bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective Nuclear Export Inhibitor KPT-330 Enhances the Antitumor Activity of Gemcitabine in Human Pancreatic Cancer
Authors: Kazim Sabiha , Malafa Mokenge P. , Coppola Domenico , Husain Kazim , Zibadi Sherma , Kashyap Trinayan , Crochiere Marsha , Landesman Yosef , Rashal Tami , Sullivan Daniel M. , Mahipal Amit
Published: May 2015

Pancreatic cancer is an aggressive and deadly malignancy responsible for the death of over 37,000 Americans each year. Gemcitabine-based therapy is the standard treatment for pancreatic cancer but has limited efficacy due to chemoresistance. In this study, we evaluated the in vitro and in vivo effects of gemcitabine combined with the selective nuclear export (CRM1) inhibitor KPT-330 on pancreatic cancer growth. Human pancreatic cancer MiaPaCa-2 and metastatic pancreatic cancer L3.6pl cell lines were treated with different concentrations of KPT-330 and gemcitabine alone or in combination, and anchorage–dependent/independent growth was recorded. In addition, L3.6pl cells with luciferase were injected orthotopically into the pancreas of athymic nude mice, which were treated with (i) vehicle (PBS 1 mL/kg i.p., 2/week and povidone/pluronic F68 1 mL/kg p.o., 3/week), (ii) KPT-330 (20 mg/kg p.o., 3/week), (iii) gemcitabine (100 mg/kg i.p., 2/week), or (iv) KPT-330 (10 mg/kg) + gemcitabine (50 mg/kg) for 4 weeks. KPT-330 and gemcitabine alone dose-dependently inhibited anchorage-dependent growth in vitro and tumor volume in vivo compared with vehicle treatment. However, the combination inhibited growth synergistically. In combination, KPT-330 and gemcitabine acted synergistically to enhance pancreatic cancer cell death greater than each single-agent therapy. Mechanistically, KPT-330 and gemcitabine promoted apoptosis, induced p27, depleted survivin, and inhibited accumulation of DNA repair proteins. Together, our data suggest that KPT-330 potentiates the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, depletion of the antiapoptotic proteins, and induction of apoptosis. Mol Cancer Ther; 14(7); 1570–81. ©2015 AACR.
Abstract 3637: Targeted inhibition of MER tyrosine kinase in the tumor microenvironment decreases tumor growth in a mouse model of breast cancer
Authors: Jacobsen Kristen M. , DeRyckere Deborah , Zhang Weihe , Wang Xiaodong , Frye Stephen V. , Earp H. Shelton , Graham Douglas K.
Published: May 2015

Tumor-associated macrophages (TAMs) and other tumor-infiltrating myeloid-derived cells are known to support tumor growth, proliferation and metastasis. Increased numbers of TAMs are also associated with poor prognosis in many solid tumors, including breast cancer. Previous studies have shown that targeting TAMs, either by re-programming or depletion, is an effective method to reduce solid tumor growth. MER, a receptor tyrosine kinase, is expressed on macrophages. MER-dependent signaling upon recognition and ingestion of apoptotic material (efferocytosis) suppresses proinflammatory cytokine production and increases secretion of immunosuppressive, wound healing cytokines. Recently we have identified MER as a potential therapeutic target in the tumor microenvironment utilizing polyoma middle T (PyVmT) orthotopic and transgenic models of breast cancer in Mertk-/- mice. Genetic deletion of MER in the tumor microenvironment led to a reduction in tumor growth, as well as increased proinflammatory cytokines and decreased IL-10 production.

To further investigate the utility of MER inhibition in the tumor microenvironment as a therapeutic strategy, the efficacy of a first in class MER-selective, orally bioavailable, small molecule tyrosine kinase inhibitor (UNC TKI) was evaluated in immunocompetent C57Bl/6 mice implanted orthotopically with PyVmT mammary gland tumor cells. These PyVmT tumors cells do not express MER, AXL or TYRO3. Treatment with UNC TKI inhibited phosphorylation of MER in mouse macrophages in vitro, but did not affect survival of macrophages or MER-negative PyVmT tumor cells. However, after four weeks of daily treatment with UNC TKI, primary tumor growth was reduced two-fold compared to vehicle-treated tumor bearing mice. Serum IL-10 and IL-4 levels were reduced by 20% and 30%, respectively, in UNC TKI treated tumor-bearing mice compared to vehicle-treated tumor-bearing mice. Taken together, these data suggest that MER inhibition in the tumor microenvironment reduces tumor growth by altering the immunosuppressive environment and stimulating anti-tumor immunity. Moreover, these data validate UNC TKI as a promising strategy for immune-mediated treatment of breast cancer.

Citation Format: Kristen M. Jacobsen, Deborah DeRyckere, Weihe Zhang, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Douglas K. Graham. Targeted inhibition of MER tyrosine kinase in the tumor microenvironment decreases tumor growth in a mouse model of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3637. doi:10.1158/1538-7445.AM2014-3637
Abstract 3774: Hyperthermia treatment overcomes temozolomide resistance in glioma cells by downregulating MGMT expression and increasing temozolomide uptake
Authors: Lee Chen-Ting , Blackley Aaron , Landon Chelsea , Spasojevic Ivan , Kirkpatrick John P. , Dewhirst Mark W.
Published: May 2015

Glioblastoma multiforme (GBM) is the most common and malignant brain tumor. Current standard treatment for GBM following maximum safe resection includes temozolomide (TMZ) with concurrent radiotherapy. Despite the improvement of survival by TMZ and radiation, the overall prognosis remains poor for GBM patients. This is partially attributed to drug resistance. Expression of DNA repair protein O6-methylguanine methyltransferase (MGMT) in gliomas confers TMZ resistance and a worse prognosis. Therefore, development of novel therapy to suppress MGMT expression and overcome TMZ resistance is highly desired. Hyperthermia has been shown to increase TMZ sensitivity in melanoma and this provides a good rationale to evaluate whether hyperthermia overcomes TMZ resistance in glioblastoma cells.

