bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and photochemical studies of a tris(4-iodophenoxy) subphthalocyaninato boron(III)-fulleropyrrolidine dyad
Authors: Cantu Robert , Gobeze Habtom B. , D’Souza Francis
Published: June 2016

A subphthalocyanine-fullerene dyad, 1 was newly synthesized through axial functionalization via central boron of subphthalocyanine with [Formula: see text]-hydroxybenzaldehyde, and subsequent dipolar cycloaddition reaction of fullerene. The subphthalocyanine entity was peripherally functionalized with moderately electron rich 4-iodophenoxy substituents to probe their effect on photoinduced processes within the SubPc-C[Formula: see text] dyad. Optical absorbance studies revealed presence of both entities of the dyad while steady-state fluorescence studies revealed quenching of subphthalocyanine emission in the dyad in both nonpolar toluene and polar benzonitrile solvents. Further, redox potentials of the donor and acceptor entities were obtained by differential pulse voltammetry, and energy of different photochemical processes was evaluated. Femtosecond transient absorption studies revealed occurrence of charge separation in the SubPc-C[Formula: see text] dyad either from the 1SubPc* or 1C[Formula: see text]* in both nonpolar and polar solvents. That is, transient peaks in the 665 nm range corresponding to SubPc[Formula: see text] and at 1015 nm corresponding to C[Formula: see text] was possible to spectrally identify. The measured rate of charge separation, [Formula: see text] was found to be ∼7.0 × 10[Formula: see text] s[Formula: see text] irrespective of the solvent. The rate of charge recombination, [Formula: see text] from the decay of the C[Formula: see text] peak was found to be 1.1 × 109 s[Formula: see text] in toluene and 1.3 × 109 s[Formula: see text] in benzonitrile, respectively. The SubPc[Formula: see text]-C[Formula: see text] radical ion-pair populated the low-laying 3SubPc* prior returning to the ground state.
Spectroscopic investigations and theoretical calculations of DABCO induced xanthene bridged self-assembled zinc(II) porphyrin dimer
Authors: Xu Li , Huang Tingting , Liang Xu , Mack John , Harris Jessica , Nyokong Tebello , Li Minzhi , Zhu Weihua
Published: June 2016

An in-depth study of the electronic structure of a 1,4-diazabicyclo[2.2.2]octane (DABCO) induced molecular self-assembled xanthene-bridged and amide-bonded porphyrin dimer is reported. Density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations are used to identify trends in the optical spectroscopic properties. B3LYP geometry optimization predicts the formation of an almost perfectly eclipsed structure with respect to the two porphyrin rings with the analogous pyrrole nitrogens separated by 7.7–8.1 Å. The observed distinctive derivative-shaped band morphology of the pseudo-Faraday-A[Formula: see text] terms in the MCD spectra has been used to identify the main electronic Q and B-bands and to validate the TD-DFT calculations. The absence of a discernible splitting of the redox steps or a quenching of the fluorescence demonstrates that there is no significant exciton coupling between the two porphyrin rings.
Reduction of (chloro)-μ-nitrido-bis[(tetra-tert-butyl-phthalocyaninato)iron(IV)] with organic N-bases
Authors: Zaitseva Svetlana V. , Zdanovich Sergei A. , Tyulyaeva Elena Y. , Grishina Ekaterina S. , Koifman Oskar I.
Published: June 2016

The interaction of (chloro)-[Formula: see text]-nitrido-bis[(tetra-tert-butyl-phthalocyaninato)iron(IV)] Cl(FePc)2N with organic [Formula: see text]-bases L as electron–donors (L [Formula: see text] diethylamine, imidazole, 1-methylimidazole, 2-methylimidazole) with the formation of one-electron reduced species (L)PcFe[Formula: see text]–N[Formula: see text]Fe[Formula: see text]Pc(L) was investigated in benzene at 298 K by UV-visible spectroscopy. The reaction was established to be stepwise process including fast reversible axial binding of two substrate molecules onto iron cations followed by slow one-electron metal-centered reduction. The results of IR, ESI-MS and EPR study support the formation of final product with Fe[Formula: see text]–N[Formula: see text]Fe[Formula: see text] unit and two substrate molecules in the first coordination sphere. The reaction kinetics was studied, the pre-equilibrium constants [Formula: see text] and rate constants [Formula: see text] were obtained. The [Formula: see text] and [Formula: see text] values were found to be linearly correlated with basicity of substrates p[Formula: see text]. The possibility of the transition Fe[Formula: see text] Fe[Formula: see text] is promoted by electron–donor properties of substrate combined with the presence of both electron-rich macrocycle and [Formula: see text]-backdonation Fe [Formula: see text] N[Formula: see text].
Mitigation Measures for Wildlife in Wind Energy Development, Consolidating the State of Knowledge — Part 2: Operation, Decommissioning
Authors: Gartman Victoria , Bulling Lea , Dahmen Marie , Geißler Gesa , Köppel Johann
Published: June 2016

During this rapid development of wind energy aiming to combat climate change worldwide, there is greater need to avoid, reduce, and compensate for impacts on wildlife: Through the effective use of mitigation, wind energy can continue to expand while reducing impacts. This is a first broad step into discussing and understanding mitigation strategies collectively, identifying the current state of knowledge and be a beneficial resource for practitioners and conservationists.

