bluuebunny/crossref_metadata_2025 huggingface dataset:
Fabrication and Characterization of ZnS/Diamond-Like Carbon Core-Shell Nanowires
Authors: Kim Jung Han , Kim Seul Cham , Kim Do Hyun , Oh Kyu Hwan , Hong Woong-Ki , Bae Tae-Sung , Chung Hee-Suk
Published: February 2016

We fabricated ZnS/diamond-like carbon (DLC) core-shell heterostructure nanowire using a simple two-step process: the vapor-liquid-solid method combined with radio frequency plasma enhanced chemical vapor deposition (rf PECVD). As a core nanowire, ZnS nanowires with face-centered cubic structure were synthesized with a sputtered Au thin film, which exhibit a length and a diameter of ~10 μm and ~30–120 nm . After rf PECVD for DLC coating, The length and width of the dense ZnS/DLC core-shell nanowires were a range of ~10 μm  and 50–150 nm , respectively. In addition, ZnS/DLC core-shell nanowires were characterized with scanning transmission electron microscopy. From the results, the products have flat and uniform DLC coating layer on ZnS nanowire in spite of high residual stress induced by the high sp3fraction. To further understanding of the DLC coating layer, Raman spectroscopy was employed with ZnS/DLC core-shell nanowires, which reveals two Raman bands at 1550 cm−1(G peak) and 1330 cm−1(D peak). Finally, we investigated the optical properties from ultraviolet to infrared wavelength region using ultraviolet-visible (UV-Vis) and Fourier transform infrared (FT-IR) spectrometry. Related to optical properties, ZnS/DLC core-shell nanowires exhibit relatively lower absorbance and higher IR transmittance than that of ZnS nanowires.
The Correlation of Serum Myeloid-Related Protein-8/14 and Eosinophil Cationic Protein in Patients with Coronary Artery Disease
Authors: Xia Guo-lian , Wang Yun-kai , Huang Zhao-quan
Published: February 2016

Objective. To investigate the changes in serum Myeloid-Related Protein 8/14 (MRP8/14) and Eosinophil Cationic Protein (ECP) levels in patients with different types of coronary artery diseases (CAD) and assess the value of MRP8/14 and ECP detection in predicting CAD.Methods. 178 patients were divided into CAD group including unstable angina pectoris (UAP), acute myocardial infarction (AMI), and stable angina pectoris (SAP). Thirty-six individuals with normal coronary artery served as the control group. Serum MRP8/14 and ECP were measured by ELISA. The severity of coronary artery stenosis was assessed by the numbers of involved coronary artery branches and the sum of Gensini scores.Results. The MRP8/14 levels were significantly higher in AMI and UAP group than SAP and control group (P<0.05). The levels of MRP8/14 in AMI group were also obviously higher than UAP group (P<0.05). The ECP levels were obviously increased in AMI group, but there was no difference between SAP and UAP group (P>0.05). The ECP was significantly increased in three impaired coronary arteries and obviously correlated with Gensini score (P<0.01), whereas the MRP8/14 was obviously positively correlated with CRP (P<0.01).Conclusions. Increased MRP8/14 levels suggest the instability of the atherosclerotic plaque. ECP reflects the severity of coronary arteries stenosis, predicting atherosclerosis burden. They may become the new biomarkers of CAD.
Tracheobronchomegaly as a Cause of Bronchiectasis in an Adult
Authors: Govindaraj Vishnukanth , Mohanty Mohapatra Madhusmita , Nagamalli Kumar Balla , Narayanasami Suryakala
Published: February 2016

Mounier-Kuhn syndrome (MKS) is a rare congenital anomaly characterized by dilated trachea and main bronchi due to atrophy of the elastic fibers and smooth muscle cells of the trachea and major airways. Patients of MKS can have varied presentation. The diagnosis is established radiologically and bronchoscopically. There is no specific treatment for MKS. We present an adult man with MKS who presented with recurrent respiratory tract infection. The diagnosis was confirmed by imaging study and fiberoptic bronchoscopy.
Copper Removal from Electroplating Wastewater by Coprecipitation of Copper-Based Supramolecular Materials: Preparation and Application Study
Authors: Bai De-Kui , Ying Quan-Hong , Wang Ni , Lin Jin-Hui
Published: February 2016

This paper describes an experimental study for the removal of copper ions from electroplating wastewater. Different metal ions are added to the wastewater to remove copper ions by coprecipitation and the copper-based supramolecular materials with layered structures are obtained. It is found that the best results are obtained with the addition of –Mg2+–Al3+mixture with ratio of 3 : 1, pH ≈ 10, and aging for 1 d at 60°C. With these conditions, the residual copper in the electroplating wastewater satisfies national emission standards and wastewater handling capacity of up to 30 mL can be achieved. The properties of the copper-based supramolecular materials prepared under these optimal conditions are characterized. The results show that the materials have a layered structure and good thermal and structural stability and achieve a saturated adsorption of iodide ions of 41.23 mg/g.
Spectroscopic Investigations and DFT Calculations on 3-(Diacetylamino)-2-ethyl-3H-quinazolin-4-one
Authors: Sert Yusuf , Ucun Fatih , El-Hiti Gamal A. , Smith Keith , Hegazy Amany S.
Published: February 2016

