bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coastal products of marine transgression in cold-temperate and high-latitude coastal-plain settings: Gulf of St Lawrence and Beaufort Sea
Authors: Forbes D. L. , Manson G. K. , Whalen D. J. R. , Couture N. J. , Hill P. R. 
Published: May 2014

Abstract
Cold climate exerts a clear influence on the processes of marine transgression in mid- and high-latitude coastal-plain settings, but its signature in the depositional record is much clearer at high latitude. Both cases selected for this study are influenced by the legacy of past glaciation and the pervasive effects of ongoing Holocene marine transgression. Both are affected by sea ice. The high-latitude site lies within the zone of continuous permafrost and the abundance of excess ground ice along the Beaufort coast is the dominant factor distinguishing it from the mid-latitude Gulf of St Lawrence (GSL) setting and standard models of transgressive coasts elsewhere. In the southern GSL, the transgressive unconformity (TU) is at the seabed (or buried by a very thin veneer) across the inner shelf; shoreface sand moves landward, keeping pace with the transgressive front through deposition in barriers, dunes and estuaries. The pace of transgression in the Beaufort Sea is influenced by a number of distinctive periglacial erosion processes, including thermal abrasion and thaw subsidence. Marine transgression across this landscape creates intricate breached-lake estuaries and low sandy barrier beaches with limited dunes, leaving distinctive facies suites and geometry, while seaward sediment transport buries the TU on the inner shelf.
Megalandslides in the Andes of central Chile and Argentina (32°–34°S) and potential hazards
Authors: Moreiras Stella M. , Sepúlveda Sergio A. 
Published: May 2014

Abstract
This review deals with an integration and update of the knowledge about large-volume landslides in the Central Andes at 32–34°S. An integrated landslide inventory for megalandslides in central Chilean and Argentinean Andean basins was developed, and dispersed chronological data on palaeolandslides were compiled, showing a dominance of Late Pleistocene and Holocene ages. Traditional hypotheses adopted for explaining landslide occurrence in the Central Andes are contrasted. Whereas seismic tremors have been widely suggested as the main triggering mechanism in Chilean collapses, palaeoclimatic conditions are considered as the main cause of Argentinean giant landslides. These different approaches denote the lack of multidisciplinary studies focused on the controversy about seismic or climate trigger mechanisms in the Central Andes. These studies are also essential to understand failure mechanisms and assessment of the related hazard and risk, which are essential to reduce social and economic impacts on vulnerable communities from future landslide events.
Discovery of Mesothelin and Exploiting It as a Target for Immunotherapy
Authors: Pastan Ira , Hassan Raffit 
Published: May 2014

Abstract
We have recently reported that an immunotoxin targeting mesothelin produced durable major tumor regressions in patients with extensive treatment-refractory mesothelioma. These unprecedented tumor responses have prompted us to review how mesothelin was discovered and the advances that led to these tumor responses. This review is not comprehensive but focuses on major developments over the past 20 years since mesothelin was first identified in our laboratory. Mesothelin is a cell-surface glycoprotein whose expression in normal human tissues is restricted to mesothelial cells. Because it is highly expressed by many solid tumors, it is an attractive immunotherapy target. Antibody-based therapies currently in clinical trials include an immunotoxin, a chimeric monoclonal antibody, and an antibody drug conjugate. In addition, a mesothelin tumor vaccine and a mesothelin- chimeric antigen receptor are being evaluated in the clinic. SS1P, an anti-mesothelin immunotoxin, was the first mesothelin-directed therapy to enter the clinic, and its use showed that mesothelin-targeted therapy was safe in patients. More importantly, our recent work has shown that SS1P in combination with pentostatin and cyclophosphamide can result in durable tumor regression in patients with advanced mesothelioma and opens up the possibility that such an approach can benefit patients with many common cancers. Cancer Res; 74(11); 2907–12. ©2014 AACR.
Phosphoproteomics of MAPK Inhibition in BRAF-Mutated Cells and a Role for the Lethal Synergism of Dual BRAF and CK2 Inhibition
Authors: Parker Robert , Clifton-Bligh Roderick , Molloy Mark P. 
Published: May 2014