We review the current state of published knowledge, both land-based and offshore, with a focus on wind energy–wildlife mitigation measures. We state measures and highlight their objective and discuss at which project stage it is most effective (e.g. planning, construction, operation). Thereafter, we discuss key findings within current wind energy mitigation research, needing improved understanding into the efficacy of wildlife mitigation as well as research into the cost aspects of mitigation implementation. This review is divided into two articles; Part 1 focuses on mitigation measures during planning, siting, and construction, while Part 2 focuses on measures during operation and decommissioning.
An Algorithm for Real-Time Optimal Photocurrent Estimation Including Transient Detection for Resource-Constrained Imaging Applications
Authors: Zemcov Michael , Crill Brendan , Ryan Matthew , Staniszewski Zak
Published: June 2016

Mega-pixel charge-integrating detectors are common in near-IR imaging applications. Optimal signal-to-noise ratio estimates of the photocurrents, which are particularly important in the low-signal regime, are produced by fitting linear models to sequential reads of the charge on the detector. Algorithms that solve this problem have a long history, but can be computationally intensive. Furthermore, the cosmic ray background is appreciable for these detectors in Earth orbit, particularly above the Earth’s magnetic poles and the South Atlantic Anomaly, and on-board reduction routines must be capable of flagging affected pixels. In this paper, we present an algorithm that generates optimal photocurrent estimates and flags random transient charge generation from cosmic rays, and is specifically designed to fit on a computationally restricted platform. We take as a case study the Spectro-Photometer for the History of the Universe, Epoch of Reionization, and Ices Explorer (SPHEREx), a NASA Small Explorer astrophysics experiment concept, and show that the algorithm can easily fit in the resource-constrained environment of such a restricted platform. Detailed simulations of the input astrophysical signals and detector array performance are used to characterize the fitting routines in the presence of complex noise properties and charge transients. We use both Hubble Space Telescope Wide Field Camera-3 and Wide-field Infrared Survey Explorer to develop an empirical understanding of the susceptibility of near-IR detectors in low earth orbit and build a model for realistic cosmic ray energy spectra and rates. We show that our algorithm generates an unbiased estimate of the true photocurrent that is identical to that from a standard line fitting package, and characterize the rate, energy, and timing of both detected and undetected transient events. This algorithm has significant potential for imaging with charge-integrating detectors in astrophysics, earth science, and remote sensing applications.
Japan’s Practice in Green Aid and Its Implications for China
Authors: Liu Qianqian
Published: June 2016

The ever-growing global environmental challenges require new thinking of development assistance from the international society. Since more than two decades ago, many countries in the Organization for Economic Cooperation and Development (OECD) have started to deliver “green aid” which integrates environmental objectives into their assistance programs. As an OECD member and one of the world’s largest green aid providers, Japan has been recognized as a good example for other countries. Based on an in-depth analysis of the motivations, priorities, approaches as well as challenges of Japan in providing green aid, this article sums up three key lessons for the international society to learn in this regard, including: (a) enhancing technological cooperation; (b) exploring such tools as trade and foreign direct investment (FDI) in addition to traditional official development assistance (ODA) channels; and (c) engaging in closer dialogue with recipient countries to better address their demands. In view of China’s recent attempts to “green” its foreign assistance, the article further suggests some potential areas where China can be more actively engaging itself to incorporate green objectives into its aid programs.
The relevance of dawsonite precipitation in CO
2
sequestration in the Mihályi-Répcelak area, NW Hungary
Authors: Király Csilla , Sendula Eszter , Szamosfalvi Ágnes , Káldos Réka , Kónya Péter , Kovács István J. , Füri Judit , Bendő Zsolt , Falus György
Published: June 2016

A natural CO
2
reservoir system with a sandstone lithology in NW Hungary has been studied due to its similarities to a large saline reservoir formation that is widespread in the the Pannonian Basin (Central Europe) and is suggested to be one of the best candidates for industrial CO
2
storage. A range of analytical techniques has been used on core samples from CO
2
-containing sandstone layers that represent a wide range of pressures (90–155 bar), temperatures (79–95°C) and pore fluid compositions (total dissolved solids between 18 000 and 50 700 mg l
−1
) to identify the mineralogy and textural characteristics of the natural reservoir.

The only clear CO
2
-related feature in the studied lithology was the occurrence of dawsonite (NaAlCO
3
(OH)
2
) in a close textural relationship with albite. This is in clear agreement with our geochemical modelling results, which also underline the presence of albite as a precondition for the crystallization of dawsonite at the given
P
–
T
–
X
conditions. Our results suggest that, at least in the Pannonian Basin, dawsonite may be an important mineral for the safe sequestration of industrial CO
2
in the subsurface.
A new perspective on sequence stratigraphy of syn-orogenic basins: insights from the Tertiary Piedmont Basin (Italy) and implications for play concepts and reservoir heterogeneity
Authors: Rossi Massimo , Craig Jonathan
Published: June 2016