The theoretical and experimental vibrational frequencies of 3-(diacetylamino)-2-ethyl-3H-quinazolin-4-one (2) were investigated. The experimental Laser-Raman spectrum (4000–100 cm−1) and FT-IR spectrum (4000–400 cm−1) of the newly synthesized compound were recorded in the solid phase. Both the theoretical vibrational frequencies and the optimized geometric parameters such as bond lengths and bond angles have for the first time been calculated using density functional theory (DFT/B3LYP and DFT/M06-2X) quantum chemical methods with the 6-311++G(d,p) basis set using Gaussian 03 software. The vibrational frequencies were assigned with the help of potential energy distribution (PED) analysis using VEDA 4 software. The calculated vibrational frequencies and the optimized geometric parameters were found to be in good agreement with the corresponding reported experimental data. Also, the energies of the lowest unoccupied molecular orbital (LUMO), highest occupied molecular orbital (HOMO), and other related molecular energies for 3-(diacetylamino)-2-ethyl-3H-quinazolin-4-one (2) have been investigated using the same computational methods.
Angiopoietin-2 Is an Early Indicator of Acute Pancreatic-Renal Syndrome in Patients with Acute Pancreatitis
Authors: Sporek Mateusz , Dumnicka Paulina , Gala-Bladzinska Agnieszka , Ceranowicz Piotr , Warzecha Zygmunt , Dembinski Artur , Stepien Ewa , Walocha Jerzy , Drozdz Ryszard , Kuzniewski Marek , Kusnierz-Cabala Beata
Published: February 2016

Within the first week of the disease, acute kidney injury (AKI) is among the most common causes of mortality in acute pancreatitis (AP). Recently, serum angiopoietin-2 (Ang-2) has been associated with hyperdynamic state of the systemic circulation. The aim of this study was to examine the associations between Ang-2 and the clinical AP severity during the first 72 hours of the disease, and organ disfunction, including AKI.Methods. Study included patients admitted to the surgery ward, diagnosed with AP. AKI was diagnosed according to KDIGO guidelines and renal failure according to modified Marshall scoring system. Ang-2 was determined in serum with ELISA.Results. AP was classified as mild (MAP) in 71% of patients, moderately severe (MSAP) in 22%, and severe (SAP) in 8%. During the first 72 hours of AP, 11 patients developed AKI and 6 developed renal failure. Ang-2 at 24, 48, and 72 hours following the onset of AP symptoms significantly predicted SAP and MSAP, as well as AKI and renal failure. Also, Ang-2 significantly correlated with acute phase proteins as well as with the indicators of renal disfunction.Conclusions. Serum Ang-2 may be a relevant predictor of AP severity, in particular of the development of AP-renal syndrome.
Efficacy and Safety in Retinal Vein Occlusion Treated with at Least Three Consecutive Intravitreal Dexamethasone Implants
Authors: Proença Pina Julia , Turki Khalil , Labreuche Julien , Duhamel Alain , Tran Thi Ha Chau
Published: February 2016

Purpose. To evaluate the effects of repeated intravitreal dexamethasone implant (DI) (Ozurdex®) in eyes with macular edema (ME) due to retinal vein occlusion (RVO).Methods. Multicenter observational study including patients who received more than three consecutive DI on an “as-needed” basis for the treatment of ME in RVO.Results. A total of 18 eyes were included for analysis. Mean interval of retreatment with DI was 5.1 months between the first and second DI and 5.4 months following the second DI. Baseline BCVA was 0.74 ± 0.08 log-Mar; it significantly improved to 0.45 ± 0.04 2 months after the 3rd DI. There was no significant difference between the 3 first postinjection BCVA. CMT decreased from 617 μm ± 120 μm (baseline) to 330 ± 109 μm two months after the third DI. Elevated intraocular pressure occurred in 50% and was controlled medically. Cataract progression leading to cataract surgery occurred in 69% of phakic eyes after a mean interval of 17 months.Conclusion. Repeated DI on an “as-needed” basis, with a retreatment interval <6 months, are effective in the long term in the management of ME due to RVO. Rates of increased intraocular pressure and cataract surgery seem to be higher than previously described when eyes were followed during a longer period.
Fracture Propagation Characteristic and Micromechanism of Rock-Like Specimens under Uniaxial and Biaxial Compression
Authors: Liu Xue-wei , Liu Quan-sheng , Huang Shi-bing , Wei Lai , Lei Guang-feng
Published: February 2016

This paper presents a set of uniaxial and biaxial compression tests on the rock-like material specimens with different fracture geometries through a rock mechanics servo-controlled testing system (RMT-150C). On the basis of experimental results, the characteristics of fracture propagation under different fracture geometries and loading conditions are firstly obtained. The newly formed fractures are observed propagating from or near the preexisting crack tips for different specimens, while the propagation paths are affected by the loading condition obviously. Then, by adopting acoustic emission (AE) location technique, AE event localization characteristics in the process of loading are investigated. The locations of AE events are in good agreement with the macroscopic fracture propagation path. Finally, the micromechanism of macroscopic fracture propagation under uniaxial and biaxial compression conditions is analyzed, and the fracture propagation can be concluded as a result of microdamage accumulation inside the material. The results of this paper are helpful for theory and engineering design of the fractured rock mass.
Cement Pastes and Mortars Containing Nitrogen-Doped and Oxygen-Functionalized Multiwalled Carbon Nanotubes
Authors: Martínez-Alanis Mauricio , López-Urías Florentino
Published: February 2016