In this study, we investigated the effect of hyperthermia treatment (43

°C) on TMZ sensitivity of four human glioblastoma cell lines using clonogenic assays. Our results showed that hyperthermia treatment increased TMZ-induced cell death in TMZ-resistant glioma cells, but had no additional beneficial effect in the TMZ-sensitive cells. Hyperthermia in combination with radiation further overcame TMZ resistance. To study the molecular targets, we found that hyperthermia downregulated MGMT expression through increasing proteasome-mediated MGMT degradation, which can be reversed by the proteasome inhibitor bortezomib. Hyperthermia had no effects on p53 expression and MGMT promoter methylation which was responsible for MGMT gene silencing. In addition, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed an increase of TMZ and its downstream product 5-aminoimidazole-4-carboxamide (AIC) in hyperthermia-treated cells, indicating an increase of TMZ drug uptake and breakdown.

In conclusion, these results suggest that hyperthermia overcomes MGMT-mediated resistance of glioblastoma cell lines to TMZ and increases TMZ drug uptake. This study suggests a potential benefit of using hyperthermia in the treatment of GBM, particularly those with more adverse prognosis.

This work was supported by Debrule Research Fund.

Citation Format: Chen-Ting Lee, Aaron Blackley, Chelsea Landon, Ivan Spasojevic, John P. Kirkpatrick, Mark W. Dewhirst. Hyperthermia treatment overcomes temozolomide resistance in glioma cells by downregulating MGMT expression and increasing temozolomide uptake. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3774. doi:10.1158/1538-7445.AM2014-3774
Abstract 3885: ITGA6 (CD49F) is directly regulated by hypoxia-inducible factors
Authors: Peacock Danielle L. , Schwab Luciana P. , Seagroves Tiffany N.
Published: May 2015

Introduction: In response to hypoxic stress, tumors must adapt to the hostile microenvironment by regulating angiogenesis, cellular metabolism, cell survival and motility. The alpha subunits of the Hypoxia-Inducible Factors (HIF-1α and HIF-2α) are oxygen-responsive, master regulators of the hypoxic response. Over-expression of HIF-1α independently correlates with decreased survival of breast cancer patients, and a hypoxic core gene signature is enriched in triple negative breast cancers (TNBC) and HER2+ cancers relative to luminal tumors (ER+). In a variety of solid tumors, HIF-1α or HIF-2α also directly promotes tumor initiating cell (TIC) activity. Methods: Mammary tumor epithelial cells (MTECs) were established from late-stage tumors of MMTV-PyMT+; Hif1α floxed mice (which model ER-negative, luminal-like tumors), and exposed to either Adenovirus-β-gal or -Cre to create wild-type (WT) and knock-out (KO) cells, respectively. MDA-MB-231 cells (a model of TNBC) were generated in which either HIF1A or HIF2A or both genes (DKD) were knocked down (KD) via shRNA. Results: When PyMT+ MTECs were transplanted into female recipients, HIF-1 deletion reduced primary tumor growth by 60%, lung metastasis by 90% and TIC activity by >35-fold (Schwab et al. 2012). The expression of cell surface markers routinely used to enrich for TICs was assayed in PyMT+ and MDA-MB-231 cells. ITGA6 mRNA and CD49f protein expression were significantly decreased in response to HIF deletion at both normoxia and hypoxia. ChIP assays showed that either HIF-1 or HIF-2 bind to at least two HREs identified within the ITGA6 promoter. When WT PyMT tumors were sorted to enrich for CD49fhi cells, limiting dilution transplantation confirmed that TIC activity was increased relative to CD49low cells. Finally, data mining of breast cancer patient repositories showed that ITGA6 mRNA expression is independently and inversely correlated with overall and recurrence free survival. Conclusions: CD49f is a direct transcriptional target of HIF-1/HIF-2. Because CD49f is known to enrich for breast TICs, we suggest that HIF-dependent regulation of ITGA6 expression contributes at least partially to HIFs promotion of TIC activity in ER-negative breast cancers.

Citation Format: Danielle L. Peacock, Luciana P. Schwab, Tiffany N. Seagroves. ITGA6 (CD49F) is directly regulated by hypoxia-inducible factors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3885. doi:10.1158/1538-7445.AM2014-3885
Therapeutic Targeting of Nuclear γ-Tubulin in RB1-Negative Tumors
Authors: Lindström Lisa , Villoutreix Bruno O. , Lehn Sophie , Hellsten Rebecka , Nilsson Elise , Crneta Enisa , Olsson Roger , Alvarado-Kristensson Maria
Published: May 2015