The Tertiary Piedmont Basin was reshaped as the Apennines progressively overrode the Alpine retroforeland. Nine basin-wide unconformities were followed by abrupt accommodation turnarounds or high-accommodation/high sediment supply intervals. Unusual stratigraphic discontinuities require a different perspective to reconcile allostratigraphy and sequence stratigraphy, highlighting a wider range of tectonically driven discontinuities (subaerial/subaqueous/regressive/transgressive), diachronism of accommodation and sediment–fairway turnarounds, unusual routing to deepwater, and relationships between fourth- and fifth-order sequences. This approach allows innovative play concepts and prediction of reservoir heterogeneity. Steep gradients and high sediment fluxes favour the development of coarse-grained deltas dominated by hyperpycnal processes and large-scale instability/sediment failures, often expressed by retrogressive slump scars, owing to over-steepening generated by drowning unconformities related to orogenic collapse or basin inversion. During increasing-accommodation intervals, subaqueous erosion leaves remnants of drowned deltas forming stratigraphic traps sealed by prodelta-slope muds. The sediments removed feed turbidites, generated during transgressive intervals and deposited at the toe of oversteepened slopes. These may eventually back-fill the slump scar system and show a fining-upward stacking-pattern owing to the re-establishment of the equilibrium profile. Another play concept relies on the combination of onlapping non-marine to marginal marine deposits against fault-bounded basement highs, sealed by marine muds deposited during the subsequent drowning.
Vitamin D Status Is Negatively Correlated with Insulin Resistance in Chinese Type 2 Diabetes
Authors: Zhang Jie , Ye Jianhong , Guo Gang , Lan Zhenhao , Li Xing , Pan Zhiming , Rao Xianming , Zheng Zongji , Luo Fangtao , Lin Luping , Lin Zhihua , Xue Yaoming
Published: June 2016

Objectives. Vitamin D deficiency plays a role in insulin resistance and the pathogenesis of type 2 diabetes mellitus. Little information is available about the association between vitamin D status and insulin resistance in the Chinese population. Currently, vitamin D status is evaluated by the concentrations of serum 25-hydroxyvitamin D [25(OH)D]. This study explores the relationship between insulin resistance and serum 25-hydroxyvitamin D concentrations in Chinese patients with type 2 diabetes mellitus.Subjects and Methods. This study included 117 patients with type 2 diabetes. The following variables were measured: 25-hydroxyvitamin D [25(OH)D], glycosylated hemoglobin A1c (HbA1c), fasting blood glucose (FBS), fasting blood insulin (FINS), fasting blood C-peptide, serum creatinine (SCr), glomerular filtration rate (eGFR), body mass index (BMI), and homeostatic model estimates of insulin resistance (HOMA-IR).Results. The cases were divided into three groups: Group 1 (G1) with 25(OH)D ≤ 20 ng/mL [≤50 nmol/L], Group 2 (G2) with 25(OH)D values from 20 ng/mL [50 nmol/L] to 30 ng/mL [75 nmol/L], and Group 3 (G3) with 25(OH)D ≥ 30 ng/mL [≥75 nmol/L], with 52.6%, 26.3%, and 21.1% of subjects in Groups 1–3, respectively. There was a negative correlation between 25(OH)D and HOMA-IR (β= −0.314,p=0.001) adjusted by age, BMI, and eGFR.Conclusion. Better vitamin D status may be protective of glucose homeostasis since 25(OH)D was negatively associated with insulin resistance in Chinese patients with type 2 diabetes.
Grey Weighted Sum Model for Evaluating Business Environment in West Africa
Authors: Esangbedo Moses Olabhele , Che Ada
Published: June 2016

As West Africa investments grow, the decision in which country to begin investment is of great importance to investors. The complexity of the criteria involved draws us to use a Multicriteria Decision-Making (MCDM) approach to address this problem. In this paper, we use grey numbers in representing ranges of data and propose Grey Weighted Sum Model (GWSM) for evaluating and ranking of alternatives. Sensitivity analysis is carried out considering wide ranges of uncertainties to verify the changes that can affect the results. The Gambia is ranked the best country in West Africa. The GWSM is highly recommended for long-term investors because GWSM considers the uncertainty of a business environment over a period of years. Finally, GWSM can be used in conjunction with various weighting techniques putting the preferences of the investors into consideration.
The Mannose Receptor Is Involved in the Phagocytosis of Mycobacteria-Induced Apoptotic Cells
Authors: Garcia-Aguilar Teresa , Espinosa-Cueto Patricia , Magallanes-Puebla Alejandro , Mancilla Raúl
Published: June 2016

UponMycobacterium tuberculosisinfection, macrophages may undergo apoptosis, which has been considered an innate immune response. The pathways underlying the removal of dead cells in homeostatic apoptosis have been extensively studied, but little is known regarding how cells that undergo apoptotic death during mycobacterial infection are removed. This study shows that macrophages induced to undergo apoptosis with mycobacteria cell wall proteins are engulfed by J-774A.1 monocytic cells through the mannose receptor. This demonstration was achieved through assays in which phagocytosis was inhibited with a blocking anti-mannose receptor antibody and with mannose receptor competitor sugars. Moreover, elimination of the mannose receptor by a specific siRNA significantly diminished the expression of the mannose receptor and the phagocytosis of apoptotic cells. As shown by immunofluorescence, engulfed apoptotic bodies are initially located in Rab5-positive phagosomes, which mature to express the phagolysosome marker LAMP1. The phagocytosis of dead cells triggered an anti-inflammatory response with the production of TGF-βand IL-10 but not of the proinflammatory cytokines IL-12 and TNF-α. This study documents the previously unreported participation of the mannose receptor in the removal of apoptotic cells in the setting of tuberculosis (TB) infection. The results challenge the idea that apoptotic cell phagocytosis in TB has an immunogenic effect.
Biological Activities of 2,3,5,4′‐Tetrahydroxystilbene‐2‐O‐β‐D‐Glucoside in Antiaging and Antiaging‐Related Disease Treatments
Authors: Ling Shuang , Xu Jin-Wen
Published: June 2016

