors: Quansheng Qiao
Published: March 2016

The Hongtong district is located in the Southern part of the Shanxi province. This paper analyzes the different uses of the aspectual particle zhe in the Hongtong dialect, especially those which are different from Contemporary Standard Chinese.

The aspectual particle zhe can follow a "Verb + Object" compound in which the object is a noun, an NP, a VP or a "Subject + predicate" construction. A resultative or directional complement can also be inserted between a verb/adjective and the particle zhe. Finally, the verb/adjective preceding zhe can be reduplicated.

All these structures were already attested in the vernacular language of the Tang and Song periods.
ACOUSTIC QUANTIFICATION OF TONE SPREADING IN DAISHAN AND MENDE
Authors: TODA Takako
Published: March 2016

This paper examines the nature of ‘tone spreading’ in Daishan , a northern Wu dialect of Chinese, from the viewpoint of acoustic phonetics. It compares the mean falling fundamental frequency (FO) contour of disyllabic lexical items with that of monosyllabic citation forms in order to investigate if they are the same. The result shows that they are nearly identical, and therefore, demonstrates phonetic tone spreading as well as phonological tone spreading

Acoustic data from Mende (Kupa Mende : Sierra Leone) are then presented and contrasted with those of Daishan. It is shown that the contouricity of the F О in fact differs between these two varieties. This result brings into question the autosegmentally based representation of tones using non-contour features such as HL, which has been commonly applied to the analysis of Wu tone sandhi. Finally, it is suggested that unitary contour features of tone, such as [falling], be applied in the case of Daishan tone spreading.
The Curious Incident of Attention in Multisensory Integration: Bottom-up vs. Top-down
Authors: Macaluso Emiliano , Noppeney Uta , Talsma Durk , Vercillo Tiziana , Hartcher-O’Brien Jess , Adam Ruth
Published: March 2016

The role attention plays in our experience of a coherent, multisensory world is still controversial. On the one hand, a subset of inputs may be selected for detailed processing and multisensory integration in a top-down manner, i.e., guidance of multisensory integration by attention. On the other hand, stimuli may be integrated in a bottom-up fashion according to low-level properties such as spatial coincidence, thereby capturing attention. Moreover, attention itself is multifaceted and can be describedviaboth top-down and bottom-up mechanisms. Thus, the interaction between attention and multisensory integration is complex and situation-dependent. The authors of this opinion paper are researchers who have contributed to this discussion from behavioural, computational and neurophysiological perspectives. We posed a series of questions, the goal of which was to illustrate the interplay between bottom-up and top-down processes in various multisensory scenarios in order to clarify the standpoint taken by each author and with the hope of reaching a consensus. Although divergence of viewpoint emerges in the current responses, there is also considerable overlap: In general, it can be concluded that the amount of influence that attention exerts on MSI depends on the current task as well as prior knowledge and expectations of the observer. Moreover stimulus properties such as the reliability and salience also determine how open the processing is to influences of attention.
Inside the Dogon Masks: The Selection of Woods for Ritual Objects
Authors: Bontadi Jarno , Bernabei Mauro
Published: March 2016

At the foot of the Bandiagara cliffs in Mali lives one of the most studied and yet most mysterious ethnic groups of West Africa, the Dogon. According to their religion, masks have a key role in traditional rites, since they are the link between the earthly and the divine. The production and maintenance of such important tools have precise rules handed down by the Dogon secret society called Awa. Fifteen traditional Dogon masks were studied to ascertain the wood species selected to carve them. The analysis shows the occasional use of marula (Sclerocarya birrea, 3 masks) and African grape (Lannea spec., 2 masks) and a preference for ceiba (Ceiba pentandra, 10 masks), a tree revered as sacred by the Dogon. The results suggest potential implications concerning the use of trees and woods in Dogon tradition.
Agapetes xiana sp. nov. (Ericaceae) from Xizang, China
Authors: TONG YI HUA
Published: March 2016

Agapetes xiana sp. nov., from Southeast Xizang, China is described and illustrated here. It is similar to A. xizangensis and A. subansirica, but differs from the former by its larger leaves, longer pedicels, smaller calyx lobes, yellowish green corollas and longer stamens, and from the latter by having inflorescences with fewer flowers, much longer pedicels, corollas and stamens. Its taxonomic position is also discussed.
Lipoprotein(a) Levels in Patients With Abdominal Aortic Aneurysm
Authors: Kotani Kazuhiko , Sahebkar Amirhossein , Serban Maria-Corina , Ursoniu Sorin , Mikhailidis Dimitri P. , Mariscalco Giovanni , Jones Steven R. , Martin Seth , Blaha Michael J. , Toth Peter P. , Rizzo Manfredi , Kostner Karam , Rysz Jacek , Banach Maciej ,   Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group
Published: March 2016

