bluuebunny/crossref_metadata_2025 huggingface dataset:
Advances in the Study of Coevolution Between Avian Brood Parasites and Their Hosts
Authors: Feeney William E. , Welbergen Justin A. , Langmore Naomi E.
Published: October 2014

The interactions between avian obligate interspecific brood parasites and their hosts provide tractable systems for studying coevolutionary processes in nature. This review highlights recent advances in understanding coevolution in these systems. First, we discuss the evolution and phylogenetic history of avian brood parasitism. Next, we examine coevolved adaptations and counteradaptations in brood parasites and hosts at all stages of the host nesting cycle: those that precede laying of the parasitic egg and those at the egg, chick, and fledgling stages. We then consider the factors that affect the evolution of offense and defense portfolios (the suites of adaptations and counteradaptations across the nesting cycle), and the outcomes of coevolutionary interactions between brood parasites and hosts. Ongoing efforts to document the diversity of host defenses and parasite offenses will facilitate understanding of coevolutionary processes and the ecological and evolutionary consequences of species interactions in the natural world.
A Multiscale, Hierarchical Model of Pulse Dynamics in Arid-Land Ecosystems
Authors: Collins S.L. , Belnap J. , Grimm N.B. , Rudgers J.A. , Dahm C.N. , D'Odorico P. , Litvak M. , Natvig D.O. , Peters D.C. , Pockman W.T. , Sinsabaugh R.L. , Wolf B.O.
Published: October 2014

Ecological processes in arid lands are often described by the pulse-reserve paradigm, in which rain events drive biological activity until moisture is depleted, leaving a reserve. This paradigm is frequently applied to processes stimulated by one or a few precipitation events within a growing season. Here we expand the original framework in time and space and include other pulses that interact with rainfall. This new hierarchical pulse-dynamics framework integrates space and time through pulse-driven exchanges, interactions, transitions, and transfers that occur across individual to multiple pulses extending from micro to watershed scales. Climate change will likely alter the size, frequency, and intensity of precipitation pulses in the future, and arid-land ecosystems are known to be highly sensitive to climate variability. Thus, a more comprehensive understanding of arid-land pulse dynamics is needed to determine how these ecosystems will respond to, and be shaped by, increased climate variability.
Resolving Conflicts During the Evolutionary Transition to Multicellular Life
Authors: Rainey Paul B. , De Monte Silvia
Published: October 2014

The evolution of multicellular life from unicellular ancestral types involves a hierarchical shift in the level at which selection operates. The shift, from cells to collectives, depends on the emergence of Darwinian properties at the level of nascent collectives. However, from the very earliest phases—even before the emergence of higher-level Darwinian properties—the stage is set for the evolution of conflict. Here we consider the range of ways by which cooperation and conflict manifest at different levels of biological organization. We give prominence to the emerging idea that conflict is a central driver in the evolution of biological complexity and, in particular, that solutions to conflict, notably those that arise from selection operating at different temporal scales, have fueled the evolution of individuality.
The Molecular Basis of Phenotypic Convergence
Authors: Rosenblum Erica Bree , Parent Christine E. , Brandt Erin E.
Published: October 2014

Understanding what aspects of evolution are predictable, and repeatable, is a central goal of biology. Studying phenotypic convergence (the independent evolution of similar traits in different organisms) provides an opportunity to address evolutionary predictability at different hierarchical levels. Here we focus on recent advances in understanding the molecular basis of convergence. Understanding when, and why, similar molecular solutions are used repeatedly provides insight into the constraints that shape biological diversity. We first distinguish between convergence as a phenotypic pattern and parallelism as a shared molecular basis for convergence. We then address the overarching question: What factors influence when parallel molecular mechanisms will underlie phenotypic convergence? We present four core determinants of convergence (natural selection, phylogenetic history, population demography, and genetic constraints) and explore specific factors that influence the probability of molecular parallelism. Finally, we address frontiers for future study, including integration across different systems, subfields, and hierarchical levels.
Stability of Constrained Capillary Surfaces
Authors: Bostwick J.B. , Steen P.H.
Published: October 2014

A capillary surface is an interface between two fluids whose shape is determined primarily by surface tension. Sessile drops, liquid bridges, rivulets, and liquid drops on fibers are all examples of capillary shapes influenced by contact with a solid. Capillary shapes can reconfigure spontaneously or exhibit natural oscillations, reflecting static or dynamic instabilities, respectively. Both instabilities are related, and a review of static stability precedes the dynamic case. The focus of the dynamic case here is the hydrodynamic stability of capillary surfaces subject to constraints of (a) volume conservation, (b) contact-line boundary conditions, and (c) the geometry of the supporting surface.
Semantics and Pragmatics of Argument Alternations
Authors: Levin Beth
Published: October 2014