2,3,5,4′‐Tetrahydroxystilbene‐2‐O‐β‐D‐glucoside (THSG) is active component of the Chinese medicinal plant Polygonum multiflorum Thunb. (THSG). Pharmacological studies have demonstrated that THSG exhibits numerous biological functions in treating atherosclerosis, lipid metabolism, vascular and cardiac remodeling, vascular fibrosis, cardiac‐cerebral ischemia, learning and memory disorders, neuroinflammation, Alzheimer and Parkinson diseases, diabetic complications, hair growth problems, and numerous other conditions. This review focuses on the biological effects of THSG in antiaging and antiaging‐related disease treatments and discusses its molecular mechanisms.
Clinical and Laboratory Diagnosis of Buruli Ulcer Disease: A Systematic Review
Authors: Sakyi Samuel A. , Aboagye Samuel Y. , Darko Otchere Isaac , Yeboah-Manu Dorothy
Published: June 2016

Background.Buruli ulcer (BU) is a necrotizing cutaneous infection caused byMycobacterium ulcerans.Early diagnosis is crucial to prevent morbid effects and misuse of drugs. We review developments in laboratory diagnosis of BU, discuss limitations of available diagnostic methods, and give a perspective on the potential of using aptamers as point-of-care.Methods.Information for this review was searched through PubMed, web of knowledge, and identified data up to December 2015. References from relevant articles and reports from WHO Annual Meeting of the Global Buruli Ulcer initiative were also used. Finally, 59 articles were used.Results.The main laboratory methods for BU diagnosis are microscopy, culture, PCR, and histopathology. Microscopy and PCR are used routinely for diagnosis. PCR targetingIS2404is the gold standard for laboratory confirmation. Culture remains the only method that detects viable bacilli, used for diagnosing relapse and accrued isolates for epidemiological investigation as well as monitoring drug resistance. Laboratory confirmation is done at centers distant from endemic communities reducing confirmation to a quality assurance.Conclusions. Current efforts aimed at developing point-of-care diagnostics are saddled with major drawbacks; we, however, postulate that selection of aptamers against MU target can be used as point of care.
Antidepressant‐Like Effects of Fractions Prepared from Danzhi‐Xiaoyao‐San Decoction in Rats with Chronic Unpredictable Mild Stress: Effects on Hypothalamic‐Pituitary‐Adrenal Axis, Arginine Vasopressin, and Neurotransmitters
Authors: Wu Li-Li , Liu Yan , Yan Can , Pan Yi , Su Jun-Fang , Wu Wei-Kang
Published: June 2016

The aim of the present study was to investigate the antidepressant‐like effects of two fractions, including petroleum ether soluble fraction (Fraction A, FA) and water‐EtOH soluble fraction (Fraction B, FB) prepared from the Danzhi‐xiaoyao‐san (DZXYS) by using chronic unpredictable mild stress‐induced depressive rat model. The results indicated that DZXYS could ameliorate the depression‐like behavior in chronic stress model of rats. The inhibition of hyperactivity of HPA axis and the modulation of monoamine and amino acid neurotransmitters in the hippocampus may be the important mechanisms underlying the action of DZXYS antidepressant‐like effect in chronically stressed rats.
Elevated Concentration of Defensins in Hepatitis C Virus-Infected Patients
Authors: Mattar Ehab H. , Almehdar Hussein A. , AlJaddawi Abdullah A. , Abu Zeid Isam ElDin M. , Redwan Elrashdy M.
Published: June 2016

Hepatitis C virus (HCV) is the major etiological agent of human non-A and non-B hepatitis, affecting around 180 million people worldwide. Defensins, small cysteine-rich cationic peptides, are shown to have potent antibacterial, antiviral, and antifungal properties. Defensins can be found in both normal and microbial infected patients, at variable concentrations. Notably, viral infections are often associated with elevated concentrations of defensins. The current study aimed to estimate the concentrations of total,α-, andβ-defensins in serum taken from normal and HCV-infected patients. 12 healthy (noninfected) and 34 HCV-infected patients were enrolled. Standardized immunoassay kits were used to obtain serum concentrations of defensins. The obtained results were calibrated against kit standard reagents. Total defensin concentrations in HCV-infected patients were significantly higher (2- to 105-fold) compared to healthy individuals. The concentrations ofα-defensins were also significantly elevated in the HCV-infected patients (31–1398 ng/50 μL). However, concentrations ofβ-defensins ranged from 44.5 ng/50 μL to 1056 ng/50 μL. The results did not reveal differences in serum defensin concentration between male and female HCV-infected patients. A-defensin concentration of ≥250 ng/50 μL was found to contain moreβ-defensins than total defensins andα-defensins. This study concludes, for the first time, that serum defensin levels are elevated in HCV-infected patients.
Physiological Importance of Hydrogen Sulfide: Emerging Potent Neuroprotector and Neuromodulator
Authors: Panthi Sandesh , Chung Hyung-Joo , Jung Junyang , Jeong Na Young
Published: June 2016

