bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metastasis Stimulation by Hypoxia and Acidosis-Induced Extracellular Lipid Uptake Is Mediated by Proteoglycan-Dependent Endocytosis
Authors: Menard Julien A. , Christianson Helena C. , Kucharzewska Paulina , Bourseau-Guilmain Erika , Svensson Katrin J. , Lindqvist Eva , Chandran Vineesh Indira , Kjellén Lena , Welinder Charlotte , Bengzon Johan , Johansson Maria C. , Belting Mattias 
Published: May 2016

AbstractHypoxia and acidosis are inherent stress factors of the tumor microenvironment and have been linked to increased tumor aggressiveness and treatment resistance. Molecules involved in the adaptive mechanisms that drive stress-induced disease progression constitute interesting candidates of therapeutic intervention. Here, we provide evidence of a novel role of heparan sulfate proteoglycans (HSPG) in the adaptive response of tumor cells to hypoxia and acidosis through increased internalization of lipoproteins, resulting in a lipid-storing phenotype and enhanced tumor-forming capacity. Patient glioblastoma tumors and cells under hypoxic and acidic stress acquired a lipid droplet (LD)-loaded phenotype, and showed an increased recruitment of all major lipoproteins, HDL, LDL, and VLDL. Stress-induced LD accumulation was associated with increased spheroid-forming capacity during reoxygenation in vitro and lung metastatic potential in vivo. On a mechanistic level, we found no apparent effect of hypoxia on HSPGs, whereas lipoprotein receptors (VLDLR and SR-B1) were transiently upregulated by hypoxia. Importantly, however, using pharmacologic and genetic approaches, we show that stress-mediated lipoprotein uptake is highly dependent on intact HSPG expression. The functional relevance of HSPG in the context of tumor cell stress was evidenced by HSPG-dependent lipoprotein cell signaling activation through the ERK/MAPK pathway and by reversal of the LD-loaded phenotype by targeting of HSPGs. We conclude that HSPGs may have an important role in the adaptive response to major stress factors of the tumor microenvironment, with functional consequences on tumor cell signaling and metastatic potential. Cancer Res; 76(16); 4828–40. ©2016 AACR.
Abstract B37: Selective tumor localization of CRLX101, a novel nanoparticle-drug conjugate
Authors: Peters Christian G. , Lazarus Douglas , Brown Donna , Zhang Ningning , Case Roy , Rohde Ellen , Eliasof Scott , Jayaraman Lata 
Published: May 2016

Abstract
CRLX101, an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin conjugated to a biocompatible copolymer of cyclodextrin and polyethylene glycol (PEG), is currently being evaluated clinically in multiple treatment-refractory solid tumors. CRLX101 is a dual inhibitor of topoisomerase 1 (TOPO 1) and hypoxia-inducible factor 1α (HIF-1α) and has been shown pre-clinically to be active in many different tumor types. It has a long circulation half-life and is believed to release camptothecin in a slow and prolonged fashion in the tumor. Camptothecin is an active anti-tumor agent preclinically but was not developed clinically due to its poor tolerability in patients. The development of CRLX101, which has not demonstrated significant toxicity in over 250 patients dosed to date, offers a unique opportunity to improve cancer treatment in a meaningful way.
We have previously published that in gastric cancer patients treated with CRLX101, camptothecin fluorescence can be visualized in tumor tissue but not adjoining normal tissue. Based on these data we hypothesized that CRLX101 utilizes the enhanced permeability and retention (EPR) effect to accumulate selectively in tumors. In this study, we sought to mechanistically dissect the process of CRLX101 entry and accumulation into tumor cells using multiple methods, both in vitro and in xenograft tumors in vivo. Using confocal microscopy, we can detect camptothecin fluorescence in CRLX101- treated tumor cells in culture as well as in tumor tissue from mice treated with CRLX101. We can co-localize this camptothecin with intact nanoparticles using an anti-PEG antibody that specifically detects the PEG loops in the NDCs. We can also demonstrate that macropinocytosis plays a role in the manner by which tumor cells take up CRLX101. Using an anti-CD31 antibody, we can visualize the distance traversed by CRLX101 from the tumor vasculature over time. We have developed novel analytical methods to precisely quantify both released and CRLX101-conjugated camptothecin over time in CRLX101 treated tumor cells in vitro, as well as in tumor tissue from mice treated with CRLX101 in vivo. Using cell viability assays, we can correlate the kinetics of camptothecin released inside tumor cells to the degree of tumor cell kill. We believe that these data are an important step forward in understanding the precise mechanism(s) underlying selective delivery of CRLX101 into tumor tissue.
Citation Format: Christian G. Peters, Douglas Lazarus, Donna Brown, Ningning Zhang, Roy Case, Ellen Rohde, Scott Eliasof, Lata Jayaraman. Selective tumor localization of CRLX101, a novel nanoparticle-drug conjugate. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B37.
Abstract C86: The clinical candidate ZEN-3694, a novel BET bromodomain inhibitor, is efficacious in the treatment of a variety of solid tumor and hematological malignancies, alone or in combination with several standard of care and targeted therapies
Authors: Attwell Sarah , Campeau Eric , Jahagirdar Ravi , Kharenko Olesya , Norek Karen , Tsujikawa Laura , Calosing Cyrus , Patel Reena , Gesner Emily , Lakhotia Sanjay , Hansen Henrik 
Published: May 2016