After setting out the challenges posed by argument alternations for linguistic theory, this article reviews the development of accounts of argument alternations over the past 50 years, documenting a shift from accounts that are primarily syntactic in nature to accounts with semantic and pragmatic components. The remainder of this review consists of case studies of the developing understanding of the semantics and pragmatics of the dative alternation and the causative alternation. Each case study stresses the interplay of semantic and contextual factors in characterizing the relation between the two variants that make up the alternation and in determining the choice of variant in a given context.
Targeting Hsp90/Hsp70-Based Protein Quality Control for Treatment of Adult Onset Neurodegenerative Diseases
Authors: Pratt William B. , Gestwicki Jason E. , Osawa Yoichi , Lieberman Andrew P.
Published: October 2014

Currently available therapies for adult onset neurodegenerative diseases provide symptomatic relief but do not modify disease progression. Here we explore a new neuroprotective approach based on drugs targeting chaperone-directed protein quality control. Critical target proteins that unfold and aggregate in these diseases, such as the polyglutamine androgen receptor in spinal and bulbar muscular atrophy, huntingtin in Huntington's disease, α-synuclein in Parkinson's disease, and tau in Alzheimer's disease, are client proteins of heat shock protein 90 (Hsp90), and their turnover is regulated by the protein quality control function of the Hsp90/Hsp70-based chaperone machinery. Hsp90 and Hsp70 have opposing effects on client protein stability in protein quality control; Hsp90 stabilizes the clients and inhibits their ubiquitination, whereas Hsp70 promotes ubiquitination dependent on CHIP (C terminus of Hsc70-interacting protein) and proteasomal degradation. We discuss how drugs that modulate proteostasis by inhibiting Hsp90 function or promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models.
Pharmacogenomics in Asthma Therapy: Where Are We and Where Do We Go?
Authors: Park Heung-Woo , Tantisira Kelan G. , Weiss Scott T.
Published: October 2014

The response to drug treatment in asthma is a complex trait and is markedly variable even in patients with apparently similar clinical features. Pharmaco-genomics, which is the study of variations of human genome characteristics as related to drug response, can play a role in asthma therapy. Both a traditional candidate-gene approach to conducting genetic association studies and genome-wide association studies have provided an increasing list of genes and variants associated with the three major classes of asthma medications: β2-agonists, inhaled corticosteroids, and leukotriene modifiers. Moreover, a recent integrative, systems-level approach has offered a promising opportunity to identify important pharmacogenomics loci in asthma treatment. However, we are still a long way away from making this discipline directly relevant to patients. The combination of network modeling, functional validation, and integrative omics technologies will likely be needed to move asthma pharmacogenomics closer to clinical relevance.
Effects of weight gain induced by controlled overfeeding on physical activity
Authors: Apolzan John W. , Bray George A. , Smith Steven R. , de Jonge Lilian , Rood Jennifer , Han Hongmei , Redman Leanne M. , Martin Corby K.
Published: October 2014

It is unclear whether physical activity changes following long-term overfeeding and in response to different dietary protein intakes. Twenty-five (16 males, 9 females) healthy adults (18–35 yr) with BMI ranging from 19 to 30 kg/m2 enrolled in this inpatient study. In a parallel group design, participants were fed 140% of energy needs, with 5, 15, or 25% of energy from protein, for 56 days. Participants wore an RT3 accelerometer for at least 59 days throughout baseline and during overfeeding and completed 24-h whole room metabolic chamber assessments at baseline and on days 1, 14, and 56 of overfeeding and on day 57, when the baseline energy intake was consumed, to measure percent of time active and spontaneous physical activity (SPA; kcal/day). Changes in activity were also assessed by doubly labeled water (DLW). From accelerometry, vector magnitude (VM), a weight-independent measure of activity, and activity energy expenditure (AEE) increased with weight gain during overfeeding. AEE remained increased after adjusting for changes in body composition. Activity-related energy expenditure (AREE) from DLW and percent activity and SPA in the metabolic chamber increased with overfeeding, but SPA was no longer significant after adjusting for change in body composition. Change in VM and AEE were positively correlated with weight gain; however, change in activity was not affected by protein intake. Overfeeding produces an increase in physical activity and in energy expended in physical activity after adjusting for changes in body composition, suggesting that increased activity in response to weight gain might be one mechanism to support adaptive thermogenesis.
Thromboxane-induced actin polymerization in hypoxic neonatal pulmonary arterial myocytes involves Cdc42 signaling
Authors: Fediuk Jena , Sikarwar Anurag S. , Nolette Nora , Dakshinamurti Shyamala
Published: October 2014