Cement pastes and mortars based on ordinary Portland cement containing nitrogen-doped multiwalled carbon nanotubes (MWCNT-Nx) or oxygen-functionalized multiwalled carbon nanotubes (MWCNT-Ox) are investigated. To incorporate MWCNTs into the cementitious matrix, the as-produced carpets are dispersed over periods of 1 and 2 hours in distilled water at pH levels of 1 and 7. The cement pastes are prepared by adding 0.1 wt% of MWCNTs to cement powder, followed by characterization with SEM and X-ray diffraction (XRD) at an early age (first hours of hydration). The mortars are mechanically characterized during the hydration process for a period of 28 days. SEM characterization of cement pastes revealed that the carbon nanotubes are well incorporated in the cementitious matrix, with the hydrated cement grains interconnected by long carbon nanotubes. XRD characterizations demonstrated that, during the hydration of cement pastes, different peaks emerged that were associated with ettringite, hydrated calcium silicate, and calcium hydroxide, among other structures. Results of the compressive strength measurements for mortars simultaneously mixed with MWCNT-Nx and MWCNT-Ox reached an increment of approximately 30% in compressive strength. In addition, density functional theory calculations were performed in nitrogen-doped and oxygen-functionalized carbon nanotubes interacting with a cement grain.
Performance Characteristics of Silane Silica Modified Asphalt
Authors: Guo Xuedong , Sun Mingzhi , Dai Wenting , Chen Shuang
Published: February 2016

At present there are many kinds of fillers and modifier used for modified asphalt, but the effect of modifier differs in thousands of ways; most of them can increase the high temperature performance of asphalt, but the modified effect of low-temperature crack resistance, water stability, and antifatigue performance is different. Aiming at the subsistent problems, this paper innovatively puts forward the idea of taking the silane silica (nanosilica modified with silane coupling agent) as filler to develop one kind of modified asphalt concrete which has excellent comprehensive performance based on the idea of enhance the whole performance of asphalt concrete and interface consolidation strength between aggregate and asphalt at the same time. The best mixing amount of silane silica and the production process of modified asphalt were conducted by contrasting the test date as penetration, viscosity, and softening point; the aging of asphalt and modified asphalt was analyzed by TG test, the superiority of silane silica modified asphalt is more clearly understandable by chemical analysis results. Meanwhile it is proved that silane silica has positive effect to improve the mixture of high and low temperature performance, water stability, and aging resistance through a series of road performance tests.
A Rare Case of Renal Infarct due to Noncompaction Cardiomyopathy: A Case Report and Literature Review
Authors: Wats Karan , Chen On , Uppal Nupur Nippun , Batul Syeda Atiqa , Moskovits Norbert , Shetty Vijay , Shani Jacob
Published: February 2016

Left ventricular noncompaction cardiomyopathy is a rare myocardial disorder which results from failure of left ventricle to compact in embryogenesis. We present a case of a 53-year-old female who came because of abdominal pain and was found to have renal infarct secondary to noncompaction cardiomyopathy.
Health Seeking Behaviour and Associated Factors among Pulmonary Tuberculosis Suspects in Lay Armachiho District, Northwest Ethiopia: A Community-Based Study
Authors: Engeda Eshetu Haileselassie , Dachew Berihun Assefa , Kassa Woreta Hiwot , Mekonnen Kelkay Mengistu , Ashenafie Tesfaye Demeke
Published: February 2016

Studies in the northern part of Ethiopia showed high prevalence of undiagnosed cluster of tuberculosis cases within the community which demanded an investigation of the health care seeking behaviour of tuberculosis suspects. A community-based cross-sectional study was conducted in Lay Armachiho district, Northwest Ethiopia. Individuals who had cough for at least two weeks and aged greater than or equal to 15 years were included in the study. Data were collected by interview using pretested and structured questionnaire. Logistic regression was computed and adjusted odds ratio with 95% confidence interval was calculated. Out of the total population surveyed (29, 735), 663 (2.2%) individuals were found to be pulmonary tuberculosis suspects. Majority of the suspects reported that they had visited a modern health care facility. Those aged 15 to 34 and aged 35–54 had secondary educational level and above; those who were civil servants, those who were farmers, those who had previous history of tuberculosis treatment, and those who perceived that they were sick were more likely to visit a modern health care facility. The proportion of respondents who had taken traditional measures was found to be higher than some other districts. Improving the socioeconomic status of the community is recommended.
Cytotoxic Activity ofHolothuria leucospilotaExtract againstLeishmania infantum In Vitro
Authors: Khademvatan Shahram , Eskandari Alborz , Saki Jasem , Foroutan-Rad Masoud
Published: February 2016

Leishmaniasis is a tropical parasitic infection. The resistance and toxicity issues are the major complications and remain significant consequences related to the treatment of leishmaniasis with the recent and classical drugs. Thus there is an immediate requirement to develop new compounds for the treatment of this protozoan disease. Sea cucumbers or holothurians are potentially presented as the marine sources of antimicrobial and cytotoxic compounds. The aim of this study was investigation ofin vitroantileishmanial activity of methanol extract of body wall, coelomic fluid, and cuvierian organs ofHolothuria leucospilotaobtained from coastal parts of Persian Gulf againstLeishmania infantumpromastigotes and axenic amastigotes. The colorimetric MTT assay was used to determineL. infantumpromastigotes and axenic amastigotes viability at different concentrations of the extracts and drug control (Glucantime®) at time dependent manner and the results are represented as IC50(50% of inhibitory concentration). Coelomic fluid was the most active extract among the three different extracts ofH. leucospilotaagainstL. infantumpromastigotes and axenic amastigotes with IC50s of 62.33 μg/mL and 22.4 μg/mL and 73 μg/mL and 46 μg/mL at 48 and 72 hours after treatment, respectively. Cuvierian organs extract showed less toxicity with IC50s more than 1000 μg/mL for bothLeishmania infantumaxenic amastigotes and promastigotes forms after 48 and 72 hours of exposure. Results acquired from the present study propose that the sea cucumberH. leucospilotamay be a provoking source of antileishmanial compounds and could be a lead source in the development of the potent antileishmanial and cytotoxic drugs.
Use of Cognitive Interviews to Adapt PROMIS Measurement Items for Spanish Speakers Living with HIV
Authors: Solorio R. , Ayala N. C. , Paez E. , Skalicky A. M. , Morales L. S.
Published: February 2016