In addition to its cytosolic function, γ-tubulin is a chromatin-associated protein. Reduced levels of nuclear γ-tubulin increase the activity of E2 promoter-binding factors (E2F) and raise the levels of retinoblastoma (RB1) tumor suppressor protein. In tumor cells lacking RB1 expression, decreased γ-tubulin levels induce cell death. Consequently, impairment of the nuclear activity of γ-tubulin has been suggested as a strategy for targeted chemotherapy of RB1-deficient tumors; thus, tubulin inhibitors were tested to identify compounds that interfere with γ-tubulin. Interestingly, citral increased E2F activity but impaired microtubule dynamics while citral analogues, such citral dimethyl acetal (CDA), increased E2F activity without affecting microtubules. The cytotoxic effect of CDA on tumor cells was attenuated by increased expression of either RB1 or γ-tubulin, and increased by reduced levels of either RB1 or γ-tubulin. Mechanistic study, in silico and in vitro, demonstrated that CDA prevents GTP binding to γ-tubulin and suggested that the FDA-approved drug dimethyl fumarate is also a γ-tubulin inhibitor. Finally, in vivo growth of xenograft tumors carrying defects in the RB1 signaling pathway were inhibited by CDA treatment. These results demonstrate that inhibition of γ-tubulin has the potential to specifically target tumor cells and may aid in the design of safer and more efficient chemotherapeutic regimes.

Implications: The in vivo antitumorigenic activity of γ-tubulin inhibitors paves the way for the development of a novel broad range targeted anticancer therapy that causes fewer side effects. Mol Cancer Res; 13(7); 1073–82. ©2015 AACR.
Targeting Translation Initiation Bypasses Signaling Crosstalk Mechanisms That Maintain High MYC Levels in Colorectal Cancer
Authors: Wiegering Armin , Uthe Friedrich W. , Jamieson Thomas , Ruoss Yvonne , Hüttenrauch Melanie , Küspert Maritta , Pfann Christina , Nixon Colin , Herold Steffi , Walz Susanne , Taranets Lyudmyla , Germer Christoph-Thomas , Rosenwald Andreas , Sansom Owen J. , Eilers Martin
Published: May 2015

Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that inhibiting MYC may have significant therapeutic value. The PI3K and mTOR pathways control MYC turnover and translation, respectively, providing a rationale to target both pathways to inhibit MYC. Surprisingly, inhibition of PI3K does not promote MYC turnover in colon carcinoma cells, but enhances MYC expression because it promotes FOXO-dependent expression of growth factor receptors and MAPK-dependent transcription of MYC. Inhibition of mTOR fails to inhibit translation of MYC, because levels of 4EBPs are insufficient to fully sequester eIF4E and because an internal ribosomal entry site element in the 5′-untranslated region of the MYC mRNA permits translation independent of eIF4E. A small-molecule inhibitor of the translation factor eIF4A, silvestrol, bypasses the signaling feedbacks, reduces MYC translation, and inhibits tumor growth in a mouse model of colorectal tumorigenesis. We propose that targeting translation initiation is a promising strategy to limit MYC expression in colorectal tumors.

Significance: Inhibiting MYC function is likely to have a significant therapeutic impact in colorectal cancers. Here, we explore several strategies to target translation initiation in order to block MYC expression. We show that a small-molecule inhibitor of eIF4A inhibits MYC expression and suppresses tumor growth in vivo. Cancer Discov; 5(7); 768–81. ©2015 AACR.

See related commentary by Castell and Larsson, p. 701.

This article is highlighted in the In This Issue feature, p. 681
Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor
Authors: Piotrowska Zofia , Niederst Matthew J. , Karlovich Chris A. , Wakelee Heather A. , Neal Joel W. , Mino-Kenudson Mari , Fulton Linnea , Hata Aaron N. , Lockerman Elizabeth L. , Kalsy Anuj , Digumarthy Subba , Muzikansky Alona , Raponi Mitch , Garcia Angel R. , Mulvey Hillary E. , Parks Melissa K. , DiCecca Richard H. , Dias-Santagata Dora , Iafrate A. John , Shaw Alice T. , Allen Andrew R. , Engelman Jeffrey A. , Sequist Lecia V.
Published: May 2015

Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790–wild-type rociletinib-resistant biopsies. Two T790–wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790–wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790–wild-type clones are required.

Significance: This report documents that half of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790–wild-type upon progression, suggesting that T790–wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms. Cancer Discov; 5(7); 713–22. ©2015 AACR.

See related commentary by Ichihara and Lovly, p. 694.

This article is highlighted in the In This Issue feature, p. 681
Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors
Authors: Wang Enxiu , Wang Liang-Chuan , Tsai Ching-Yi , Bhoj Vijay , Gershenson Zack , Moon Edmund , Newick Kheng , Sun Jing , Lo Albert , Baradet Timothy , Feldman Michael D. , Barrett David , Puré Ellen , Albelda Steven , Milone Michael C.
Published: May 2015

Chimeric antigen receptors (CAR) bearing an antigen-binding domain linked in cis to the cytoplasmic domains of CD3ζ and costimulatory receptors have provided a potent method for engineering T-cell cytotoxicity toward B-cell leukemia and lymphoma. However, resistance to immunotherapy due to loss of T-cell effector function remains a significant barrier, especially in solid malignancies. We describe an alternative chimeric immunoreceptor design in which we have fused a single-chain variable fragment for antigen recognition to the transmembrane and cytoplasmic domains of KIR2DS2, a stimulatory killer immunoglobulin-like receptor (KIR). We show that this simple, KIR-based CAR (KIR-CAR) triggers robust antigen-specific proliferation and effector function in vitro when introduced into human T cells with DAP12, an immunotyrosine-based activation motifs-containing adaptor. T cells modified to express a KIR-CAR and DAP12 exhibit superior antitumor activity compared with standard first- and second-generation CD3ζ-based CARs in a xenograft model of mesothelioma highly resistant to immunotherapy. The enhanced antitumor activity is associated with improved retention of chimeric immunoreceptor expression and improved effector function of isolated tumor-infiltrating lymphocytes. These results support the exploration of KIR-CARs for adoptive T-cell immunotherapy, particularly in immunotherapy-resistant solid tumors. Cancer Immunol Res; 3(7); 815–26. ©2015 AACR.
High-Speed Imaging Analysis of Register Transitions in Classically and Jazz-Trained Male Voices
Authors: Dippold Sebastian , Voigt Daniel , Richter Bernhard , Echternach Matthias
Published: May 2015