In hypoxic pulmonary arterial (PA) myocytes, challenge with thromboxane mimetic U46619 induces marked actin polymerization and contraction, phenotypic features of persistent pulmonary hypertension of the newborn (PPHN). Rho GTPases regulate the actin cytoskeleton. We previously reported that U46619-induced actin polymerization in hypoxic PA myocytes occurs independently of the RhoA pathway and hypothesized involvement of the Cdc42 pathway. PA myocytes grown in normoxia or hypoxia for 72 h were stimulated with U46619, then analyzed for Rac/Cdc42 activation by affinity precipitation, phosphatidylinositide-3-kinase (PI3K) activity by phospho-Akt, phospho-p21-activated kinase (PAK) by immunoblot, and association of Cdc42 with neuronal Wiskott Aldrich Syndrome protein (N-WASp) by immunoprecipitation. The effect of Rac or PAK inhibition on filamentous actin was quantified by laser-scanning cytometry and by cytoskeletal fractionation; effects of actin-modifying agents were measured by isometric myography. Basal Cdc42 activity increased in hypoxia, whereas Rac activity decreased. U46619 challenge increased Cdc42 and Rac activity in hypoxic cells, independently of PI3K. Hypoxia increased phospho-PAK, unaltered by U46619. Association of Cdc42 with N-WASp decreased in hypoxia but increased after U46619 exposure. Hypoxia doubled filamentous-to-globular ratios of α- and γ-actin isoforms. Jasplakinolide stabilized γ-filaments, increasing force; cytochalasin D depolymerized all actin isoforms, decreasing force. Rac and PAK inhibition decreased filamentous actin in tissues although without decrease in force. Rho inhibition decreased myosin phosphorylation and force. Hypoxia induces actin polymerization in PA myocytes, particularly increasing filamentous α- and γ-actin, contributing to U46619-induced contraction. Hypoxic PA myocytes challenged with a thromboxane mimetic polymerize actin via the Cdc42 pathway, reflecting increased Cdc42 association with N-WASp. Mechanisms regulating thromboxane-mediated actin polymerization are potential targets for future PPHN pharmacotherapy.
Animal models of bronchopulmonary dysplasia. The preterm baboon models
Authors: Yoder Bradley A. , Coalson Jacqueline J.
Published: October 2014

Much of the progress in improved neonatal care, particularly management of underdeveloped preterm lungs, has been aided by investigations of multiple animal models, including the neonatal baboon ( Papio species). In this article we highlight how the preterm baboon model at both 140 and 125 days gestation (term equivalent 185 days) has advanced our understanding and management of the immature human infant with neonatal lung disease. Not only is the 125-day baboon model extremely relevant to the condition of bronchopulmonary dysplasia but there are also critical neurodevelopmental and other end-organ pathological features associated with this model not fully discussed in this limited forum. We also describe efforts to incorporate perinatal infection into these preterm models, both fetal and neonatal, and particularly associated with Ureaplasma/ Mycoplasma organisms. Efforts to rekindle the preterm primate model for future evaluations of therapies such as stem cell replacement, early lung recruitment interventions coupled with noninvasive surfactant and high-frequency nasal ventilation, and surfactant therapy coupled with antioxidant or anti-inflammatory medications, to name a few, should be undertaken.
TRPV4: an exciting new target to promote alveolocapillary barrier function
Authors: Morty Rory E. , Kuebler Wolfgang M.
Published: October 2014

Transient receptor potential (TRP) channels are emerging as important players and drug targets in respiratory disease. Amongst the vanilloid-type TRP channels (which includes the six members of the TRPV family), target diseases include cough, asthma, cancer, and more recently, pulmonary edema associated with acute respiratory distress syndrome. Here, we critically evaluate a recent report that addresses TRPV4 as a candidate target for the management of acute lung injury that develops as a consequence of aspiration of gastric contents, or acute chlorine gas exposure. By use of two new TRPV4 inhibitors (GSK2220691 or GSK2337429A) and a trpv4−/−mouse strain, TRPV4 was implicated as a key mediator of pulmonary inflammation after direct chemical insult. Additionally, applied therapeutically, TRPV4 inhibitors exhibited vasculoprotective effects after chlorine gas exposure, inhibiting vascular leakage, and improving blood oxygenation. These observations underscore TRPV4 channels as candidate therapeutic targets in the management of lung injury, with the added need to balance these against the potential drawbacks of TRPV4 inhibition, such as the danger of limiting the immune response in settings of pathogen-provoked injury.
A Novel Cryptic Three-Way Translocation t(2;9;18)(p23.2;p21.3;q21.33) with Deletion of Tumor Suppressor Genes in 9p21.3 and 13q14 in a T-Cell Acute Lymphoblastic Leukemia
Authors: Othman Moneeb A. K. , Rincic Martina , Melo Joana B. , Carreira Isabel M. , Alhourani Eyad , Hunstig Friederike , Glaser Anita , Liehr Thomas
Published: October 2014