Abstract
ZEN-3694 is an orally bioavailable small molecule discovered and developed from a BET bromodomain inhibitor discovery platform. In vitro, ZEN-3694 selectively binds to both bromodomains of the BET proteins, inhibiting the interaction of acetylated histone peptide with IC50 values in low nM range. ZEN-3694 inhibits proliferation of MV4-11 AML cells with an IC50 of 0.2 uM, and inhibits MYC mRNA expression with an IC50 of 0.16 uM.
ZEN-3694 has also demonstrated strong activity against many solid tumor and hematological cell lines with sub-uM IC50 values. In vitro synergy with Standard of Care (SOC) agents has been shown in a wide variety of malignancies including Breast, Prostate, Lung, Melanoma, AML, and DLBCL. Xenograft studies conducted with ZEN-3694 in AML, prostate and breast cancer models have demonstrated that it is efficacious at well-tolerated doses, modulating target gene expression and halting tumor growth in a dose-dependent manner.
In the AR positive VCAP prostate cancer cell line, ZEN-3694 inhibits proliferation synergistically with the AR antagonists enzalutamide and ARN-509. In an in vitro enzalutamide resistance model characterized by the up-regulation of the glucocorticoid receptor (GR), GR expression was inhibited by ZEN-3694 in a dose-dependent manner. Sensitivity to ZEN-3694 was unaltered, suggesting that it could be a valid therapeutic approach in patients developing resistance to AR antagonists through GR induction.
Robust PD modulation has been observed across multiple matrices for ZEN-3694 and will be explored further in the clinic. Promising target validation data, excellent pharmacological properties, and robust activity of ZEN-3694 across a variety of hematological malignancy and solid tumor settings support the clinical development of ZEN-3694 in various oncologic indications.
Citation Format: Sarah Attwell, Eric Campeau, Ravi Jahagirdar, Olesya Kharenko, Karen Norek, Laura Tsujikawa, Cyrus Calosing, Reena Patel, Emily Gesner, Sanjay Lakhotia, Henrik Hansen. The clinical candidate ZEN-3694, a novel BET bromodomain inhibitor, is efficacious in the treatment of a variety of solid tumor and hematological malignancies, alone or in combination with several standard of care and targeted therapies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C86.
Abstract IA32: Optimizing kinase inhibitors to treat cancer
Authors: Bollag Gideon 
Published: May 2016