Background: Little data are available concerning register functions in different styles of singing such as classically or jazz-trained voices. Differences between registers seem to be much more audible in jazz singing than classical singing, and so we hypothesized that classically trained singers exhibit a smoother register transition, stemming from more regular vocal fold oscillation patterns. Methods: High-speed digital imaging (HSDI) was used for 19 male singers (10 jazz-trained singers, 9 classically trained) who performed a glissando from modal to falsetto register across the register transition. Vocal fold oscillation patterns were analyzed in terms of different parameters of regularity such as relative average perturbation (RAP), correlation dimension (D2) and shimmer. Results: HSDI observations showed more regular vocal fold oscillation patterns during the register transition for the classically trained singers. Additionally, the RAP and D2 values were generally lower and more consistent for the classically trained singers compared to the jazz singers. However, intergroup comparisons showed no statistically significant differences. Conclusion: Some of our results may support the hypothesis that classically trained singers exhibit a smoother register transition from modal to falsetto register.
Latência, adolescência e saber
Authors: Viola Daniela Teixeira Dutra , Vorcaro Ângela Maria Resende
Published: May 2015

A partir da hipótese de que a relação com o saber durante o período de latência e na passagem à puberdade tem um papel fundamental nas vicissitudes constitutivas do sujeito e no transcurso da adolescência, este trabalho se propõe a traçar um breve percurso na teoria psicanalítica no lastro das articulações entre latência, adolescência e saber, a fim de delinear uma linhainvestigativa, nas obras de Freud e de Lacan, sobre a problemática da puberdade. Com isso, almeja-se compreender melhoros impasses e embaraços que se apresentam na adolescência na contemporaneidade.
Stent Thrombosis and Dual Antiplatelet Therapy Interruption With Everolimus-Eluting Stents
Authors: Généreux Philippe , Rutledge David R. , Palmerini Tullio , Caixeta Adriano , Kedhi Elvin , Hermiller James B. , Wang Jin , Krucoff Mitchell W. , Jones-McMeans Jennifer , Sudhir Krishnankutty , Simonton Charles A. , Serruys Patrick W. , Stone Gregg W.
Published: May 2015

Background—

Whether premature dual antiplatelet therapy (DAPT) interruption is safe in patients receiving cobalt chromium everolimus–eluting stents remains controversial. We sought to examine the relationship between DAPT discontinuation and stent thrombosis (ST) after cobalt chromium everolimus-eluting stents.

Methods and Results—

Outcomes from 11 219 patients were pooled from 3 randomized trials and 4 registries with 2-year follow-up period after cobalt chromium everolimus–eluting stent implantation. Rates of definite/probable ST were analyzed according to DAPT discontinuation in the following time intervals: 0 to 30, 30 to 90, 90 to 180, 180 to 365, and 365 to 730 days. Eighty-five cases of ST (0.75%) occurred in 83 patients during 2 years, with 41 (48.2%) events occurring within 30 days. The 2-year ST rate in patients interrupting DAPT at any time was similar to that in patients never interrupting DAPT through 2 years (25/4067 [0.63%] versus 58/7152 [0.83%] respectively;
P
=0.27]. By propensity and DAPT usage–adjusted multivariable analysis, permanent DAPT discontinuation before 30 days was independently associated with the occurrence of ST (hazard ratio [95% confidence interval], 26.8 [8.4–85.4];
P
<0.0001), whereas permanent DAPT discontinuation in any interval after 90 days was not associated with ST. Only 2 ST events occurred after DAPT discontinuation between 30 and 90 days (both between 30 and 60 days), and the association between permanent DAPT discontinuation and ST during this period is unclear (hazard ratio [95% confidence interval], 8.7 [2.0–37.3];
P
=0.004 for adjusted analysis and 3.4 [0.8–13.8];
P
=0.07 for the unadjusted analysis).

Conclusions—

In this large pooled experience, permanent DAPT discontinuation before 30 days after cobalt chromium everolimus–eluting stent implantation was strongly associated with ST, whereas DAPT discontinuation beyond 90 days appeared safe.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00180310, NCT00180479, NCT00307047, NCT00402272, NCT00496938, NCT00676520, and NCT00631228.
Pharmacokinetics of Sirolimus-Eluting Stents Implanted in the Neonatal Arterial Duct
Authors: Lee Kyong-Jin , Seto Winnie , Benson Lee , Chaturvedi Rajiv R.
Published: May 2015

Background—

Sirolimus-eluting stents may have clinical advantages over bare-metal stents in the extremely proliferative environment of the neonatal arterial duct. However, sirolimus has immunosuppressive actions and little is known regarding sirolimus pharmacokinetics in the newborn.