Acute leukemia often presents with pure chromosomal resolution; thus, aberrations may not be detected by banding cytogenetics. Here, a case of 26-year-old male diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) and a normal karyotype after standard GTG-banding was studied retrospectively in detail by molecular cytogenetic and molecular approaches. Besides fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and high resolution array-comparative genomic hybridization (aCGH) were applied. Thus, cryptic chromosomal aberrations not observed before were detected: three chromosomes were involved in a cytogenetically balanced occurring translocation t(2;9;18)(p23.2;p21.3;q21.33). Besides a translocation t(10;14)(q24;q11) was identified, an aberration known to be common in T-ALL. Due to the three-way translocation deletion of tumor suppressor genes CDKN2A/INK4A/p16, CDKN2B/INK4B/p15, and MTAP/ARF/p14 in 9p21.3 took place. Additionally RB1 in 13q14 was deleted. This patient, considered to have a normal karyotype after low resolution banding cytogenetics, was treated according to general protocol of anticancer therapy (ALL-BFM 95).
Globo-H Ceramide Shed from Cancer Cells Triggers Translin-Associated Factor X-Dependent Angiogenesis
Authors: Cheng Jing-Yan , Wang Sheng-Hung , Lin Juway , Tsai Yi-Chien , Yu John , Wu Jen-Chine , Hung Jung-Tung , Lin Jin-Jin , Wu Yih-Yiing , Yeh Kun-Tu , Yu Alice L.
Published: October 2014

Tumor angiogenesis is a critical element of cancer progression, and strategies for its selective blockade are still sought. Here, we examine the angiogenic effects of Globo-H ceramide (GHCer), the most prevalent glycolipid in a majority of epithelial cancers and one that acts as an immune checkpoint. Here, we report that GHCer becomes incorporated into endothelial cells through the absorption of microvesicles shed from tumor cells. In endothelial cells, GHCer addition induces migration, tube formation, and intracellular Ca2+ mobilization in vitro and angiogenesis in vivo. Breast cancer cells expressing high levels of GHCer displayed relatively greater tumorigenicity and angiogenesis compared with cells expressing low levels of Globo-H. Clincally, GHCer+ breast cancer specimens contained higher vessel density than GHCer− breast cancer specimens. Mechanistic investigations linked the angiogenic effects of GHCer to its endocytosis and binding to TRAX, with consequent release of PLCβ1 from TRAX to trigger Ca2+ mobilization. Together, our findings highlight the importance of GHC as a target for cancer therapy by providing new information on its key role in tumor angiogenesis. Cancer Res; 74(23); 6856–66. ©2014 AACR.
Early Pregnancy Sex Steroids and Maternal Breast Cancer: A Nested Case–Control Study
Authors: Fortner Renée T. , Schock Helena , Kaaks Rudolf , Lehtinen Matti , Pukkala Eero , Lakso Hans-Åke , Tanner Minna , Kallio Raija , Joensuu Heikki , Grankvist Kjell , Zeleniuch-Jacquotte Anne , Toniolo Paolo , Lundin Eva , Surcel Helja-Marja
Published: October 2014

Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case–control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n = 1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. ORs were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age <40 [4th vs. 1st quartile OR 1.60 (1.07–2.39); Ptrend = 0.01], and inversely associated with breast cancer diagnosed at age ≥40 [4th vs. 1st quartile OR 0.71 (0.51–1.00); Ptrend = 0.02]. Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors in women age <40 at diagnosis. We observed no association between steroid hormones and ER+/PR+ disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER−/PR− breast cancer in women diagnosed age <40, and an inverse association for overall breast cancer diagnosed age ≥40. Further research on pregnancy hormones and risk of steroid receptor–negative cancers is needed to further characterize this association. Cancer Res; 74(23); 6958–67. ©2014 AACR.
DNA Methylation Status of Key Cell-Cycle Regulators Such as CDKNA2/p16 and CCNA1 Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors
Authors: Klajic Jovana , Busato Florence , Edvardsen Hege , Touleimat Nizar , Fleischer Thomas , Bukholm Ida , Børresen-Dale Anne-Lise , Lønning Per Eystein , Tost Jörg , Kristensen Vessela N.
Published: October 2014

Purpose: To explore alterations in gene promoter methylation as a potential cause of acquired drug resistance to doxorubicin or combined treatment with 5-fluorouracil and mitomycin C in human breast cancers.

Experimental Design: Paired tumor samples from locally advanced breast cancer patients treated with doxorubicin and 5-fluorouracil-mitomycin C were used in the genome-wide DNA methylation analysis as discovery cohort. An enlarged cohort from the same two prospective studies as those in the discovery cohort was used as a validation set in pyrosequencing analysis.