Hydrogen sulfide (H2S) is an emerging neuromodulator that is considered to be a gasotransmitter similar to nitrogen oxide (NO) and carbon monoxide (CO). H2S exerts universal cytoprotective effects and acts as a defense mechanism in organisms ranging from bacteria to mammals. It is produced by the enzymes cystathionine β‐synthase (CBS), cystathionine ϒ‐lyase (CSE), 3‐mercaptopyruvate sulfurtransferase (MST), and D‐amino acid oxidase (DAO), which are also involved in tissue‐specific biochemical pathways for H2S production in the human body. H2S exerts a wide range of pathological and physiological functions in the human body, from endocrine system and cellular longevity to hepatic protection and kidney function. Previous studies have shown that H2S plays important roles in peripheral nerve regeneration and degeneration and has significant value during Schwann cell dedifferentiation and proliferation but it is also associated with axonal degradation and the remyelination of Schwann cells. To date, physiological and toxic levels of H2S in the human body remain unclear and most of the mechanisms of action underlying the effects of H2S have yet to be fully elucidated. The primary purpose of this review was to provide an overview of the role of H2S in the human body and to describe its beneficial effects.
Expansion of a BDCA1+CD14+ Myeloid Cell Population in Melanoma Patients May Attenuate the Efficacy of Dendritic Cell Vaccines
Authors: Bakdash Ghaith , Buschow Sonja I. , Gorris Mark A.J. , Halilovic Altuna , Hato Stanleyson V. , Sköld Annette E. , Schreibelt Gerty , Sittig Simone P. , Torensma Ruurd , Duiveman-de Boer Tjitske , Schröder Christoph , Smits Evelien L. , Figdor Carl G. , de Vries I. Jolanda M.
Published: June 2016

The tumor microenvironment is characterized by regulatory T cells, type II macrophages, myeloid-derived suppressor cells, and other immunosuppressive cells that promote malignant progression. Here we report the identification of a novel BDCA1+CD14+ population of immunosuppressive myeloid cells that are expanded in melanoma patients and are present in dendritic cell–based vaccines, where they suppress CD4+ T cells in an antigen-specific manner. Mechanistic investigations showed that BDCA1+CD14+ cells expressed high levels of the immune checkpoint molecule PD-L1 to hinder T-cell proliferation. While this BDCA1+CD14+ cell population expressed markers of both BDCA1+ dendritic cells and monocytes, analyses of function, transcriptome, and proteome established their unique nature as exploited by tumors for immune escape. We propose that targeting these cells may improve the efficacy of cancer immunotherapy. Cancer Res; 76(15); 4332–46. ©2016 AACR.
Therapeutic Efficacy of Cancer Stem Cell Vaccines in the Adjuvant Setting
Authors: Hu Yangyang , Lu Lin , Xia Yang , Chen Xin , Chang Alfred E. , Hollingsworth Robert E. , Hurt Elaine , Owen John , Moyer Jeffrey S. , Prince Mark E.P. , Dai Fu , Bao Yangyi , Wang Yi , Whitfield Joel , Xia Jian-Chuan , Huang Shiang , Wicha Max S. , Li Qiao
Published: June 2016

Dendritic cell (DC)-based vaccine strategies aimed at targeting cancer stem–like cells (CSC) may be most efficacious if deployed in the adjuvant setting. In this study, we offer preclinical evidence that this is the case for a CSC-DC vaccine as tested in murine models of SCC7 squamous cell cancer and D5 melanoma. Vaccination of mice with an ALDHhigh SCC7 CSC-DC vaccine after surgical excision of established SCC7 tumors reduced local tumor relapse and prolonged host survival. This effect was augmented significantly by simultaneous administration of anti-PD-L1, an immune checkpoint inhibitor. In the minimal disease setting of D5 melanoma, treatment of mice with ALDHhigh CSC-DC vaccination inhibited primary tumor growth, reduced spontaneous lung metastases, and increased host survival. In this setting, CCR10 and its ligands were downregulated on ALDHhigh D5 CSCs and in lung tissues, respectively, after vaccination with ALDHhigh D5 CSC-DC. RNAi-mediated attenuation of CCR10 blocked tumor cell migration in vitro and metastasis in vivo. T cells harvested from mice vaccinated with ALDHhigh D5 CSC-DC selectively killed ALDHhigh D5 CSCs, with additional evidence of humoral immunologic engagement and a reduction in ALDHhigh cells in residual tumors. Overall, our results offered a preclinical proof of concept for the use of ALDHhigh CSC-DC vaccines in the adjuvant setting to more effectively limit local tumor recurrence and spontaneous pulmonary metastasis, as compared with traditional DC vaccines, with increased host survival further accentuated by simultaneous PD-L1 blockade. Cancer Res; 76(16); 4661–72. ©2016 AACR.
RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo–Yap Pathway
Authors: Guo Peng-Da , Lu Xing-Xing , Gan Wen-Juan , Li Xiu-Ming , He Xiao-Shun , Zhang Shen , Ji Qing-Hua , Zhou Feng , Cao Yue , Wang Jing-Ru , Li Jian-Ming , Wu Hua
Published: June 2016