Abstract
Kinase inhibitors have become important therapeutic agents with at least 27 FDA-approved compounds currently available. While this success has brought important benefit to cancer patients, new challenges have been revealed. In particular, resistances to therapy and novel therapy-induced side effects have introduced rationale for optimizing next-generation treatment regimens. Two specific examples will be discussed: RAF and KIT inhibitors for BRAF- and KIT-driven cancers.
Oncogenic activation of BRAF fuels cancer growth by constitutively promoting MAPK pathway signaling independent of RAS activation. Efforts to develop agents to block mutated BRAF have brought substantial therapeutic improvement in personalized treatment of metastatic melanoma. Nonetheless, many patients relapse and relapsed tumors generally display MAPK pathway re-activation. The development of these agents also revealed an unexpected consequence of these targeted therapies: stimulated growth of certain cancers. Structurally-diverse ATP-competitive RAF kinase inhibitors can either inhibit or paradoxically activate the MAPK pathway depending whether the pathway is activated by a BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. We have identified next generation RAF inhibitors (dubbed “paradox breakers”) that inhibit mutant RAF cells without activating the MAPK pathway in cells containing an upstream activation event. These new inhibitors maintain efficacy in BRAF-driven cell and animal models. In addition, PLX8394 is able to overcome several known mechanisms of resistance to first generation RAF inhibitors. By dissociating MAPK pathway inhibition from pathway activation, the next generation RAF inhibitors may yield both improved safety and more durable efficacy than first generation RAF inhibitors.
KIT inhibitors are now standard therapy for advanced gastrointestinal stromal tumors, and indeed comprise 1st, 2nd and 3rd line treatments reflecting both the marked dependence of these tumors on KIT and also the facile development of resistance. Even with multiple compounds approved, resistance mutations - in exon 17 in particular - still limit the durability of clinical benefit. We have discovered PLX9486 as an effective inhibitor of mutant KIT, including exon 17 mutations, with the added feature of selectivity versus the wild-type KIT kinase activity. This compound shows potent activity against exon 17 mutant tumors both in vitro and in vivo. Anticipating the obstacle of polyclonal KIT mutations in standard TKI-resistant patients, clinical development plans include a study combining PLX9486 with PLX3397, a potent KIT inhibitor addressing complementary KIT mutational profiles.
Citation Format: Gideon Bollag. Optimizing kinase inhibitors to treat cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA32.
Abstract OT3-01-12: Phase II trial of lapatinib and everolimus for HER2 positive metastatic breast cancer
Authors: Barr JA , Sharma P , Fabian CJ , Yeh H , Baccaray S , Springer M , Khan QJ 
Published: May 2016

Abstract
Background:
Although the treatment of HER2 positive metastatic breast cancer (MBC) has improved with anti-HER2 agents and chemotherapy, most patients will eventually develop resistance to these agents. Preclinical studies have shown that mTOR inhibition may reverse trastuzumab resistance. We hypothesize that combining mTOR inhibitor everolimus with lapatinib will be an effective strategy for patients who have progressed on prior anti-HER2 therapies.
Trial Design:
We are conducting an open-label phase II pilot study of the combination of everolimus and lapatinib for pts with HER-2 positive MBC. Eligible pts must have histologically documented locally advanced (inoperable) or metastatic HER-2 positive breast cancer that have progressed on at least one HER-2 based regimen in the metastatic or locally advanced setting. Pts with disease progression during or within 12 mos of the completion of adjuvant trastuzumab are eligible. Pts with untreated asymptomatic brain metastases are allowed. Pts with symptomatic brain metastases are allowed to enroll after they have completed radiation and are off steroids. Eligible pts are started on everolimus 5 mg PO daily and lapatinib 1250 mg PO daily without interruption. Among subjects progressing on lapatinib, lapatinib is continued and everolimus initiated. Pts will continue to receive treatment until there is evidence of progressive disease (PD), unacceptable toxicity, or withdrawal of consent. Pts will have radiological evaluation every 8 weeks with CT, bone scan, and MRI brain (for pts with known brain metastasis at baseline).
Specific Aims:
Primary objective is to assess the effectiveness of the combination of RAD-001 and lapatinib as measured by the six-month Overall Response Rate in women with MBC who have progressed on trastuzumab and/or lapatinib based therapies. Secondary objectives are six-month PFS, safety and tolerability of the combination, six-month objective CNS response rate, six-month clinical benefit rate of systemic disease, and six-month clinical benefit rate in CNS.
Statistical methods:
The response rate of lapatinib monotherapy in heavily pre-treated patients is estimated to be 7% (Blackwell 2009). For an expected ORR of 17%, a sample size of 45 subjects will provide 79% power to detect the difference at 0.10 Type I error rate according to 1-sided exact binomial test.
Present accrual and target accrual:
The trial has accrued 20 patients with a target accrual of 45 patients.
Citation Format: Barr JA, Sharma P, Fabian CJ, Yeh H, Baccaray S, Springer M, Khan QJ. Phase II trial of lapatinib and everolimus for HER2 positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-12.
Deficiency of ATP-Binding Cassette Transporters A1 and G1 in Endothelial Cells Accelerates Atherosclerosis in Mice
Authors: Westerterp Marit , Tsuchiya Kyoichiro , Tattersall Ian W. , Fotakis Panagiotis , Bochem Andrea E. , Molusky Matthew M. , Ntonga Vusisizwe , Abramowicz Sandra , Parks John S. , Welch Carrie L. , Kitajewski Jan , Accili Domenico , Tall Alan R. 
Published: May 2016