Purpose.To use cognitive interviewing techniques to assess comprehension of existing Patient-Reported Outcomes Measurement Information System (PROMIS) items among Latinos living with HIV and then refine items based on participant feedback.Methods.Latino monolingual Spanish speakers living with HIV (n=56) participated in cognitive interviews. Items from four PROMIS domains, including depression, anxiety, fatigue, and alcohol use, were assessed for comprehension. Audiotaped interviews and handwritten notes were subjected to content analysis to identify problems specific to each instrument for each domain.Results.The assessments from the cognitive interviews identified areas for improvement in each domain. We present data on the type of items that were difficult to comprehend and provide examples for how items were refined based on participants’ and PROMIS Statistical Coordinating Center (PSCC) feedback. Six out of 48 depression items, 7 out of the 61 anxiety items, 18 out of 42 fatigue items, and 7 out of 44 alcohol use items were found to have poor comprehension. These items were refined based on participant feedback; the items were then submitted to the PSCC for additional guidance on linguistics and grammar to improve comprehension.Conclusions.Cognitive interviews may be used to enhance comprehension of PROMIS items among Latinos.
Does the Gadoxetic Acid-Enhanced Liver MRI Impact on the Treatment of Patients with Colorectal Cancer? Comparison Study with18F-FDG PET/CT
Authors: Oh Ji-Won , Oh Soon Nam , Choi Joon Il , Choi Moon Hyung , Yoo Ie Ryung , Lee Myung Ah , Yoo Young-Kyung , Oh Seong Taek
Published: February 2016

Objectives. We evaluated the value of Gadoxetic acid-enhanced liver MRI in the preoperative staging of colorectal cancer and estimated the clinical impact of liver MRI in the management plan of liver metastasis.Methods. We identified 108 patients who underwent PET/CT and liver MRI as preoperative evaluation of colorectal cancer, between January 2011 and December 2013. We evaluated the per nodule sensitivity of PET/CT and liver MRI for liver metastasis. Management plan changes were estimated for patients with metastatic nodules newly detected on liver MRI, to assess the clinical impact.Results. We enrolled 131 metastatic nodules (mean size 1.6 cm) in 41 patients (mean age 65 years). The per nodule sensitivities of PET/CT and liver MRI were both 100% for nodules measuring 2 cm or larger but were significantly different for nodules measuring less than 2 cm (59.8% and 95.1%, resp.,P=0.0001). At least one more metastatic nodule was detected on MRI in 16 patients. Among these, 7 patients indicated changes of management plan after performing MRI.Conclusions. Gadoxetic acid-enhanced liver MRI detected more metastatic nodules compared with PET/CT, especially for small (<2 cm) nodules. The newly detected nodules induced management plan change in 43.8% (7/16) of patients.
Maternal Health-Related Quality of Life and Its Predicting Factors in the Postpartum Period in Iran
Authors: Rezaei Nazanin , Azadi Arman , Zargousi Razieh , Sadoughi Zinab , Tavalaee Zahra , Rezayati Maryam
Published: February 2016

Background/Purpose. Postpartum period is accompanied by many physical, emotional, and social changes in women’s health. The aim of this study was to examine the mothers’ quality of life in postpartum period. In addition, it also sought to recognize the variables that predict their quality of life.Methods. This cross-sectional, descriptive study was undertaken among 380 women in 10 urban health centers in Ilam province in west of Iran. They were selected using proportional random sampling method. The SF-36 questionnaire was used to identify women’s health-related quality of life (HRQoL). Data were analyzed using SPSS version 15.Results. Women who were employed, aged less than 30 years, had college degree, have no history of disease in pregnancy, and had given birth more than 3 months ago had higher quality of life scores. Independent predictors for lower physical HRQoL were being with history of disease in pregnancy; being with high school diploma or lower education; and giving birth less than 3 months ago. Also, independent predictor for lower mental HRQoL was being housewife.Conclusion. According to study findings, greater attention must be paid to providing postpartum healthcare for housewife and less educated women as well as those with history of disease in pregnancy.
Hydrogen Sulfide Improves Vascular Calcification in Rats by Inhibiting Endoplasmic Reticulum Stress
Authors: Yang Rui , Teng Xu , Li Hui , Xue Hong-Mei , Guo Qi , Xiao Lin , Wu Yu-Ming
Published: February 2016