Circulating markers relevant to the development of abdominal aortic aneurysm (AAA) are currently required. Lipoprotein(a), Lp(a), is considered a candidate marker associated with the presence of AAA. The present meta-analysis aimed to evaluate the association between circulating Lp(a) levels and the presence of AAA. The PubMed-based search was conducted up to April 30, 2015, to identify the studies focusing on Lp(a) levels in patients with AAA and controls. Quantitative data synthesis was performed using a random effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. Overall, 9 studies were identified. After a combined analysis, patients with AAA were found to have a significantly higher level of Lp(a) compared to the controls (SMD: 0.87, 95% CI: 0.41-1.33, P < .001). This result remained robust in the sensitivity analysis, and its significance was not influenced after omitting each of the included studies from the meta-analysis. The present meta-analysis confirmed a higher level of circulating Lp(a) in patients with AAA compared to controls. High Lp(a) levels can be associated with the presence of AAA, and Lp(a) may be a marker in screening for AAA. Further studies are needed to establish the clinical utility of measuring Lp(a) in the prevention and management of AAA.
Endovascular Therapy for Infrainguinal Artery Disease With Coronary Devices
Authors: Giordano Arturo , Ferraro Paolo , Corcione Nicola , Messina Stefano , Maresca Gennaro , Coscioni Enrico , Avellino Raffaella , Giordano Gabriele , Peruzzi Mariangela , Biondi-Zoccai Giuseppe
Published: March 2016

Several devices are available for infrainguinal endovascular therapy, with drug-eluting stents (DES) among the most promising. Bioresorbable vascular scaffolds (BVS) may further improve outcomes. We have liberally used in our practice coronary DES and BVS for infrainguinal endovascular therapy and hereby report our preliminary results. We conducted an observational study by retrospectively identifying characteristics of patients undergoing infrainguinal implantation of coronary DES or BVS. We compared the risk of major adverse events (MAE: death, amputation, or target vessel revascularization [TVR]) and components of MAE in the overall sample and after propensity matching. We included a total of 204 patients (207 limbs), 148 (72.5%) treated with DES and 56 (27.5%) with BVS. Bivariate analysis showed that TVR was less common in the DES group (41.9% vs 18.4%, P = .014). However, propensity-matched analysis showed nearly identical risks of MAE, amputation, TVR, or symptom burden with DES and BVS (all P > .05). In conclusion, the present pilot experience with coronary BVS suggests that they could provide acceptable results for infrainguinal endovascular procedures, comparable to those obtained by their metallic counterpart.
Efficacy and Safety of Endovascular Therapy for Aortoiliac TASC D Lesions
Authors: Suzuki Kenji , Mizutani Yukiko , Soga Yoshimitsu , Iida Osamu , Kawasaki Daizo , Yamauchi Yasutaka , Hirano Keisuke , Koshida Ryouji , Kamoi Daisuke , Tazaki Junichi , Higashitani Michiaki , Shintani Yoshiaki , Yamaoka Terutoshi , Okazaki Shinya , Suematsu Nobuhiro , Tsuchiya Taketsugu , Miyashita Yusuke , Shinozaki Norihiko , Takahashi Hiroki , Inoue Naoto
Published: March 2016

Background:

Although there is increasing evidence of the effectiveness of endovascular therapy for complex aortoiliac (AI) occlusive disease, it is not universally applied to TASC D lesions.

Methods:

A total of 2096 patients, 2601 limbs with AI occlusive disease, were enrolled. The lesions were categorized as TASC D (395) or TASC A-C (2206), and we compared baseline data, procedure, and follow-up result between the 2 groups.

Results:

The success rate of the procedure was significantly lower in the TASC D group (91.6% vs 99.3%, P < .01), and more procedure complications occurred in the TASC D group (11.1% vs 5.2%, P < .01). The results of a 5-year follow-up revealed no significant difference in primary patency (77.9% vs 77.1%, P = .17) and major adverse cardiovascular and limb events (MACLE; 30.5% vs 33.4%, P = .42) between the 2 groups. A multivariate analysis revealed complications and critical limb ischemia are independent predictors of MACLE in the TASC D group.

Conclusion:

The success rate of the procedure was lower in the TASC D group. Complications were more frequent in the TASC D group, and they were related to MACLE.
Bourdieu and the gendered social structure of working time: A study of self-employed human resources professionals
Authors: Vincent Steve
Published: March 2016

This article uses the sociology of Bourdieu to explore the social structure of working time and uses this approach to analyse interview data from 25 self-employed human resources professionals practicing in the UK. Bourdieu’s approach to exploring resources, as forms of capital that are deployed strategically by actors within social fields, is used to compare outcomes for respondents with different working time patterns. The findings demonstrate that self-employed professionals’ uses of resources are affected by distinctive and gendered temporal rhythms within and between social fields. These temporal patterns typically serve the interests of well-resourced (more typically male) actors who structure their lives according to specific routines. Self-employed people with less working time often struggle to synchronize their lives with their environments and so are often at a disadvantage in accessing and using resources. The analysis, which develops novel propositions about the ways in which actors become differentially adapted to the social structure of time, facilitates a more fine-grained and relational appreciation of gendered advantages within self-employed careers, which is likely to have wider applicability and the potential for broader impact.