Objective—

Plasma high-density lipoproteins have several putative antiatherogenic effects, including preservation of endothelial functions. This is thought to be mediated, in part, by the ability of high-density lipoproteins to promote cholesterol efflux from endothelial cells (ECs). The ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) interact with high-density lipoproteins to promote cholesterol efflux from ECs. To determine the impact of endothelial cholesterol efflux pathways on atherogenesis, we prepared mice with endothelium-specific knockout of
Abca1
and
Abcg1
.

Approach and Results—

Generation of mice with EC-ABCA1 and ABCG1 deficiency required crossbreeding
Abca1

fl/fl

Abcg1

fl/fl

Ldlr

−/−

mice with the Tie2Cre strain, followed by irradiation and transplantation of
Abca1

fl/fl

Abcg1

fl/fl

bone marrow to abrogate the effects of macrophage ABCA1 and ABCG1 deficiency induced by Tie2Cre. After 20 to 22 weeks of Western-type diet, both single EC-
Abca1
and
Abcg1
deficiency increased atherosclerosis in the aortic root and whole aorta. Combined EC-
Abca1/g1
deficiency caused a significant further increase in lesion area at both sites. EC-
Abca1/g1
deficiency dramatically enhanced macrophage lipid accumulation in the branches of the aorta that are exposed to disturbed blood flow, decreased aortic endothelial NO synthase activity, and increased monocyte infiltration into the atherosclerotic plaque.
Abca1/g1
deficiency enhanced lipopolysaccharide-induced inflammatory gene expression in mouse aortic ECs, which was recapitulated by
ABCG1
deficiency in human aortic ECs.

Conclusions—
These studies provide direct evidence that endothelial cholesterol efflux pathways mediated by ABCA1 and ABCG1 are nonredundant and atheroprotective, reflecting preservation of endothelial NO synthase activity and suppression of endothelial inflammation, especially in regions of disturbed arterial blood flow.
Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration
Authors: Williams Helen , Mill Carina A.E. , Monk Bethan A. , Hulin-Curtis Sarah , Johnson Jason L. , George Sarah J. 
Published: May 2016

Objective—
Increased vascular smooth muscle cell (VSMC) migration leads to intimal thickening which acts as a soil for atherosclersosis, as well as causing coronary artery restenosis after stenting and vein graft failure. Investigating factors involved in VSMC migration may enable us to reduce intimal thickening and improve patient outcomes. In this study, we determined whether Wnt proteins regulate VSMC migration and thereby intimal thickening.

Approach and Results—

Wnt2 mRNA and protein expression were specifically increased in migrating mouse aortic VSMCs. Moreover, VSMC migration was induced by recombinant Wnt2 in vitro. Addition of recombinant Wnt2 protein increased Wnt1-inducible signaling pathway protein-1 (WISP-1) mRNA by ≈1.7-fold, via β-catenin/T-cell factor signaling, whereas silencing RNA knockdown of Wnt-2 reduced WISP-1 mRNA by ≈65%. Treatment with rWISP-1 significantly increased VSMC migration by ≈1.5-fold, whereas WISP-1 silencing RNA knockdown reduced migration by ≈40%. Wnt2 and WISP-1 effects were integrin-dependent and not additive, indicating that Wnt2 promoted VSMC migration via WISP-1. Additionally, Wnt2 and WISP-1 were significantly increased and colocated in human coronary arteries with intimal thickening. Reduced Wnt2 and WISP-1 levels in mouse carotid arteries from Wnt2
+/−
and WISP-1
−/−
mice, respectively, significantly suppressed intimal thickening in response to carotid artery ligation. In contrast, elevation of plasma WISP-1 via an adenovirus encoding WISP-1 significantly increased intimal thickening by ≈1.5-fold compared with mice receiving control virus.