In this study, the vitamin D3 plus nicotine (VDN) model of rats was used to prove that H2S alleviates vascular calcification (VC) and phenotype transformation of vascular smooth muscle cells (VSMC). Besides, H2S can also inhibit endoplasmic reticulum stress (ERS) of calcified aortic tissues. The effect of H2S on alleviating VC and phenotype transformation of VSMC can be blocked by TM, while PBA also alleviated VC and phenotype transformation of VSMC that was similar to the effect of H2S. These results suggest that H2S may alleviate rat aorta VC by inhibiting ERS, providing new target and perspective for prevention and treatment of VC.
Chinese Herbs Interfering with Cancer Reprogramming Metabolism
Authors: Zhong Zhangfeng , Qiang William W. , Tan Wen , Zhang Haotian , Wang Shengpeng , Wang Chunming , Qiang Wenan , Wang Yitao
Published: February 2016

Emerging evidence promotes a reassessment of metabolic reprogramming regulation in cancer research. Although there exists a long history of Chinese herbs applied in cancer treatment, few reports have addressed the effects of Chinese herbal components on metabolic reprogramming, which is a central cancer hallmark involved in the slowing or prevention of chemoresistance in cancer cells. In this review, we have focused on four core elements altered by metabolic reprogramming in cancer cells. These include glucose transport, glycolysis, mitochondrial oxidative phosphorylation, and fatty acid synthesis. With this focus, we have summarized recent advances in metabolic reprogramming of cancer cells in response to specific Chinese herbal components. We propose that exploring Chinese herbal interference in cancer metabolic reprogramming might identify new therapeutic targets for cancer and more ways in which to approach metabolism‐related diseases.
Phosphatase PTP4A3 Promotes Triple-Negative Breast Cancer Growth and Predicts Poor Patient Survival
Authors: den Hollander Petra , Rawls Kathryn , Tsimelzon Anna , Shepherd Jonathan , Mazumdar Abhijit , Hill Jamal , Fuqua Suzanne A.W. , Chang Jenny C. , Osborne C. Kent , Hilsenbeck Susan G. , Mills Gordon B. , Brown Powel H.
Published: February 2016

Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and women diagnosed with TNBC currently lack targeted treatment options. To identify novel targets for TNBC, we evaluated phosphatase expression in breast tumors and characterized their contributions to in vitro and in vivo growth of TNBC. Using Affymetrix microarray analysis of 102 breast cancers, we identified 146 phosphatases that were significantly differentially expressed in TNBC compared with estrogen receptor (ER)-positive tumors. Of these, 19 phosphatases were upregulated (0.66-fold; FDR = 0.05) in TNBC compared with ER-positive breast cancers. We knocked down 17 overexpressed phosphatases in four triple-negative and four ER-positive breast cancer lines using specific siRNAs and found that depletion of six of these phosphatases significantly reduced growth and anchorage-independent growth of TNBC cells to a greater extent than ER-positive cell lines. Further analysis of the phosphatase PTP4A3 (also known as PRL-3) demonstrated its requirement for G1–S cell-cycle progression in all breast cancer cells, but PTP4A3 regulated apoptosis selectively in TNBC cells. In addition, PTP4A3 inhibition reduced the growth of TNBC tumors in vivo. Moreover, in silico analysis revealed the PTP4A3 gene to be amplified in 29% of basal-like breast cancers, and high expression of PTP4A3 could serve as an independent prognostic indicator for worse overall survival. Collectively, these studies define the importance of phosphatase overexpression in TNBC and lay the foundation for the development of new targeted therapies directed against phosphatases or their respective signaling pathways for TNBC patients. Cancer Res; 76(7); 1942–53. ©2016 AACR.
Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer
Authors: Ando Mizuo , Kawazu Masahito , Ueno Toshihide , Koinuma Daizo , Ando Koji , Koya Junji , Kataoka Keisuke , Yasuda Takahiko , Yamaguchi Hiroyuki , Fukumura Kazutaka , Yamato Azusa , Soda Manabu , Sai Eirin , Yamashita Yoshihiro , Asakage Takahiro , Miyazaki Yasushi , Kurokawa Mineo , Miyazono Kohei , Nimer Stephen D. , Yamasoba Tatsuya , Mano Hiroyuki
Published: February 2016

ELF4 (also known as MEF) is a member of the ETS family of transcription factors. An oncogenic role for ELF4 has been demonstrated in hematopoietic malignancies, but its function in epithelial tumors remains unclear. Here, we show that ELF4 can function as a tumor suppressor and is somatically inactivated in a wide range of human tumors. We identified a missense mutation affecting the transactivation potential of ELF4 in oral squamous cell carcinoma cells. Restoration of the transactivation activity through introduction of wild-type ELF4 significantly inhibited cell proliferation in vitro and tumor xenograft growth. Furthermore, we found that ELF1 and ELF2, closely related transcription factors to ELF4, also exerted antiproliferative effects in multiple cancer cell lines. Mutations in ELF1 and ELF2, as in ELF4, were widespread across human cancers, but were almost all mutually exclusive. Moreover, chromatin immunoprecipitation coupled with high-throughput sequencing revealed ELF4-binding sites in genomic regions adjacent to genes related to cell-cycle regulation and apoptosis. Finally, we provide mechanistic evidence that the antiproliferative effects of ELF4 were mediated through the induction of HRK, an activator of apoptosis, and DLX3, an inhibitor of cell growth. Collectively, our findings reveal a novel subtype of human cancer characterized by inactivating mutations in the ELF subfamily of proteins, and warrant further investigation of the specific settings where ELF restoration may be therapeutically beneficial. Cancer Res; 76(7); 1814–24. ©2016 AACR.
MCAM and LAMA4 Are Highly Enriched in Tumor Blood Vessels of Renal Cell Carcinoma and Predict Patient Outcome
Authors: Wragg Joseph W. , Finnity Jonathan P. , Anderson Jane A. , Ferguson Henry J.M. , Porfiri Emilio , Bhatt Rupesh I. , Murray Paul G. , Heath Victoria L. , Bicknell Roy
Published: February 2016