Methods and Results—

This is a retrospective review of sirolimus pharmacokinetics in neonates who underwent sirolimus-eluting stent implantation in the arterial duct for pulmonary blood flow augmentation. Pharmacokinetic parameters were obtained by noncompartmental analysis and by a Bayesian one-compartment nonlinear mixed model. Nine neonates received a single sirolimus-eluting stent with a total sirolimus dose of 245 μg (n=1), 194 μg (n=5), or 143 μg (n=3). Peak sirolimus concentrations were 13.6±4.5 μg/L (24.8 μg/L highest) and clearance was 0.042±0.03 L/hour (noncompartmental analysis) and 0.051 L/hour (95% credible intervals 0.037–0.069, nonlinear mixed model). Sirolimus remained >5 μg/L, the trough level used in oral immunosuppressive therapy, for (95% credible interval) 15.9 (11.4, 22.8), 12.9 (7.6, 19.0), and 8.4 (2.3, 14.5) days for the 245, 194, and 143 μg sirolimus dose stents, respectively. Estimates of the duration of systemic immunosuppression are provided for combinations of 2 stents.

Conclusions—

In neonates after sirolimus-eluting stent implantation, peak sirolimus levels were 20× higher and clearance 30× lower than previously reported in older children and adults. Sirolimus levels were within the immunosuppressive range for a prolonged period, but with no observable clinically significant adverse outcomes.
Platelet Extracellular Regulated Protein Kinase 5 Is a Redox Switch and Triggers Maladaptive Platelet Responses and Myocardial Infarct Expansion
Authors: Cameron Scott J. , Ture Sara K. , Mickelsen Deanne , Chakrabarti Enakshi , Modjeski Kristina L. , McNitt Scott , Seaberry Michael , Field David J. , Le Nhat-Tu , Abe Jun-ichi , Morrell Craig N.
Published: May 2015

Background—

Platelets have a pathophysiologic role in the ischemic microvascular environment of acute coronary syndromes. In comparison with platelet activation in normal healthy conditions, less attention is given to mechanisms of platelet activation in diseased states. Platelet function and mechanisms of activation in ischemic and reactive oxygen species–rich environments may not be the same as in normal healthy conditions. Extracellular regulated protein kinase 5 (ERK5) is a mitogen-activated protein kinase family member activated in hypoxic, reactive oxygen species–rich environments and in response to receptor-signaling mechanisms. Prior studies suggest a protective effect of ERK5 in endothelial and myocardial cells after ischemia. We present evidence that platelets express ERK5 and that platelet ERK5 has an adverse effect on platelet activation via selective receptor-dependent and receptor-independent reactive oxygen species–mediated mechanisms in ischemic myocardium.

Methods and Results—

Using isolated human platelets and a mouse model of myocardial infarction (MI), we found that platelet ERK5 is activated post-MI and that platelet-specific ERK5
–/–
mice have less platelet activation, reduced MI size, and improved post-MI heart function. Furthermore, the expression of downstream ERK5-regulated proteins is reduced in ERK5
–/–
platelets post-MI.

Conclusions—

ERK5 functions as a platelet activator in ischemic conditions, and platelet ERK5 maintains the expression of some platelet proteins after MI, leading to infarct expansion. This demonstrates that platelet function in normal healthy conditions is different from platelet function in chronic ischemic and inflammatory conditions. Platelet ERK5 may be a target for acute therapeutic intervention in the thrombotic and inflammatory post-MI environment.
Increased Epithelial Sodium Channel Activity Contributes to Hypertension Caused by Na
+
-HCO
3
−
Cotransporter Electrogenic 2 Deficiency
Authors: Wen Donghai , Yuan Yang , Warner Paige C. , Wang Bangchen , Cornelius Ryan J. , Wang-France Jun , Li Huaqing , Boettger Thomas , Sansom Steven C.
Published: May 2015

The gene SLC4A5 encodes the Na
+
-HCO
3
−
cotransporter electrogenic 2, which is located in the distal nephron. Genetically deleting Na
+
-HCO
3
−
cotransporter electrogenic 2 (knockout) causes Na
+
-retention and hypertension, a phenotype that is diminished with alkali loading. We performed experiments with acid-loaded mice and determined whether overactive epithelial Na
+
channels (ENaC) or the Na
+
-Cl
−
cotransporter causes the Na
+
retention and hypertension in knockout. In untreated mice, the mean arterial pressure was higher in knockout, compared with wild-type (WT); however, treatment with amiloride, a blocker of ENaC, abolished this difference. In contrast, hydrochlorothiazide, an inhibitor of Na
+
-Cl
−
cotransporter, decreased mean arterial pressure in WT, but not knockout. Western blots showed that quantity of plasmalemmal full-length ENaC-α was significantly higher in knockout than in WT. Amiloride treatment caused a 2-fold greater increase in Na
+
excretion in knockout, compared with WT. In knockout, but not WT, amiloride treatment decreased plasma [Na
+
] and urinary K
+
excretion, but increased hematocrit and plasma [K
+
] significantly. Micropuncture with microelectrodes showed that the [K
+
] was significantly higher and the transepithelial potential (V
te
) was significantly lower in the late distal tubule of the knockout compared with WT. The reduced V
te
in knockout was amiloride sensitive and therefore revealed an upregulation of electrogenic ENaC-mediated Na
+
reabsorption in this segment. These results show that, in the absence of Na
+
-HCO
3
−
cotransporter electrogenic 2 in the late distal tubule, acid-loaded mice exhibit disinhibition of ENaC-mediated Na
+
reabsorption, which results in Na
+
retention, K
+
wasting, and hypertension.
Classical Complement Pathway Activation in the Kidneys of Women With Preeclampsia
Authors: Penning Marlies , Chua Jamie S. , van Kooten Cees , Zandbergen Malu , Buurma Aletta , Schutte Joke , Bruijn Jan Anthonie , Khankin Eliyahu V. , Bloemenkamp Kitty , Karumanchi S. Ananth , Baelde Hans
Published: May 2015