Results: A total of 469 genes were differentially methylated after treatment with doxorubicin and revealed a significant association with canonical pathways enriched for immune cell response and cell-cycle regulating genes including CDKN2A, CCND2, CCNA1, which were also associated to treatment response. Treatment with FUMI resulted in 343 differentially methylated genes representing canonical pathways such as retinoate biosynthesis, gαi signaling, and LXR/RXR activation. Despite the clearly different genes and pathways involved in the metabolism and therapeutic effect of both drugs, 46 genes were differentially methylated before and after treatment with both doxorubicin and FUMI. DNA methylation profiles in genes such as BRCA1, FOXC1, and IGFBP3, and most notably repetitive elements like ALU and LINE1, were associated with TP53 mutations status.

Conclusion: We identified and validated key cell-cycle regulators differentially methylated before and after neoadjuvant chemotherapy such as CDKN2A and CCNA1 and reported that methylation patterns of these genes may be potential predictive markers to anthracycline/mitomycine sensitivity. Clin Cancer Res; 20(24); 6357–66. ©2014 AACR.
Ramucirumab: Successfully Targeting Angiogenesis in Gastric Cancer
Authors: Javle Milind , Smyth Elizabeth C. , Chau Ian
Published: October 2014

Gastric cancer is the fourth most common cancer globally and represents the second most common cause of cancer-related mortality. Early detection, aggressive surgical resection, and postoperative adjuvant therapy have led to survival improvement for early-stage gastric cancer, particularly in Asian countries. Unfortunately, advanced gastric cancer continues to pose a formidable challenge with few gains being reported recently. Trastuzumab was the first targeted agent to be approved for the treatment of advanced gastric cancer in 2010. The failure of the AVAGAST trial was a setback for antiangiogenic therapy for this disease. Ramucirumab is a monoclonal antibody that binds to VEGF-R2 and prevents its activation. The recent REGARD trial was a randomized phase III trial of ramucirumab vs. placebo for patients with advanced, pretreated gastric cancer that met its primary endpoint of increased overall survival. The toxicity of ramucirumab was modest in this setting, with an increased risk of grade 3 or higher hypertension (8% vs. 3%, with ramucirumab and placebo, respectively). The subsequent RAINBOW trial of paclitaxel plus ramucirumab vs. paclitaxel plus placebo for advanced pretreated gastric cancer confirmed the survival advantage of this antiangiogenic agent in gastric cancer. Ramucirumab is the first FDA-approved therapy for advanced gastric cancer after prior chemotherapy. Clin Cancer Res; 20(23); 5875–81. ©2014 AACR.
A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma
Authors: Sborov Douglas W. , Nuovo Gerard J. , Stiff Andrew , Mace Thomas , Lesinski Gregory B. , Benson Don M. , Efebera Yvonne A. , Rosko Ashley E. , Pichiorri Flavia , Grever Michael R. , Hofmeister Craig C.
Published: October 2014

Purpose: Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies.

Experimental Design: A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti-reovirus antibody assay was performed weekly during cycle 1.

Results: There were no dose-limiting toxicities, patients reached the 3 × 1010 TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months.

Conclusions: Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers. Clin Cancer Res; 20(23); 5946–55. ©2014 AACR.
Team Work Matters: Dual Inhibition Puts Non-Hodgkin Lymphoma Under Siege
Authors: Bianchi Giada , Ghobrial Irene M.
Published: October 2014

Inhibitors of PI3K/mTOR and histone deacetylases (HDAC) are effective in non-Hodgkin lymphoma (NHL). However, clinical resistance eventually ensues and combinatory therapies are sought to prevent it. Preclinical evaluation of dual PI3K/mTOR and HDAC inhibition is synergistic against NHL, paving the way for bench-to-bedside translation. Clin Cancer Res; 20(23); 5863–5. ©2014 AACR.
Inhibition of Monocarboxylate Transporter-1 (MCT1) by AZD3965 Enhances Radiosensitivity by Reducing Lactate Transport
Authors: Bola Becky M. , Chadwick Amy L. , Michopoulos Filippos , Blount Kathryn G. , Telfer Brian A. , Williams Kaye J. , Smith Paul D. , Critchlow Susan E. , Stratford Ian J.
Published: October 2014

Inhibition of the monocarboxylate transporter MCT1 by AZD3965 results in an increase in glycolysis in human tumor cell lines and xenografts. This is indicated by changes in the levels of specific glycolytic metabolites and in changes in glycolytic enzyme kinetics. These drug-induced metabolic changes translate into an inhibition of tumor growth in vivo. Thus, we combined AZD3965 with fractionated radiation to treat small cell lung cancer (SCLC) xenografts and showed that the combination provided a significantly greater therapeutic effect than the use of either modality alone. These results strongly support the notion of combining MCT1 inhibition with radiotherapy in the treatment of SCLC and other solid tumors. Mol Cancer Ther; 13(12); 2805–16. ©2014 AACR.
Therapeutic Silencing of KRAS Using Systemically Delivered siRNAs
Authors: Pecot Chad V. , Wu Sherry Y. , Bellister Seth , Filant Justyna , Rupaimoole Rajesha , Hisamatsu Takeshi , Bhattacharya Rajat , Maharaj Anshumaan , Azam Salma , Rodriguez-Aguayo Cristian , Nagaraja Archana S. , Morelli Maria Pia , Gharpure Kshipra M. , Waugh Trent A. , Gonzalez-Villasana Vianey , Zand Behrouz , Dalton Heather J. , Kopetz Scott , Lopez-Berestein Gabriel , Ellis Lee M. , Sood Anil K.
Published: October 2014