The Hippo–Yap pathway conveys oncogenic signals, but its regulation during cancer development is not well understood. Here, we identify the nuclear receptor RARγ as a regulator of the Hippo–Yap pathway in colorectal tumorigenesis and metastasis. RARγ is downregulated in human colorectal cancer tissues, where its expression correlates inversely with tumor size, TNM stage, and distant metastasis. Functional studies established that silencing of RARγ drove colorectal cancer cell growth, invasion, and metastatic properties both in vitro and in vivo. Mechanistically, RARγ controlled Hippo–Yap signaling to inhibit colorectal cancer development, acting to promote phosphorylation and binding of Lats1 to its transcriptional coactivator Yap and thereby inactivating Yap target gene expression. In clinical specimens, RARγ expression correlated with overall survival outcomes and expression of critical Hippo–Yap pathway effector molecules in colorectal cancer patients. Collectively, our results defined RARγ as tumor suppressor in colorectal cancer that acts by restricting oncogenic signaling by the Hippo–Yap pathway, with potential implications for new approaches to colorectal cancer therapy. Cancer Res; 76(13); 3813–25. ©2016 AACR.
CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma
Authors: Feber Andrew , Worth Daniel C. , Chakravarthy Ankur , de Winter Patricia , Shah Kunal , Arya Manit , Saqib Muhammad , Nigam Raj , Malone Peter R. , Tan Wei Shen , Rodney Simon , Freeman Alex , Jameson Charles , Wilson Gareth A. , Powles Tom , Beck Stephan , Fenton Tim , Sharp Tyson V. , Muneer Asif , Kelly John D.
Published: June 2016

Other than an association with HPV infection, little is known about the genetic alterations determining the development of penile cancer. Although penile cancer is rare in the developed world, it presents a significant burden in developing countries. Here, we report the findings of whole-exome sequencing (WES) to determine the somatic mutational landscape of penile cancer. WES was performed on penile cancer and matched germline DNA from 27 patients undergoing surgical resection. Targeted resequencing of candidate genes was performed in an independent 70 patient cohort. Mutation data were also integrated with DNA methylation and copy-number information from the same patients. We identified an HPV-associated APOBEC mutation signature and an NpCpG signature in HPV-negative disease. We also identified recurrent mutations in the novel penile cancer tumor suppressor genes CSN1(GPS1) and FAT1. Expression of CSN1 mutants in cells resulted in colocalization with AGO2 in cytoplasmic P-bodies, ultimately leading to the loss of miRNA-mediated gene silencing, which may contribute to disease etiology. Our findings represent the first comprehensive analysis of somatic alterations in penile cancer, highlighting the complex landscape of alterations in this malignancy. Cancer Res; 76(16); 4720–7. ©2016 AACR.
Molecular Pathology of Patient Tumors, Patient-Derived Xenografts, and Cancer Cell Lines
Authors: Guo Sheng , Qian Wubin , Cai Jie , Zhang Likun , Wery Jean-Pierre , Li Qi-Xiang
Published: June 2016

The Cancer Genome Atlas (TCGA) project has generated abundant genomic data for human cancers of various histopathology types and enabled exploring cancer molecular pathology per big data approach. We developed a new algorithm based on most differentially expressed genes (DEG) per pairwise comparisons to calculate correlation coefficients to be used to quantify similarity within and between cancer types. We systematically compared TCGA cancers, demonstrating high correlation within types and low correlation between types, thus establishing molecular specificity of cancer types and an alternative diagnostic method largely equivalent to histopathology. Different coefficients for different cancers in study may reveal that the degree of the within-type homogeneity varies by cancer types. We also performed the same calculation using the TCGA-derived DEGs on patient-derived xenografts (PDX) of different histopathology types corresponding to the TCGA types, as well as on cancer cell lines. We, for the first time, demonstrated highly similar patterns for within- and between-type correlation between PDXs and patient samples in a systematic study, confirming the high relevance of PDXs as surrogate experimental models for human diseases. In contrast, cancer cell lines have drastically reduced expression similarity to both PDXs and patient samples. The studies also revealed high similarity between some types, for example, LUSC and HNSCC, but low similarity between certain subtypes, for example, LUAD and LUSC. Our newly developed algorithm seems to be a practical diagnostic method to classify and reclassify a disease, either human or xenograft, with better accuracy than traditional histopathology. Cancer Res; 76(16); 4619–26. ©2016 AACR.
Preclinical Efficacy of Bevacizumab with CRLX101, an Investigational Nanoparticle–Drug Conjugate, in Treatment of Metastatic Triple-Negative Breast Cancer
Authors: Pham Elizabeth , Yin Melissa , Peters Christian G. , Lee Christina R. , Brown Donna , Xu Ping , Man Shan , Jayaraman Lata , Rohde Ellen , Chow Annabelle , Lazarus Douglas , Eliasof Scott , Foster F. Stuart , Kerbel Robert S.
Published: June 2016

VEGF pathway–targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1α (HIF1α) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and CRLX101, an investigational nanoparticle–drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of CRLX101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. CRLX101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, CRLX101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. CRLX101 durably suppressed HIF1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493–503. ©2016 AACR.
OncomiR or Tumor Suppressor? The Duplicity of MicroRNAs in Cancer
Authors: Svoronos Alexander A. , Engelman Donald M. , Slack Frank J.
Published: June 2016