The structure and molecular signature of tumor-associated vasculature are distinct from those of the host tissue, offering an opportunity to selectively target the tumor blood vessels. To identify tumor-specific endothelial markers, we performed a microarray on tumor-associated and nonmalignant endothelium collected from patients with renal cell carcinoma (RCC), colorectal carcinoma, or colorectal liver metastasis. We identified a panel of genes consistently upregulated by tumor blood vessels, of which melanoma cell adhesion molecule (MCAM) and its extracellular matrix interaction partner laminin alpha 4 (LAMA4) emerged as the most consistently expressed genes. This result was subsequently confirmed by immunohistochemical analysis of MCAM and LAMA4 expression in RCC and colorectal carcinoma blood vessels. Strong MCAM and LAMA4 expression was also shown to predict poor survival in RCC, but not in colorectal carcinoma. Notably, MCAM and LAMA4 were enhanced in locally advanced tumors as well as both the primary tumor and secondary metastases. Expression analysis in 18 different cancers and matched healthy tissues revealed vascular MCAM as highly specific in RCC, where it was induced strongly by VEGF, which is highly abundant in this disease. Lastly, MCAM monoclonal antibodies specifically localized to vessels in a murine model of RCC, offering an opportunity for endothelial-specific targeting of anticancer agents. Overall, our findings highlight MCAM and LAMA4 as prime candidates for RCC prognosis and therapeutic targeting. Cancer Res; 76(8); 2314–26. ©2016 AACR.
Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade
Authors: Eichten Alexandra , Su Jia , Adler Alexander P. , Zhang Li , Ioffe Ella , Parveen Asma A. , Yancopoulos George D. , Rudge John , Lowy Israel , Lin Hsin Chieh , MacDonald Douglas , Daly Christopher , Duan Xunbao , Thurston Gavin
Published: February 2016

Anti-VEGF therapies benefit several cancer types, but drug resistance that limits therapeutic response can emerge. We generated cell lines from anti-VEGF–resistant tumor xenografts to investigate the mechanisms by which resistance develops. Of all tumor cells tested, only A431 (A431-V) epidermoid carcinoma cells developed partial resistance to the VEGF inhibitor aflibercept. Compared with the parental tumors, A431-V tumors secreted greater amounts of IL6 and exhibited higher levels of phospho-STAT3. Notably, combined blockade of IL6 receptor (IL6R) and VEGF resulted in enhanced activity against A431-V tumors. Similarly, inhibition of IL6R enhanced the antitumor effects of aflibercept in DU145 prostate tumor cells that displays high endogenous IL6R activity. In addition, post hoc stratification of data obtained from a clinical trial investigating aflibercept efficacy in ovarian cancer showed poorer survival in patients with high levels of circulating IL6. These results suggest that the activation of the IL6/STAT3 pathway in tumor cells may provide a survival advantage during anti-VEGF treatment, suggesting its utility as a source of response biomarkers and as a therapeutic target to heighten efficacious results. Cancer Res; 76(8); 2327–39. ©2016 AACR.
A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk
Authors: Travis Ruth C. , Appleby Paul N. , Martin Richard M. , Holly Jeff M.P. , Albanes Demetrius , Black Amanda , Bueno-de-Mesquita H. Bas , Chan June M. , Chen Chu , Chirlaque Maria-Dolores , Cook Michael B. , Deschasaux Mélanie , Donovan Jenny L. , Ferrucci Luigi , Galan Pilar , Giles Graham G. , Giovannucci Edward L. , Gunter Marc J. , Habel Laurel A. , Hamdy Freddie C. , Helzlsouer Kathy J. , Hercberg Serge , Hoover Robert N. , Janssen Joseph A.M.J.L. , Kaaks Rudolf , Kubo Tatsuhiko , Le Marchand Loic , Metter E. Jeffrey , Mikami Kazuya , Morris Joan K. , Neal David E. , Neuhouser Marian L. , Ozasa Kotaro , Palli Domenico , Platz Elizabeth A. , Pollak Michael N. , Price Alison J. , Roobol Monique J. , Schaefer Catherine , Schenk Jeannette M. , Severi Gianluca , Stampfer Meir J. , Stattin Pär , Tamakoshi Akiko , Tangen Catherine M. , Touvier Mathilde , Wald Nicholas J. , Weiss Noel S. , Ziegler Regina G. , Key Timothy J. , Allen Naomi E.
Published: February 2016

The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16–1.43) for IGF-I, 0.81 (0.68–0.96) for IGFBP-1, and 1.25 (1.12–1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. Cancer Res; 76(8); 2288–300. ©2016 AACR.
Intracellular Released Payload Influences Potency and Bystander-Killing Effects of Antibody-Drug Conjugates in Preclinical Models
Authors: Li Fu , Emmerton Kim K. , Jonas Mechthild , Zhang Xinqun , Miyamoto Jamie B. , Setter Jocelyn R. , Nicholas Nicole D. , Okeley Nicole M. , Lyon Robert P. , Benjamin Dennis R. , Law Che-Leung
Published: February 2016