Abstract
Activating mutations in the MAPK pathway are prevalent drivers of several cancers. The chief consequence of these mutations is a hyperactive ERK1/2 MAPK able to promote cell proliferation, producing a critical hallmark of metastatic disease. The biochemistry of the ERK pathway is well characterized; however, how the pathway achieves different outcomes in the face of genetic aberrations of cancer and subsequent treatment with chemical inhibitors is not clear. To investigate this, we used mass spectrometry to complete a global phosphoproteomic analysis of a BRAFV600E thyroid cancer cell line (SW1736) after treatment with the mutation-selective inhibitor vemurafenib (PLX4032) and MEK1/2 inhibitor selumetinib (AZD6244). We identified thousands of phosphorylation events orchestrated in BRAFV600E cells and performed kinase landscape analysis to identify putative kinases regulated in response to MAPK blockade. The abundance of phosphopeptides containing consensus motifs for acidophilic kinases increased after short-term inhibition with these compounds. We showed that coinhibition of the pleiotropic acidophilic protein kinase CK2 (CK2) and BRAFV600E synergistically reduced proliferation in patient-derived melanomas and thyroid cancer cells harboring the BRAF lesion. We investigated this mechanism and show a role for CK2 in controlling AKT activation that was not reliant on changes to PTEN or PDK1 phosphorylation. These findings highlight a role for CK2 blockade in potentiating the antiproliferative effects of BRAF and MEK inhibition in BRAF cancers. Mol Cancer Ther; 13(7); 1894–906. ©2014 AACR.
Combination of Conventional Chemotherapeutics with Redox-Active Cerium Oxide Nanoparticles—A Novel Aspect in Cancer Therapy
Authors: Sack Maren , Alili Lirija , Karaman Elif , Das Soumen , Gupta Ankur , Seal Sudipta , Brenneisen Peter 
Published: May 2014

Abstract
Nanotechnology is becoming an important field of biomedical and clinical research and the application of nanoparticles in disease may offer promising advances in treatment of many diseases, especially cancer. Malignant melanoma is one of the most aggressive forms of cancer and its incidence is rapidly increasing. Redox-active cerium oxide nanoparticles (CNP) are known to exhibit significant antitumor activity in cells derived from human skin tumors in vitro and in vivo, whereas CNP is nontoxic and beyond that even protective (antioxidative) in normal, healthy cells of the skin. As the application of conventional chemotherapeutics is associated with harmful side effects on healthy cells and tissues, the clinical use is restricted. In this study, we addressed the question of whether CNP supplement a classical chemotherapy, thereby enhancing its efficiency without additional damage to normal cells. The anthracycline doxorubicin, one of the most effective cancer drugs, was chosen as reference for a classical chemotherapeutic agent in this study. Herein, we show that CNP enhance the antitumor activity of doxorubicin in human melanoma cells. Synergistic effects on cytotoxicity, reactive oxygen species generation, and oxidative damage in tumor cells were observed after co-incubation. In contrast to doxorubicin, CNP do not cause DNA damage and even protect human dermal fibroblasts from doxorubicin-induced cytotoxicity. A combination of classical chemotherapeutics with nongenotoxic but antitumor active CNP may provide a new strategy against cancer by improving therapeutic outcome and benefit for patients. Mol Cancer Ther; 13(7); 1740–9. ©2014 AACR.
Anti-miR182 Reduces Ovarian Cancer Burden, Invasion, and Metastasis: An In Vivo Study in Orthotopic Xenografts of Nude Mice
Authors: Xu Xiaofei , Ayub Bushra , Liu Zhaojian , Serna Vanida Ann , Qiang Wenan , Liu Yugang , Hernando Eva , Zabludoff Sonya , Kurita Takeshi , Kong Beihua , Wei Jian-Jun 
Published: May 2014

Abstract
High-grade serous ovarian carcinoma (HGSOC) is a fatal disease, and its grave outcome is largely because of widespread metastasis at the time of diagnosis. Current chemotherapies reduce tumor burden, but they do not provide long-term benefits for patients with cancer. The aggressive tumor growth and metastatic behavior characteristic of these tumors demand novel treatment options such as anti-microRNA treatment, which is emerging as a potential modality for cancer therapy. MicroRNA-182 (miR182) overexpression contributes to aggressive ovarian cancer, largely by its negative regulation of multiple tumor suppressor genes involved in tumor growth, invasion, metastasis, and DNA instability. In this study, we examined the therapeutic potential of anti-miR182 utilizing the animal orthotopic model to mimic human ovarian cancer using ovarian cancer cells SKOV3 (intrabursal xenografts) and OVCAR3 (intraperitoneal injection). These models provide a valuable model system for the investigation of ovarian cancer therapy in vivo. Through a combination of imaging, histological, and molecular analyses, we found that anti-miR182 treatment can significantly reduce tumor burden (size), local invasion, and distant metastasis compared with its control in both models. The bases of anti-miR182 treatment are mainly through the restoration of miR182 target expression, including but not limited to BRCA1, FOXO3a, HMGA2, and MTSS1. Overall, our results strongly suggest that anti-miR182 can potentially be used as a therapeutic modality in treating HGSOC. Mol Cancer Ther; 13(7); 1729–39. ©2014 AACR.
Effector-Mediated Eradication of Precursor B Acute Lymphoblastic Leukemia with a Novel Fc-Engineered Monoclonal Antibody Targeting the BAFF-R
Authors: Parameswaran Reshmi , Lim Min , Fei Fei , Abdel-Azim Hisham , Arutyunyan Anna , Schiffer Isabelle , McLaughlin Margaret E. , Gram Hermann , Huet Heather , Groffen John , Heisterkamp Nora 
Published: May 2014