MicroRNAs (miRNA) are short, noncoding RNAs whose dysregulation has been implicated in most, if not all, cancers. They regulate gene expression by suppressing mRNA translation and reducing mRNA stability. To this end, there is a great deal of interest in modifying miRNA expression levels for the treatment of cancer. However, the literature is fraught with inconsistent accounts as to whether various miRNAs are oncogenic or tumor suppressive. In this review, we directly examine these inconsistencies and propose several mechanisms to explain them. These mechanisms include the possibility that specific miRNAs can simultaneously produce competing oncogenic and tumor suppressive effects by suppressing both tumor suppressive mRNAs and oncogenic mRNAs, respectively. In addition, miRNAs can modulate tumor-modifying extrinsic factors, such as cancer-immune system interactions, stromal cell interactions, oncoviruses, and sensitivity to therapy. Ultimately, it is the balance between these processes that determines whether a specific miRNA produces a net oncogenic or net tumor suppressive effect. A solid understanding of this phenomenon will likely prove valuable in evaluating miRNA targets for cancer therapy. Cancer Res; 76(13); 3666–70. ©2016 AACR.
Functional Flow Patterns and Static Blood Pooling in Tumors Revealed by Combined Contrast-Enhanced Ultrasound and Photoacoustic Imaging
Authors: Bar-Zion Avinoam , Yin Melissa , Adam Dan , Foster F. Stuart
Published: June 2016

Alterations in tumor perfusion and microenvironment have been shown to be associated with aggressive cancer phenotypes, raising the need for noninvasive methods of tracking these changes. Dynamic contrast–enhanced ultrasound (DCEUS) and photoacoustic (PA) imaging serve as promising candidates—one has the ability to measure tissue perfusion, whereas the other can be used to monitor tissue oxygenation and hemoglobin concentration. In this study, we investigated the relationship between the different functional parameters measured with DCEUS and PA imaging, using two morphologically different hind-limb tumor models and drug-induced alterations in an orthotopic breast tumor model. Imaging results showed some correlation between perfusion and oxygen saturation maps and the ability to sensitively monitor antivascular treatment. In addition, DCEUS measurements revealed different vascular densities in the core of specific tumors compared with their rims. Noncorrelated perfusion and hemoglobin concentration measurements facilitated discrimination between blood lakes and necrotic areas. Taken together, our results illustrate the utility of a combined contrast-enhanced ultrasound method with photoacoustic imaging to visualize blood flow patterns in tumors. Cancer Res; 76(15); 4320–31. ©2016 AACR.
Cholesterol Metabolism and Prostate Cancer Lethality
Authors: Stopsack Konrad H. , Gerke Travis A. , Sinnott Jennifer A. , Penney Kathryn L. , Tyekucheva Svitlana , Sesso Howard D. , Andersson Swen-Olof , Andrén Ove , Cerhan James R. , Giovannucci Edward L. , Mucci Lorelei A. , Rider Jennifer R.
Published: June 2016

Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to nonlethal disease without evidence of metastases after at least 8 years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease. Cancer Res; 76(16); 4785–90. ©2016 AACR.
Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models
Authors: Jansen Marc H.A. , Lagerweij Tonny , Sewing A. Charlotte P. , Vugts Danielle J. , van Vuurden Dannis G. , Molthoff Carla F.M. , Caretti Viola , Veringa Susanna J.E. , Petersen Naomi , Carcaboso Angel M. , Noske David P. , Vandertop W. Peter , Wesseling Pieter , van Dongen Guus A.M.S. , Kaspers Gertjan J.L. , Hulleman Esther
Published: June 2016

The role of the VEGF inhibitor bevacizumab in the treatment of diffuse intrinsic pontine glioma (DIPG) is unclear. We aim to study the biodistribution and uptake of zirconium-89 (89Zr)-labeled bevacizumab in DIPG mouse models. Human E98-FM, U251-FM glioma cells, and HSJD-DIPG-007-FLUC primary DIPG cells were injected into the subcutis, pons, or striatum of nude mice. Tumor growth was monitored by bioluminescence imaging (BLI) and visualized by MRI. Seventy-two to 96 hours after 89Zr-bevacizumab injections, mice were imaged by positron emission tomography (PET), and biodistribution was analyzed ex vivo. High VEGF expression in human DIPG was confirmed in a publically available mRNA database, but no significant 89Zr-bevacizumab uptake could be detected in xenografts located in the pons and striatum at an early or late stage of the disease. E98-FM, and to a lesser extent the U251-FM and HSJD-DIPG-007 subcutaneous tumors, showed high accumulation of 89Zr-bevacizumab. VEGF expression could not be demonstrated in the intracranial tumors by in situ hybridization (ISH) but was clearly present in the perinecrotic regions of subcutaneous E98-FM tumors. The poor uptake of 89Zr-bevacizumab in xenografts located in the brain suggests that VEGF targeting with bevacizumab has limited efficacy for diffuse infiltrative parts of glial brain tumors in mice. Translating these results to the clinic would imply that treatment with bevacizumab in patients with DIPG is only justified after targeting of VEGF has been demonstrated by 89Zr-bevacizumab immuno-PET. We aim to confirm this observation in a clinical PET study with patients with DIPG. Mol Cancer Ther; 15(9); 2166–74. ©2016 AACR.
ST-11: A New Brain-Penetrant Microtubule-Destabilizing Agent with Therapeutic Potential for Glioblastoma Multiforme
Authors: Cherry Allison E. , Haas Brian R. , Naydenov Alipi V. , Fung Susan , Xu Cong , Swinney Katie , Wagenbach Michael , Freeling Jennifer , Canton David A. , Coy Jonathan , Horne Eric A. , Rickman Barry , Vicente Juan Jesus , Scott John D. , Ho Rodney J.Y. , Liggitt Denny , Wordeman Linda , Stella Nephi
Published: June 2016