Despite being among the most common oncogenes in human cancer, to date, there are no effective clinical options for inhibiting KRAS activity. We investigated whether systemically delivered KRAS siRNAs have therapeutic potential in KRAS-mutated cancer models. We identified KRAS siRNA sequences with notable potency in knocking down KRAS expression. Using lung and colon adenocarcinoma cell lines, we assessed antiproliferative effects of KRAS silencing in vitro. For in vivo experiments, we used a nanoliposomal delivery platform, DOPC, for systemic delivery of siRNAs. Various lung and colon cancer models were used to determine efficacy of systemic KRAS siRNA based on tumor growth, development of metastasis, and downstream signaling. KRAS siRNA sequences induced >90% knockdown of KRAS expression, significantly reducing viability in mutant cell lines. In the lung cancer model, KRAS siRNA treatment demonstrated significant reductions in primary tumor growth and distant metastatic disease, while the addition of CDDP was not additive. Significant reductions in Ki-67 indices were seen in all treatment groups, whereas significant increases in caspase-3 activity were only seen in the CDDP treatment groups. In the colon cancer model, KRAS siRNA reduced tumor KRAS and pERK expression. KRAS siRNAs significantly reduced HCP1 subcutaneous tumor growth, as well as outgrowth of liver metastases. Our studies demonstrate a proof-of-concept approach to therapeutic KRAS targeting using nanoparticle delivery of siRNA. This study highlights the potential translational impact of therapeutic RNA interference, which may have broad applications in oncology, especially for traditional “undruggable” targets. Mol Cancer Ther; 13(12); 2876–85. ©2014 AACR.
Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer
Authors: Puig Marta , Lugo Roberto , Gabasa Marta , Giménez Alícia , Velásquez Adriana , Galgoczy Roland , Ramírez Josep , Gómez-Caro Abel , Busnadiego Óscar , Rodríguez-Pascual Fernando , Gascón Pere , Reguart Noemí , Alcaraz Jordi
Published: October 2014

The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non–small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal- or tumor-like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues of matrix rigidity were driven by β1 integrin mechano-sensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in β1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC–TAFs exhibited higher FAK (pY397), β1 expression, and ERK1/2 (pT202/Y204) than ADC–TAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC–TAFs (>50%) compared with ADC–TAFs (10%–20%). In contrast, SCC–TAFs were largely serum desensitized, whereas ADC–TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC–TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or β1 integrin-dependent mechano regulation may be effective against SCC–TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC–TAFs.

Implications: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells. Mol Cancer Res; 13(1); 161–73. ©2014 AACR.
A DRD1 Polymorphism Predisposes to Lung Cancer among Those Exposed to Secondhand Smoke during Childhood
Authors: Robles Ana I. , Yang Ping , Jen Jin , McClary Andrew C. , Calhoun Kara , Bowman Elise D. , Vähäkangas Kirsi , Greathouse K. Leigh , Wang Yi , Olivo-Marston Susan , Wenzlaff Angela S. , Deng Bo , Schwartz Ann G. , Ryan Bríd M.
Published: October 2014

Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3′UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60–0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62–0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47–0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53–0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62–0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3′UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood. Cancer Prev Res; 7(12); 1210–8. ©2014 AACR.
Crucial Role of c-Jun Phosphorylation at Ser63/73 Mediated by PHLPP Protein Degradation in the Cheliensisin A Inhibition of Cell Transformation
Authors: Zhu Junlan , Zhang Jingjie , Huang Haishan , Li Jingxia , Yu Yonghui , Jin Honglei , Li Yang , Deng Xu , Gao Jimin , Zhao Qinshi , Huang Chuanshu
Published: October 2014