Abstract
B-cell activating factor receptor (BAFF-R) is expressed on precursor B acute lymphoblastic leukemia (pre-B ALL) cells, but not on their pre-B normal counterparts. Thus, selective killing of ALL cells is possible by targeting this receptor. Here, we have further examined therapeutic targeting of pre-B ALL based on the presence of the BAFF-R. Mouse pre-B ALL cells lacking BAFF-R function had comparable viability and proliferation to wild-type cells, but were more sensitive to drug treatment in vitro. Viability of human pre-B ALL cells was further reduced when antibodies to the BAFF-R were combined with other drugs, even in the presence of stromal protection. This indicates that inhibition of BAFF-R function reduces fitness of stressed pre-B ALL cells. We tested a novel humanized anti–BAFF-R monoclonal antibody optimalized for FcRγIII-mediated, antibody-dependent cell killing by effector cells. Antibody binding to human ALL cells was inhibitable, in a dose-dependent manner, by recombinant human BAFF. There was no evidence for internalization of the antibodies. The antibodies significantly stimulated natural killer cell–mediated killing of different human patient-derived ALL cells. Moreover, incubation of such ALL cells with these antibodies stimulated phagocytosis by macrophages. When this was tested in an immunodeficient transplant model, mice that were treated with the antibody had a significantly decreased leukemia burden in bone marrow and spleen. In view of the restricted expression of the BAFF-R on normal cells and the multiple anti–pre-B ALL activities stimulated by this antibody, a further examination of its use for treatment of pre-B ALL is warranted. Mol Cancer Ther; 13(6); 1567–77. ©2014 AACR.
Mammary Cancer Chemoprevention by Withaferin A Is Accompanied byIn VivoSuppression of Self-Renewal of Cancer Stem Cells
Authors: Kim Su-Hyeong , Singh Shivendra V. 
Published: May 2014

AbstractCurrent dogma favors elimination of therapy-resistant cancer stem cells for chemoprevention of breast cancer. We showed recently that mammary cancer development in a transgenic mouse model (mouse mammary tumor virus-neu; MMTV-neu) was inhibited significantly upon treatment with withaferin A (WA), a steroidal lactone derived from a medicinal plant. Herein, we demonstrate that the mammary cancer prevention by WA is accompanied by in vivo suppression of breast cancer stem cells (bCSC). In vitro mammosphere formation was dose-dependently inhibited by WA treatment in MCF-7 and SUM159 human breast cancer cells. Other markers of bCSC, including aldehyde dehydrogenase 1 (ALDH1) activity and CD44high/CD24low/epithelial-specific antigen-positive (ESA+) fraction, were also decreased significantly in the presence of plasma achievable doses of WA. However, WA exposure resulted in cell line–specific changes in Oct4, SOX-2, and Nanog mRNA expression. WA administration to MMTV-neu mice (0.1 mg/mouse, 3 times/week for 28 weeks) resulted in inhibition of mammosphere number and ALDH1 activity in vivo. Mechanistic studies revealed that although urokinase-type plasminogen activator receptor overexpression conferred partial protection against bCSC inhibition by WA, Notch4 was largely dispensable for this response. WA treatment also resulted in sustained (MCF-7) or transient (SUM159) downregulation of Bmi-1 (B-cell–specific Moloney murine leukemia virus insertion region-1) protein. Ectopic expression of Bmi-1 conferred partial but significant protection against ALDH1 activity inhibition by WA. Interestingly, WA treatment caused induction of Kruppel-like factor 4 (KLF4) and its knockdown augmented bCSC inhibition by WA. In conclusion, this study shows in vivo effectiveness of WA against bCSC. Cancer Prev Res; 7(7); 738–47. ©2014 AACR.
Autophagy Inhibition Improves Chemosensitivity in BRAFV600E Brain Tumors
Authors: Levy Jean M. Mulcahy , Thompson Joshua C. , Griesinger Andrea M. , Amani Vladimir , Donson Andrew M. , Birks Diane K. , Morgan Michael J. , Mirsky David M. , Handler Michael H. , Foreman Nicholas K. , Thorburn Andrew 
Published: May 2014