A growing body of evidence suggests that complement dysregulation plays a role in the pathogenesis of preeclampsia. The kidney is one of the major organs affected in preeclampsia. Because the kidney is highly susceptible to complement activation, we hypothesized that preeclampsia is associated with renal complement activation. We performed a nationwide search for renal autopsy material in the Netherlands using a computerized database (PALGA). Renal tissue was obtained from 11 women with preeclampsia, 25 pregnant controls, and 14 nonpregnant controls with hypertension. The samples were immunostained for C4d, C1q, mannose-binding lectin, properdin, C3d, C5b-9, IgA, IgG, and IgM. Preeclampsia was significantly associated with renal C4d—a stable marker of complement activation—and the classical pathway marker C1q. In addition, the prevalence of IgM was significantly higher in the kidneys of the preeclamptic women. No other complement markers studied differed between the groups. Our findings in human samples were validated using a soluble fms-like tyrosine kinase 1 mouse model of preeclampsia. The kidneys in the soluble fms-like tyrosine kinase 1−injected mice had significantly more C4 deposits than the control mice. The association between preeclampsia and renal C4d, C1q, and IgM levels suggests that the classical complement pathway is involved in the renal injury in preeclampsia. Moreover, our finding that soluble fms-like tyrosine kinase 1−injected mice develop excess C4 deposits indicates that angiogenic dysregulation may play a role in complement activation within the kidney. We suggest that inhibiting complement activation may be beneficial for preventing the renal manifestations of preeclampsia.
New records of marine tardigrades from Moorea, French Polynesia, with the description of Styraconyx turbinarium sp. nov. (Arthrotardigrada, Halechiniscidae)
Authors: Bartels Paul J. , Fontoura PAULO , NELSON DIANE R.
Published: May 2015

Five marine arthrotardigrade species are recorded from Moorea, Society Islands, French Polynesia. Four were collected from coral sand; two, Dipodarctus anaholiensis Pollock, 1995 and Florarctus kwoni Chang & Rho, 1997, are new records for the region, and two, Halechiniscus perfectus Schulz, 1955 and Styraconyx kristenseni kristenseni Renaud-Mornant, 1981, have been previously reported. The fifth, a new species Styraconyx turbinarium sp. nov., is described and was collected from the drifting brown alga Turbinaria ornata. The new species is characterized by the presence of peduncles on all digits, an elongate primary clava, and the lateral cirrus A arising from a common pedestal and enveloped by a common membrane extending almost to the claval tip. The new species differs from the most similar species, Styraconyx tyrrhenus D’Addabbo Gallo, Morone De Lucia & de Zio Grimaldi, 1989, by having longer and differently shaped primary clavae which are elongated in the new species and club-shaped in S. tyrrhenus. By having a dorsal cuticle that is coarsely punctated but without folds or other ornamentations, the new species can be easily distinguished from S. craticulus (Pollock, 1983), a species with similar primary clavae, but with cuticular dorsal folds ornamented with a grid-like pattern.
A Synoptic Classification of Inflow-Generating Precipitation in the Snowy Mountains, Australia
Authors: Theobald Alison , McGowan Hamish , Speirs Johanna , Callow Nik
Published: May 2015

Precipitation falling in the Snowy Mountains region of southeastern Australia provides fuel for hydroelectric power generation and environmental flows along major river systems, as well as critical water resources for agricultural irrigation. A synoptic climatology of daily precipitation that triggers a quantifiable increase in streamflow in the headwater catchments of the Snowy Mountains region is presented for the period 1958–2012. Here, previous synoptic-meteorological studies of the region are extended by using a longer-term, year-round precipitation and reanalysis dataset combined with a novel, automated synoptic-classification technique. A three-dimensional representation of synoptic circulation is developed by effectively combining meteorological variables through the depth of the troposphere. Eleven distinct synoptic types are identified, describing key circulation features and moisture pathways that deliver precipitation to the Snowy Mountains. Synoptic types with the highest precipitation totals are commonly associated with moisture pathways originating from the northeast and northwest of Australia. These systems generate the greatest precipitation totals across the westerly and high-elevation areas of the Snowy Mountains, but precipitation is reduced in the eastern-elevation areas in the lee of the mountain ranges. In eastern regions, synoptic types with onshore transport of humid air from the Tasman Sea are the major source of precipitation. Strong seasonality in synoptic types is evident, with frontal and cutoff-low types dominating in winter and inland heat troughs prevailing in summer. Interaction between tropical and extratropical systems is evident in all seasons.
Il tabarro: Maschilità in crisi nell’Italia fin de siècle
Authors: Cecconi Annamaria
Published: May 2015