Antibody-drug conjugates (ADC) comprise targeting antibodies armed with potent small-molecule payloads. ADCs demonstrate specific cell killing in clinic, but the basis of their antitumor activity is not fully understood. In this study, we investigated the degree to which payload release predicts ADC activity in vitro and in vivo. ADCs were generated to target different receptors on the anaplastic large cell lymphoma line L-82, but delivered the same cytotoxic payload (monomethyl auristatin E, MMAE), and we found that the intracellular concentration of released MMAE correlated with in vitro ADC-mediated cytotoxicity independent of target expression or drug:antibody ratios. Intratumoral MMAE concentrations consistently correlated with the extent of tumor growth inhibition in tumor xenograft models. In addition, we developed a robust admixed tumor model consisting of CD30+ and CD30− cancer cells to study how heterogeneity of target antigen expression, a phenomenon often observed in cancer specimens, affects the treatment response. CD30-targeting ADC delivering membrane permeable MMAE or pyrrolobenzodiazepine dimers demonstrated potent bystander killing of neighboring CD30− cells. In contrast, a less membrane permeable payload, MMAF, failed to mediate bystander killing in vivo, suggesting local diffusion and distribution of released payloads represents a potential mechanism of ADC-mediated bystander killing. Collectively, our findings establish that the biophysical properties and amount of released payloads are chief factors determining the overall ADC potency and bystander killing. Cancer Res; 76(9); 2710–9. ©2016 AACR.
Delivery of Therapeutics Targeting the mRNA-Binding Protein HuR Using 3DNA Nanocarriers Suppresses Ovarian Tumor Growth
Authors: Huang Yu-Hung , Peng Weidan , Furuuchi Narumi , Gerhart Jacquelyn , Rhodes Kelly , Mukherjee Neelanjan , Jimbo Masaya , Gonye Gregory E. , Brody Jonathan R. , Getts Robert C. , Sawicki Janet A.
Published: February 2016

Growing evidence shows that cancer cells use mRNA-binding proteins and miRNAs to posttranscriptionally regulate signaling pathways to adapt to harsh tumor microenvironments. In ovarian cancer, cytoplasmic accumulation of mRNA-binding protein HuR (ELAVL1) is associated with poor prognosis. In this study, we observed high HuR expression in ovarian cancer cells compared with ovarian primary cells, providing a rationale for targeting HuR. RNAi-mediated silencing of HuR in ovarian cancer cells significantly decreased cell proliferation and anchorage-independent growth, and impaired migration and invasion. In addition, HuR-depleted human ovarian xenografts were smaller than control tumors. A biodistribution study showed effective tumor-targeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA). We combined siRNAs against HuR with FA-3DNA and found that systemic administration of the resultant FA-3DNA-siHuR conjugates to ovarian tumor–bearing mice suppressed tumor growth and ascites development, significantly prolonging lifespan. NanoString gene expression analysis identified multiple HuR-regulated genes that function in many essential cellular and molecular pathways, an attractive feature of candidate therapeutic targets. Taken together, these results are the first to demonstrate the versatility of the 3DNA nanocarrier for in vivo–targeted delivery of a cancer therapeutic and support further preclinical investigation of this system adapted to siHuR-targeted therapy for ovarian cancer. Cancer Res; 76(6); 1549–59. ©2016 AACR.
Extracellular Adenosine Production by ecto-5′-Nucleotidase (CD73) Enhances Radiation-Induced Lung Fibrosis
Authors: Wirsdörfer Florian , de Leve Simone , Cappuccini Federica , Eldh Therese , Meyer Alina V. , Gau Eva , Thompson Linda F. , Chen Ning-Yuan , Karmouty-Quintana Harry , Fischer Ute , Kasper Michael , Klein Diana , Ritchey Jerry W. , Blackburn Michael R. , Westendorf Astrid M. , Stuschke Martin , Jendrossek Verena
Published: February 2016

Radiation-induced pulmonary fibrosis is a severe side effect of thoracic irradiation, but its pathogenesis remains poorly understood and no effective treatment is available. In this study, we investigated the role of the extracellular adenosine as generated by the ecto-5′-nucleotidase CD73 in fibrosis development after thoracic irradiation. Exposure of wild-type C57BL/6 mice to a single dose (15 Gray) of whole thorax irradiation triggered a progressive increase in CD73 activity in the lung between 3 and 30 weeks postirradiation. In parallel, adenosine levels in bronchoalveolar lavage fluid (BALF) were increased by approximately 3-fold. Histologic evidence of lung fibrosis was observed by 25 weeks after irradiation. Conversely, CD73-deficient mice failed to accumulate adenosine in BALF and exhibited significantly less radiation-induced lung fibrosis (P < 0.010). Furthermore, treatment of wild-type mice with pegylated adenosine deaminase or CD73 antibodies also significantly reduced radiation-induced lung fibrosis. Taken together, our findings demonstrate that CD73 potentiates radiation-induced lung fibrosis, suggesting that existing pharmacologic strategies for modulating adenosine may be effective in limiting lung toxicities associated with the treatment of thoracic malignancies. Cancer Res; 76(10); 3045–56. ©2016 AACR.
An Atlas of the Human Kinome Reveals the Mutational Landscape Underlying Dysregulated Phosphorylation Cascades in Cancer
Authors: Olow Aleksandra , Chen Zhongzhong , Niedner R. Hannes , Wolf Denise M. , Yau Christina , Pankov Aleksandr , Lee Evelyn Pei Rong , Brown-Swigart Lamorna , van ‘t Veer Laura J. , Coppé Jean-Philippe
Published: February 2016