Cheliensisin A (Chel A), as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been demonstrated to have an inhibition of EGF-induced Cl41 cell transformation via stabilizing p53 protein in a Chk1-dependent manner, suggesting its chemopreventive activity in our previous studies. However, its underlying molecular mechanisms have not been fully characterized yet. In the current study, we found that Chel A treatment could increase c-Jun protein phosphorylation and activation, whereas the inhibition of c-Jun phosphorylation, by ectopic expression of a dominant-negative mutant of c-Jun, TAM67, reversed the Chel A inhibition of EGF-induced cell transformation and impaired Chel A induction of p53 protein and apoptosis. Moreover, our results indicated that Chel A treatment led to a PHLPP downregulation by promoting PHLPP protein degradation. We also found that PHLPP could interact with and bind to c-Jun protein, whereas ectopic PHLPP expression blocked c-Jun activation, p53 protein and apoptotic induction by Chel A, and further reversed the Chel A inhibition of EGF-induced cell transformation. With the findings, we have demonstrated that Chel A treatment promotes a PHLPP protein degradation, which can bind to c-Jun and mediates c-Jun phosphorylation, and further leading to p53 protein induction, apoptotic responses, subsequently resulting in cell transformation inhibition and chemopreventive activity of Chel A. Cancer Prev Res; 7(12); 1270–81. ©2014 AACR.
Hypotension During Hospitalization for Acute Heart Failure Is Independently Associated With 30-Day Mortality
Authors: Patel Priyesh A. , Heizer Gretchen , O’Connor Christopher M. , Schulte Phillip J. , Dickstein Kenneth , Ezekowitz Justin A. , Armstrong Paul W. , Hasselblad Vic , Mills Roger M. , McMurray John J.V. , Starling Randall C. , Tang W.H. Wilson , Califf Robert M. , Hernandez Adrian F.
Published: October 2014

Background—

Outcomes associated with episodes of hypotension while hospitalized with acute decompensated heart failure are not well understood.

Methods and Results—

Using data from Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), we assessed factors associated with in-hospital hypotension and subsequent 30-day outcomes. Patients were classified as having symptomatic or asymptomatic hypotension. Multivariable logistic regression was used to determine factors associated with in-hospital hypotension, and Cox proportional hazards models were used to assess the association between hypotension and 30-day outcomes. We also tested for treatment interaction with nesiritide on 30-day outcomes and the association between in-hospital hypotension and renal function at hospital discharge. Overall, 1555 of 7141 (21.8%) patients had an episode of hypotension, of which 73.1% were asymptomatic and 26.9% were symptomatic. Factors strongly associated with in-hospital hypotension included randomization to nesiritide (odds ratio, 1.98; 95% confidence interval [CI], 1.76–2.23;
P
<0.001), chronic metolazone therapy (odds ratio, 1.74; 95% CI, 1.17–2.60;
P
<0.001), and baseline orthopnea (odds ratio, 1.31; 95% CI, 1.13–1.52;
P
=0.001) or S3 gallop (odds ratio, 1.21; 95% CI, 1.06–1.40;
P
=0.006). In-hospital hypotension was associated with increased hazard of 30-day mortality (hazard ratio, 2.03; 95% CI, 1.57–2.61;
P
<0.001), 30-day heart failure hospitalization or mortality (hazard ratio, 1.58; 95% CI, 1.34–1.86;
P
<0.001), and 30-day all-cause hospitalization or mortality (hazard ratio, 1.40; 95% CI, 1.22–1.61;
P
<0.001). Nesiritide had no interaction on the relationship between hypotension and 30-day outcomes (interaction
P
=0.874 for death,
P
=0.908 for death/heart failure hospitalization,
P
=0.238 death/all-cause hospitalization).

Conclusions—

Hypotension while hospitalized for acute decompensated heart failure is an independent risk factor for adverse 30-day outcomes, and its occurrence highlights the need for modified treatment strategies.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00475852.
Growth Differentiation Factor 15, a Marker of Oxidative Stress and Inflammation, for Risk Assessment in Patients With Atrial Fibrillation
Authors: Wallentin Lars , Hijazi Ziad , Andersson Ulrika , Alexander John H. , De Caterina Raffaele , Hanna Michael , Horowitz John D. , Hylek Elaine M. , Lopes Renato D. , Åsberg Signild , Granger Christopher B. , Siegbahn Agneta
Published: October 2014

Background—

Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation.

Methods and Results—

The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment, and other biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile range, 977–2052 ng/L). Annual rates of stroke or systemic embolism ranged from 0.9% to 2.03% (
P
<0.001); of major bleeding, from 1.22% to 4.53% (
P
<0.001); and of mortality, from 1.34% to 7.19% (
P
<0.001) in the lowest compared with the highest GDF-15 quartile. The prognostic information provided by GDF-15 was independent of clinical characteristics and clinical risk scores. Adjustment for the other cardiac biomarkers attenuated the prognostic value for stroke, whereas the prognostic value for mortality and major bleeding remained. Apixaban consistently reduced stroke, mortality, and bleeding, regardless of GDF-15 levels.

Conclusions—

GDF-15 is a risk factor for major bleeding, mortality, and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00412984.
Electrophysiologic Substrate in Congenital Long QT Syndrome
Authors: Vijayakumar Ramya , Silva Jennifer N.A. , Desouza Kavit A. , Abraham Robert L. , Strom Maria , Sacher Frederic , Van Hare George F. , Haïssaguerre Michel , Roden Dan M. , Rudy Yoram
Published: October 2014

Background—

Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. Although its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging to map the cardiac electrophysiological substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate that promotes arrhythmogenesis.