Abstract
Autophagy inhibition is a potential therapeutic strategy in cancer, but it is unknown which tumors will benefit. The BRAFV600E mutation has been identified as important in pediatric central nervous system (CNS) tumors and is known to affect autophagy in other tumor types. We evaluated CNS tumor cells with BRAFV600E and found that mutant (but not wild-type) cells display high rates of induced autophagy, are sensitive to pharmacologic and genetic autophagy inhibition, and display synergy when the clinically used autophagy inhibitor chloroquine was combined with the RAF inhibitor vemurafenib or standard chemotherapeutics. Importantly, we also demonstrate that chloroquine can improve vemurafenib sensitivity in a resistant ex vivo primary culture and provide the first demonstration in a patient harboring the V600E mutation treated with vemurafenib that the addition of chloroquine can improve clinical outcomes. These findings suggest that CNS tumors with BRAFV600E are autophagy-dependent and should be targeted with autophagy inhibition in combination with other therapeutic strategies.
Significance: Autophagy inhibition may improve cancer therapy, but it is unclear which tumors will benefit. We found that BRAF mutations cause brain tumor cells to depend on autophagy and display selective chemosensitization with autophagy inhibition. We present a pediatric case in which deliberate autophagy inhibition halted tumor growth and overcame acquired BRAF-inhibition resistance. Cancer Discov; 4(7); 773–80. ©2014 AACR.
This article is highlighted in the In This Issue feature, p. 745
Comparison of Biolimus A9–Eluting (Nobori) and Everolimus-Eluting (Promus Element) Stents in Patients With De Novo Native Long Coronary Artery Lesions
Authors: Lee Jong-Young , Park Duk-Woo , Kim Young-Hak , Ahn Jung-Min , Kim Won-Jang , Kang Soo-Jin , Lee Seung-Whan , Lee Cheol Whan , Park Seong-Wook , Yun Sung-Cheol , Yang Tae-Hyun , Lee Bong-Ki , Lee Nae-Hee , Yang Joo-Young , Shin Won-Yong , Park Hun Sik , Kim Kee-Sik , Hur Seung Ho , Lee Sung Yun , Park Jong-Seon , Choi Yun Seok , Lee Seung Uk , Her Sung-Ho , Park Seung-Jung 
Published: May 2014

Background—
Procedural and clinical outcomes still remain unfavorable for patients with long coronary lesions who undergo percutaneous coronary intervention. The current study, therefore, evaluated 2 innovative drug-eluting stents for the management of long-lesion coronary artery disease.

Methods and Results—

This randomized, multicenter, prospective trial, called the Long Drug-Eluting Stent (LONG-DES) V trial, compared the biodegradable polymer–based biolimus A9–eluting stent (BES) and the durable polymer–based platinum chromium everolimus-eluting stent (PtCr-EES) in 500 patients with long (≥25 mm) coronary lesions. The primary end point of the trial was in-segment late luminal loss at the 9-month angiographic follow-up. The BES and PtCr-EES groups had similar baseline characteristics, with a slightly shorter lesion length in the BES group versus the PtCr-EES group (29.24±12.17 versus 32.27±13.84 mm;
P
=0.016). In-segment late luminal loss was comparable between the 2 groups at the 9-month angiographic follow-up (BES, 0.14±0.38 versus PtCr-EES, 0.11±0.37 mm; difference, 0.031; 95% confidence interval, −0.053 to 0.091;
P
=0.03 for a noninferiority margin of 0.11,
P
=0.45 for superiority), as was in-stent late luminal loss (0.20±0.41 versus 0.24±0.38 mm;
P
=0.29). The incidence of in-segment (6.1% versus 4.9%;
P
=0.63) and in-stent (3.7% versus 4.9%;
P
=0.59) binary restenosis was also similar between the groups. There was no significant between-group difference in the rate of composite outcome of death, myocardial infarction, and target vessel revascularization (41, 16.7% in BES versus 42, 16.5% in PtCr-EES;
P
=0.94).