Glioblastoma multiforme is a devastating and intractable type of cancer. Current antineoplastic drugs do not improve the median survival of patients diagnosed with glioblastoma multiforme beyond 14 to 15 months, in part because the blood–brain barrier is generally impermeable to many therapeutic agents. Drugs that target microtubules (MT) have shown remarkable efficacy in a variety of cancers, yet their use as glioblastoma multiforme treatments has also been hindered by the scarcity of brain-penetrant MT-targeting compounds. We have discovered a new alkylindole compound, ST-11, that acts directly on MTs and rapidly attenuates their rate of assembly. Accordingly, ST-11 arrests glioblastoma multiforme cells in prometaphase and triggers apoptosis. In vivo analyses reveal that unlike current antitubulin agents, ST-11 readily crosses the blood–brain barrier. Further investigation in a syngeneic orthotopic mouse model of glioblastoma multiforme shows that ST-11 activates caspase-3 in tumors to reduce tumor volume without overt toxicity. Thus, ST-11 represents the first member of a new class of brain-penetrant antitubulin therapeutic agents. Mol Cancer Ther; 15(9); 2018–29. ©2016 AACR.
MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition inBRAF-Mutated Colorectal Cancer
Authors: Pietrantonio Filippo , Oddo Daniele , Gloghini Annunziata , Valtorta Emanuele , Berenato Rosa , Barault Ludovic , Caporale Marta , Busico Adele , Morano Federica , Gualeni Ambra Vittoria , Alessi Alessandra , Siravegna Giulia , Perrone Federica , Di Bartolomeo Maria , Bardelli Alberto , de Braud Filippo , Di Nicolantonio Federica
Published: June 2016

A patient with metastatic BRAF-mutated colorectal cancer initially responded to combined EGFR and BRAF inhibition with panitumumab plus vemurafenib. Pre-existing cells with increased MET gene copy number in the archival tumor tissue likely underwent clonal expansion during treatment, leading to the emergence of MET amplification in the rebiopsy taken at progression. In BRAF-mutated colorectal cancer cells, ectopic expression of MET conferred resistance to panitumumab and vemurafenib, which was overcome by combining BRAF and MET inhibition. Based on tumor genotyping and functional in vitro data, the patient was treated with the dual ALK–MET inhibitor crizotinib plus vemurafenib, thus switching to dual MET and BRAF blockade, with rapid and marked effectiveness of such strategy. Although acquired resistance is a major limitation to the clinical efficacy of anticancer agents, the identification of molecular targets emerging during the first treatment may afford the opportunity to design the next line of targeted therapies, maximizing patient benefit.

Significance: MET amplification is here identified—clinically and preclinically—as a new mechanism of resistance to EGFR and BRAF dual/triple block combinations in BRAF-mutated colorectal cancer. Switching from EGFR to MET inhibition, while maintaining BRAF inhibition, resulted in clinical benefit after the occurrence of MET-driven acquired resistance. Cancer Discov; 6(9); 963–71. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 932
The Paris System for Reporting Urinary Cytology: The Quest to Develop a Standardized Terminology
Authors: Barkan Güliz A. , Wojcik Eva M. , Nayar Ritu , Savic-Prince Spasenija , Quek Marcus L. , Kurtycz Daniel F.I. , Rosenthal Dorothy L.
Published: June 2016

The main purpose of urine cytology is to detect high-grade urothelial carcinoma (HGUC). With this principle in mind, The Paris System (TPS) Working Group, composed of cytopathologists, surgical pathologists, and urologists, has proposed and published a standardized reporting system that includes specific diagnostic categories and cytomorphologic criteria for the reliable diagnosis of HGUC. This paper outlines the essential elements of TPS and the process that led to the formation and rationale of the reporting system. The Paris System Working Group, organized at the 2013 International Congress of Cytology, conceived a standardized platform on which to base cytologic interpretation of urine samples. The widespread dissemination of this approach to cytologic examination and reporting of urologic samples and the scheme's universal acceptance by pathologists and urologists is critical for its success. For urologists, understanding the diagnostic criteria, their clinical implications, and the limitations of TPS is essential if they are to utilize urine cytology and noninvasive ancillary tests in a thoughtful and practical manner. This is the first international/inclusive attempt at standardizing urinary cytology. The success of TPS will depend on the pathology and urology communities working collectively to improve this seminal paradigm shift, and optimize the impact on patient care.
A Rare Case of Basioccipital Encephalomeningocele with Tethered Dermoid Presenting as Cranial Nerve Palsy: A Case Report
Authors: Jaganmohan Deepasree , Krishnan Nagarajan , Ananthakrishnan Ramesh , Gopalakrishna Pillai Gopan
Published: June 2016

The basioccipital skull base is an extremely rare site for meningoencephalocele. The herniation of the brainstem or part of it through a basioccipital defect is even rarer. We report a case of rhombencephalomeningocele associated with a tethered dermoid. An extensive literature search revealed no such case report of basioccipital cranial dysraphism so far presenting with cranial nerve palsy.