Methods and Results—

Twenty-five subjects (9 LQT1, 9 LQT2, 5 LQT3, and 2 LQT5) with genotype and phenotype positive LQTS underwent ECG imaging. Seven normal subjects provided control. Epicardial maps of activation, recovery times, activation-recovery intervals, and repolarization dispersion were constructed. Activation was normal in all patients. However, recovery times and activation–recovery intervals were prolonged relative to control, indicating delayed repolarization and abnormally long action potential duration (312±30 ms versus 235±21 ms in control). Activation–recovery interval prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119±19 ms/cm versus 2.0±2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130±27 ms/cm in 12 symptomatic patients versus 98±19 ms/cm in 13 asymptomatic patients;
P
<0.05).

Conclusions—

LQTS patients display regions with steep repolarization dispersion caused by localized action potential duration prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECG imaging in risk stratification.
Application of Single-Stage Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations >10 cm
3
Authors: Hanakita Shunya , Koga Tomoyuki , Shin Masahiro , Igaki Hiroshi , Saito Nobuhito
Published: October 2014

Background and Purpose—

Stereotactic radiosurgery (SRS) is a safe and effective treatment for small arteriovenous malformations (AVMs), the use of this modality for the treatment of large AVMs is still controversial, although it has been used in difficult cases. The aim of this study was to evaluate the treatment outcomes of patients who underwent single-stage SRS for large AVMs and to discuss the role of SRS in the treatment of these challenging lesions.

Methods—

Between 1998 and 2010, 65 patients with AVMs >10 cm
3
underwent single-stage SRS using the Leksell Gamma Knife. Patients who had prospective volume-staged SRS were excluded from this series. Outcomes including the rates of obliteration, hemorrhage after treatment, and adverse events were retrospectively evaluated.

Results—

The mean nidus volume was 14.9 cm
3
(±3.8 cm
3
), and a mean margin dose of 20 Gy (±1.5 Gy) was applied. The mean observation period was 60 months (range, 7–178 months). The nidus obliteration rates after SRS were 44%, 76%, and 81% at 3, 5, and 6 years, respectively. The annual hemorrhage rate after SRS was 1.94% and permanent adverse events were observed in 2 patients (3%).

Conclusions—

For large AVMs <20 cm
3
, single-stage radiosurgery by applying >16 Gy marginal dose presented favorable obliteration rates with relatively low rate of morbidity. Further accumulation of cases is awaited to fully evaluate the results of single-stage radiosurgery for large AVMs.
A review of the genus Bullanga Navás, 1917 (Neuroptera: Myrmeleontidae)
Authors: ZHAN QINGBIN , WANG XINLI
Published: October 2014

A review of genus Bullanga Navás, 1917 is presented. All three species of Bullanga are redescribed and illustrated in detail. The female of Bullanga florida is described for the first time. A key to Bullanga species is also provided.
Dreams Deferred
Authors: Martinez Lisa M.
Published: October 2014

Deferred Action for Childhood Arrivals was enacted in August 2012, allowing undocumented youth who meet eligibility criteria to live and work in the United States for a period of 2 years. In April 2013, the Governor of Colorado signed the Advancing Students for a Stronger Economy Tomorrow bill granting undocumented students reduced tuition in the state’s public universities. In the absence of comprehensive immigration reform, this article addresses how legal reforms affect undocumented Latina/o youth in the context of a shifting political landscape in Colorado. Specifically, I address how these reforms affect immigrant youths’ access to higher education and employment opportunities. Data from qualitative interviews with 18 Latina/o undocumented youth ages 16 to 25 show that, while immigration reforms have created some opportunities, the policies’ limitations leave immigrant youth in “holding patterns” that delay or impede their access to higher education and, consequently, upward mobility. I also shed light on their perceptions of these reforms.
India’s Urban Future
Authors: Nijman Jan
Published: October 2014

About 32% of the Indian population presently resides in towns and cities, and national and state governments are intent on increasing that number. Based on the past experience of most of the developed world, urbanization is considered integral to modernization and progress. However, India’s urbanization rate is particularly low and this is partly related to the country’s low level of industrialization. At the same time, urban slums have expanded and their populations have increased despite successive policies aimed at slum eradication or rehabilitation. This study aims to connect macro trends in urbanization and the space economy with a finer scale analysis of the logic of slums and slum dweller views in order to consider the future of India’s cities. Most of the data presented here are based on extensive surveys of households and firms in Dharavi (Mumbai) that investigated work, well-being, livelihoods, community, and environmental issues. It is argued that slums may well be a structural feature of India’s modern urban landscape given India’s enormous challenge of creating significant employment opportunities in modern industries. Furthermore, urban slum environments, with all their shortcomings and challenges, may be conducive to small-scale, labor-intensive productive activity and provide relatively secure livelihoods.