L’opera lirica può offrire un punto privilegiato di osservazione dei cambiamenti antropologici della società italiana riguardo a due aspetti: la rappresentazione delle relazioni tra i generi e la percezione socialmente condivisa dell’identità maschile, in particolare nell’evoluzione storica dello stato postunitario. Alla luce degli sviluppi dei men’s studies e, segnatamente, della storia della maschilità tra la fine del XIX e gli inizi del XX secolo, l’articolo propone una lettura de Il tabarro di Giacomo Puccini e Giuseppe Adami come esempio di dissoluzione del modello di italica virilità proposto dal melodramma verdiano e, in seguito, dall’opera verista. Il paesaggio sonoro metropolitano, in particolare l’erotizzazione della Senna come luogo della sessualità instabile, diventa proiezione del dramma, delle inquietudini e incertezze di nuove identità maschili proletarie. I protagonisti dell’opera soffrono di angoscia e oppressione senza speranza di riscatto. L’opposizione tra maschilità egemone e subalterna (baritono/tenore), la rivalità sessuale, il tema della decadenza della potenza sessuale maschile (rintracciata anche in due gustosi scritti dello stesso Puccini) sono leggibili come sintomi della disgregazione in atto del modello di maschilità patriarcale, ovvero dell’ordine famigliare, della paternità, della rispettabilità, nella società italiana fin de siècle.
RMG in Bangladesh
Authors: Kamal Rifat Darina , Kaiser Z.R.M. Abdullah
Published: May 2015

Hostile political conflicts have caused Bangladesh to miss out many global economic opportunities despite much achievements made since independence. Its evolving readymade garments (RMG) sector is one of the most affected sectors of this malicious politics. The focal point of this article is to demonstrate the recent violence of vicious politics of Bangladesh and its effect on the evolving RMG sector. The result shows that the average losses in this sector due to the recent political turmoil are very alarming. Moreover, foreign buyers have cancelled their orders from Bangladesh for uncertain shipment for the same reason. It is an ominous sign for a developing sector. So, the main objective of this article is to figure out the losses and missed opportunities of the RMG sector caused by the political impasse and to provide some suggestions to protect the RMG sector from these political atrocities.
Effects of ageing on mechanical properties of stiffened syntactic foam core sandwich composites for marine applications
Authors: Kumar SJ Amith , Ahmed K Sabeel
Published: May 2015

Foam core based sandwich composite materials are extensively used in marine sectors because of its high strength and stiffness to weight ratios. The structural materials used for marine applications should possess good damage tolerance capability. Hence, it is essential that these materials shall be tested for their residual mechanical properties when exposed to marine environment. In the present work, syntactic foam is prepared by uniform mixing of dry fly ash cenosphere and phenolic resin in equal proportions. Syntactic foam is further stiffened by integrating it with honeycomb structure during manufacturing. Sandwich composites are developed with core of syntactic foam (with and without honeycomb structure) and face skins of glass/epoxy composite. Sandwich coupons are prepared in two batches; one being subjected to ageing in natural sea water and other under accelerated environment. Both aged and unaged coupons are subjected to mechanical tests to determine their residual properties under compression, flexure, and low-velocity impact as per ASTM standards. Results showed that the moisture absorption is significant up to about 60 days beyond which it is marginal. The saturation level was attained for an immersion period of about one year, at which the material exhibited significant damage, at the interfacial regions of core-skin, cenosphere-phenolic resin, and fiber-matrix. Ageing of sandwich composites under sea water and accelerated environment has shown detrimental effect on their mechanical properties. However, the extent of degradation in properties due to ageing can be reduced by the incorporation of resin impregnated honeycomb structure in syntactic foam. Microscopic features of aged coupons are also investigated to predict mode of damage due to ageing.
Drawdown prepreg coating method using epoxy terminated butadiene nitrile rubber to improve fracture toughness of glass epoxy composites
Authors: Gouda PS Shivakumar , Williams John D , Yasaee Mehdi , Chatterjee Vijay , Jawali Dayananda , Rahatekar Sameer S , Wisnom MR
Published: May 2015

Laminates of fibre-reinforced prepreg have excellent in-plane mechanical properties, but have inadequate performance in the through thickness direction. Here, we address this issue by application of epoxy-terminated butadiene nitrile (ETBN) liquid rubber between the prepreg laminae using an automatic draw bar coating technique. Test results reveal that by adding ETBN in small quantities in the range of 9.33–61.33 g/m2, the interlaminar critical energy release rates (GIc and GIIc) are improved by up to 122% in mode-I and 49% in mode-II. Moreover, this finding is further supported by the dynamic mechanical analysis thermograms that clearly indicate that coating has not altered the Tg of ETBN-coated samples. Scanning electron microscopic analysis of fracture surfaces showed that rubber particles formed micro cavitations in the epoxy, causing localised rubber rich regions. These resin-rich regions require more energy to fracture, resulting in increased toughness of the glass epoxy prepreg systems.
Intestinal Microbiota Signatures Associated With Histological Liver Steatosis in Pediatric‐Onset Intestinal Failure
Authors: Korpela Katri , Mutanen Annika , Salonen Anne , Savilahti Erkki , de Vos Willem M. , Pakarinen Mikko P.
Published: May 2015