Conclusions—
BES and PtCr-EES implantation showed analogous angiographic and clinical outcomes for patients with de novo long coronary lesions.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01186120.
Left Ventricular Reverse Remodeling, Device-Related Adverse Events, and Long-Term Outcome After Cardiac Resynchronization Therapy in the Elderly
Authors: Höke Ulas , Putter Hein , Van Der Velde Enno T. , Schalij Martin J. , Delgado Victoria , Bax Jeroen J. , Marsan Nina Ajmone 
Published: May 2014

Background—
Limited data are available on efficacy, safety, and long-term prognosis after cardiac resynchronization therapy (CRT) in elderly patients. We aimed at evaluating the effect of CRT, device-related adverse events, and long-term outcome after CRT among elderly patients.

Methods and Results—

A total of 798 CRT recipients (208 elderly: age, ≥75 years; 590 nonelderly: age, <75 years) underwent clinical and echocardiographic evaluation at baseline and 6-month follow-up. Elderly patients had similar improvements in clinical symptoms, left ventricular function, and left ventricular reverse remodeling as their counterparts. Similar rates of device-related in-hospital (within 24 hours;
P
=0.552), early (within 30 days;
P
=0.984), and long-term adverse events (entire follow-up; hazard ratio, 0.90;
P
=0.620) were observed between groups. During long-term follow-up (median, 38.6 months; interquartile range, 22.5–61.8 months), all-cause mortality rate was significantly higher among the elderly patients. However, the differences in cumulative event rates started after 4 years of follow-up (
P
=0.013), and the cause of death was mainly noncardiac (29% in the elderly versus 19% in nonelderly;
P
<0.001). Diabetes mellitus (hazard ratio, 2.322;
P
=0.019), impaired renal function (hazard ratio, 0.975;
P
=0.006), and reduced 6-minute walk distance (hazard ratio, 0.996;
P
<0.019) were independently associated with all-cause mortality in elderly patients.

Conclusions—
CRT efficacy and device-related adverse events in elderly patients were comparable with that of nonelderly patients. However, after 4 years of follow-up, elderly patients showed worse survival and the cause of death was mainly noncardiac. Diabetes mellitus, impaired renal function, and reduced 6-minute walk distance were independently associated with all-cause mortality of elderly patients.
Risk Factors for Computed Tomography Angiography Spot Sign in Deep and Lobar Intracerebral Hemorrhage Are Shared
Authors: Radmanesh Farid , Falcone Guido J. , Anderson Christopher D. , Battey Thomas W.K. , Ayres Alison M. , Vashkevich Anastasia , McNamara Kristen A. , Schwab Kristin , Romero Javier M. , Viswanathan Anand , Greenberg Steven M. , Goldstein Joshua N. , Rosand Jonathan , Brouwers H. Bart 
Published: May 2014

Background and Purpose—
Patients with intracerebral hemorrhage (ICH) who present with a spot sign on computed tomography angiography are at increased risk of hematoma expansion and poor outcome. Because primary ICH is the acute manifestation of chronic cerebral small vessel disease, we investigated whether different clinical or imaging characteristics predict spot sign presence, using ICH location as a surrogate for arteriolosclerosis- and cerebral amyloid angiopathy–related ICH.

Methods—
Patients with primary ICH and available computed tomography angiography at presentation were included. Predictors of spot sign were assessed using uni- and multivariable regression, stratified by ICH location.

Results—

Seven hundred forty-one patients were eligible, 335 (45%) deep and 406 (55%) lobar ICH. At least one spot sign was present in 76 (23%) deep and 102 (25%) lobar ICH patients. In multivariable regression, warfarin (odds ratio [OR], 2.42; 95% confidence interval [CI], 1.01–5.71;
P
=0.04), baseline ICH volume (OR, 1.20; 95% CI, 1.09–1.33, per 10 mL increase;
P
<0.001), and time from symptom onset to computed tomography angiography (OR, 0.89; 95% CI, 0.80–0.96, per hour;
P
=0.009) were associated with the spot sign in deep ICH. Predictors of spot sign in lobar ICH were warfarin (OR, 3.95; 95% CI, 1.87–8.51;
P
<0.001) and baseline ICH volume (OR, 1.20; 95% CI, 1.10–1.31, per 10 mL increase;
P
<0.001).

Conclusions—
The most potent associations with spot sign are shared between deep and lobar ICH, suggesting that the acute bleeding process that arises in the setting of different chronic small vessel diseases shares commonalities.