Conclusions—
Upregulation of Wnt2 expression enhanced WISP-1 and promoted VSMC migration and thereby intimal thickening. As novel regulators of VSMC migration and intimal thickening, Wnt2 or WISP-1 may provide a potential therapy for restenosis and vein graft failure.
Procalcitonin and Midregional Proatrial Natriuretic Peptide as Markers of Ischemic Stroke
Authors: Katan Mira , Moon Yeseon P. , Paik Myunghee C. , Mueller Beat , Huber Andreas , Sacco Ralph L. , Elkind Mitchell S.V. 
Published: May 2016

Background and Purpose—
Chronic infections and neuroendocrine dysfunction may be risk factors for ischemic stroke (IS). We hypothesized that selected blood biomarkers of infection (procalcitonin [PCT]), hypothalamic–pituitary–axis function (copeptin), and hemodynamic dysfunction (midregional proatrial natriuretic peptide [MRproANP]) are associated with incident IS risk in the multiethnic, urban Northern Manhattan Study (NOMAS) cohort.

Methods—
A nested case–control study was performed among initially stroke-free participants. Cases were defined as first IS (n=172). We randomly selected controls among those who did not develop an event (n=344). We calculated Cox proportional hazards models with inverse probability weighting to estimate the association of blood biomarkers with risk of stroke after adjusting for demographic, behavioral, and medical risk factors.

Results—
Those with PCT and MRproANP, but not copeptin, in the top quartile, compared with the lowest quartile, were associated with IS (for PCT adjusted hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.0–3.8 and for MRproANP adjusted HR, 3.5; 95% CI, 1.6–7.5). The associations of PCT and MRproANP differed by stroke etiology; PCT levels in the top quartile were particularly associated with small vessel stroke (adjusted HR, 5.1; 95% CI, 1.4–18.7) and MRproANP levels with cardioembolic stroke (adjusted HR, 16.3; 95% CI, 3.7–70.9).

Conclusions—
Higher levels of PCT, a marker of infection, and MRproANP, a marker for hemodynamic stress, were independently associated with IS risk. PCT was specifically associated with small vessel and MRproANP with cardioembolic stroke risk. Further study is needed to validate these biomarkers and determine their significance in stroke risk prediction and prevention.
Utility of Computed Tomographic Perfusion in Thrombolysis for Minor Stroke
Authors: Ng Felix C. , Coote Skye , Frost Tanya , Bladin Chris , Choi Philip M. 
Published: May 2016

Background and Purpose—
The use of thrombolysis in acute minor ischemic stroke (MIS) remains controversial. We sought to determine the safety and efficacy of intravenous tissue-type plasminogen activator (IV-tPA) in acute MIS patients with demonstrable penumbra on computed tomographic perfusion study.

Methods—
Consecutive MIS patients with National Institutes of Health Stroke Scale ≤3 were identified from a prospective single tertiary-center database over a 4.5-year period (2011–2015). Cases with demonstrable penumbra were analyzed according to treatment received: IV-tPA versus standard stroke-unit care without thrombolysis.

Results—

Seventy-three patients of 195 acute MIS admissions had a demonstrable penumbra (34 IV-tPA versus 39 standard stroke-unit care). Overall median National Institutes of Health Stroke Scale and premorbid modified Rankin Scale were 2 and 0, respectively. Median age was 73.2 (interquartile range, 67.3–82.8) years. There were no differences in baseline demographics, risk factors, stroke localization and cause, rates of vascular occlusion (38.2% versus 38.5%;
P
=1.000), or mean penumbral volume (41.3 versus 25.1 mL;
P
=0.150; IV-tPA versus standard stroke-unit care) between groups. There were no symptomatic intracerebral hemorrhages in either group. Patients treated with IV-tPA were more likely to have an excellent functional outcome at discharge (88.2% versus 53.9%;
P
=0.002) and 90 days (91.2% versus 71.8%;
P
=0.042). Ordinal analysis demonstrated a favorable shift in modified Rankin Scale with IV-tPA both at discharge (odds ratio, 5.23; 95% confidence interval, 1.83–12.20) and 90 days (odds ratio, 4.35; 95% confidence interval, 1.77–11.36).

Conclusions—
In selected MIS patients with demonstrable penumbra on computed tomographic perfusion, IV-tPA is safe and associated with significant improvement in functional outcome at discharge and 90 days.