Background: Intestinal failure (IF)–associated liver disease (IFALD) is the major cause of mortality in IF. The link between intestinal microbiota and IFALD is unclear. Methods: We compared intestinal microbiota of patients with IF (n = 23) with healthy controls (n = 58) using culture‐independent phylogenetic microarray analysis. The microbiota was related to histological liver injury, fecal markers of intestinal inflammation, matrix metalloproteinase 9 and calprotectin, and disease characteristics. Results: Overabundance of Lactobacilli, Proteobacteria, and Actinobacteria was observed in IF, whereas bacteria related to Clostridium clusters III, IV, and XIVa along with overall diversity and richness were reduced. Patients were segregated into 3 subgroups based on dominating bacteria: Clostridium cluster XIVa, Proteobacteria, and bacteria related to Lactobacillus plantarum. In addition to liver steatosis and fibrosis, Proteobacteria were associated with prolonged current parenteral nutrition (PN) as well as liver and intestinal inflammation. Lactobacilli were related to advanced steatosis and fibrosis mostly after weaning off PN without associated inflammation. In multivariate permutational analysis of variance, liver steatosis, bowel length, PN calories, and antibiotic treatment best explained the microbiota variation among patients with IF. Conclusions: Intestinal microbiota composition was associated with liver steatosis in IF and better predicted steatosis than duration of PN or length of the remaining intestine. Our results may be explained by a model in which steatosis is initiated during PN in response to proinflammatory lipopolysaccharides produced by Proteobacteria and progresses after weaning off PN, as the L plantarum group Lactobacilli becomes dominant and affects lipid metabolism by altering bile acid signaling.
Bombesin Preserves Goblet Cell Resistin‐Like Molecule β During Parenteral Nutrition but Not Other Goblet Cell Products
Authors: Busch Rebecca A. , Heneghan Aaron F. , Pierre Joseph F. , Neuman Joshua C. , Reimer Claire A. , Wang Xinying , Kimple Michelle E. , Kudsk Kenneth A.
Published: May 2015

Introduction: Parenteral nutrition (PN) increases the risk of infection in critically ill patients and is associated with defects in gastrointestinal innate immunity. Goblet cells produce mucosal defense compounds, including mucin (principally MUC2), trefoil factor 3 (TFF3), and resistin‐like molecule β (RELMβ). Bombesin (BBS), a gastrin‐releasing peptide analogue, experimentally reverses PN‐induced defects in Paneth cell innate immunity. We hypothesized that PN reduces goblet cell product expression and PN+BBS would reverse these PN‐induced defects. Methods: Two days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 15), PN (n = 13), or PN+BBS (15 µg tid) (n = 12) diets for 5 days. Defined segments of ileum and luminal fluid were analyzed for MUC2, TFF3, and RELMβ by quantitative reverse transcriptase polymerase chain reaction and Western blot. Th2 cytokines interleukin (IL)–4 and IL‐13 were measured by enzyme‐linked immunosorbent assay. Results: Compared with chow, PN significantly reduced MUC2 in ileum (P < .01) and luminal fluid (P = .01). BBS supplementation did not improve ileal or luminal MUC2 compared with PN (P > .3). Compared with chow, PN significantly reduced TFF3 in ileum (P < .02) and luminal fluid (P < .01). BBS addition did not improve ileal or luminal TFF3 compared with PN (P > .3). Compared with chow, PN significantly reduced ileal RELMβ (P < .01). BBS supplementation significantly increased ileal RELMβ to levels similar to chow (P < .03 vs PN; P > .6 vs chow). Th2 cytokines were decreased with PN and returned to chow levels with BBS. Conclusion: PN significantly impairs the goblet cell component of innate mucosal immunity. BBS only preserves goblet cell RELMβ during PN but not other goblet cell products measured.
Contradictory yet Coherent? Inconsistency in Performance Feedback and R&D Investment Change
Authors: Lucas Gerardus J. M. , Knoben Joris , Meeus Marius T. H.
Published: May 2015

In this paper, we study to what extent inconsistent feedback signals about performance affect firm adaptive behavior in terms of changes made to research-and-development (R&D) investments. We argue that inconsistency in performance feedback—based on discrepancies between two distinct performance signals—affects the degree to which such investments will be changed. Our aim is to show that accounting for inconsistent performance feedback is necessary as predictions for the direction of change in R&D investments based on the individual performance feedback signals are contradictory. Furthermore, we contribute by proposing a holistic consideration mechanism as an alternative to the selective attention mechanism previously applied to inconsistent performance feedback. Our findings show that the impact of inconsistency depends on the exact configuration of the underlying performance feedback signal discrepancies. While consistently negative performance feedback signals would amplify their impact in stimulating increased R&D investments, inconsistent performance feedback signals created more nuanced effects. Having lower performance compared to an industry-based peer group—despite doing well compared to the previous year—made firms decrease their R&D investments. For the opposite case of inconsistent performance feedback, we did not find an effect on change in R&D investments. These findings support to a degree our contention that explaining the effects of inconsistent performance feedback requires a holistic consideration theoretical mechanism instead of one involving selective attention. In sum, these findings suggest future research should take into account the differences between distinct instances of inconsistent performance feedback.
Strategic Science Translation and Environmental Controversies
Authors: Cordner Alissa
Published: May 2015

In contested areas of environmental research and policy, all stakeholders are likely to claim that their position is scientifically grounded but disagree about the relevant scientific conclusions or the weight of the evidence. In this article, I draw on a year of participant observation and over 110 in-depth interviews, with the case study of controversial chemicals used as flame retardants in consumer products. I develop the concept of strategic science translation (SST), the process of interpreting and communicating scientific evidence to an intended audience in order to advance certain goals and interests. Engaging in selective, interpretive, or inaccurate SST allows competing stakeholders to bolster their arguments, strengthen their authority, and inspire change regarding a policy-relevant issue. Because stakeholders deploy imbalanced resources when they participate in contested environmental fields, their actions in those fields and the resulting policy outcomes often reduce not to the settling of scientific truths but to power differentials.