Kinase inhibitors are used widely to treat various cancers, but adaptive reprogramming of kinase cascades and activation of feedback loop mechanisms often contribute to therapeutic resistance. Determining comprehensive, accurate maps of kinase circuits may therefore help elucidate mechanisms of response and resistance to kinase inhibitor therapies. In this study, we identified and validated phosphorylatable target sites across human cell and tissue types to generate PhosphoAtlas, a map of 1,733 functionally interconnected proteins comprising the human phospho-reactome. A systematic curation approach was used to distill protein phosphorylation data cross-referenced from 38 public resources. We demonstrated how a catalog of 2,617 stringently verified heptameric peptide regions at the catalytic interface of kinases and substrates could expose mutations that recurrently perturb specific phospho-hubs. In silico mapping of 2,896 nonsynonymous tumor variants identified from thousands of tumor tissues also revealed that normal and aberrant catalytic interactions co-occur frequently, showing how tumors systematically hijack, as well as spare, particular subnetworks. Overall, our work provides an important new resource for interrogating the human tumor kinome to strategically identify therapeutically actionable kinase networks that drive tumorigenesis. Cancer Res; 76(7); 1733–45. ©2016 AACR.
Cyclin A1 and P450 Aromatase Promote Metastatic Homing and Growth of Stem-like Prostate Cancer Cells in the Bone Marrow
Authors: Miftakhova Regina , Hedblom Andreas , Semenas Julius , Robinson Brian , Simoulis Athanasios , Malm Johan , Rizvanov Albert , Heery David M. , Mongan Nigel P. , Maitland Norman J. , Allegrucci Cinzia , Persson Jenny L.
Published: February 2016

Bone metastasis is a leading cause of morbidity and mortality in prostate cancer. While cancer stem-like cells have been implicated as a cell of origin for prostate cancer metastasis, the pathways that enable metastatic development at distal sites remain largely unknown. In this study, we illuminate pathways relevant to bone metastasis in this disease. We observed that cyclin A1 (CCNA1) protein expression was relatively higher in prostate cancer metastatic lesions in lymph node, lung, and bone/bone marrow. In both primary and metastatic tissues, cyclin A1 expression was also correlated with aromatase (CYP19A1), a key enzyme that directly regulates the local balance of androgens to estrogens. Cyclin A1 overexpression in the stem-like ALDHhigh subpopulation of PC3M cells, one model of prostate cancer, enabled bone marrow integration and metastatic growth. Further, cells obtained from bone marrow metastatic lesions displayed self-renewal capability in colony-forming assays. In the bone marrow, cyclin A1 and aromatase enhanced local bone marrow-releasing factors, including androgen receptor, estrogen and matrix metalloproteinase MMP9 and promoted the metastatic growth of prostate cancer cells. Moreover, ALDHhigh tumor cells expressing elevated levels of aromatase stimulated tumor/host estrogen production and acquired a growth advantage in the presence of host bone marrow cells. Overall, these findings suggest that local production of steroids and MMPs in the bone marrow may provide a suitable microenvironment for ALDHhigh prostate cancer cells to establish metastatic growths, offering new approaches to therapeutically target bone metastases. Cancer Res; 76(8); 2453–64. ©2016 AACR.
p28-Mediated Activation of p53 in G2–M Phase of the Cell Cycle Enhances the Efficacy of DNA Damaging and Antimitotic Chemotherapy
Authors: Yamada Tohru , Das Gupta Tapas K. , Beattie Craig W.
Published: February 2016

p28 is an anionic cell-penetrating peptide of 28 amino acids that activates wild-type and mutated p53, leading subsequently to selective inhibition of CDK2 and cyclin A expression and G2–M cell-cycle arrest. In this study, we investigated the cytotoxic effects of p28 treatment alone and in combination with DNA-damaging and antimitotic agents on human cancer cells. p28 enhanced the cytotoxic activity of lower concentrations (IC20-50) of DNA-damaging drugs (doxorubicin, dacarbazine, temozolamide) or antimitotic drugs (paclitaxel and docetaxel) in a variety of cancer cells expressing wild-type or mutated p53. Mechanistic investigations revealed that p28 induced a post-translational increase in the expression of wild-type or mutant p53 and p21, resulting in cell-cycle inhibition at the G2–M phase. The enhanced activity of these anticancer agents in combination with p28 was facilitated through the p53/p21/CDK2 pathway. Taken together, these results highlight a new approach to maximize the efficacy of chemotherapeutic agents while reducing dose-related toxicity. Cancer Res; 76(8); 2354–65. ©2016 AACR.
Low Levels of Circulating Adiponectin Are Associated with Multiple Myeloma Risk in Overweight and Obese Individuals
Authors: Hofmann Jonathan N. , Birmann Brenda M. , Teras Lauren R. , Pfeiffer Ruth M. , Wang Ye , Albanes Demetrius , Baris Dalsu , Colditz Graham A. , De Roos Anneclaire J. , Giles Graham G. , Hosgood H. Dean , Lan Qing , Landgren Ola , Liao Linda M. , Rothman Nathaniel , Weinstein Stephanie J. , Pollak Michael N. , Neuhouser Marian L. , Purdue Mark P.
Published: February 2016

The association between obesity and multiple myeloma risk may be partly attributed to reduced circulating levels of adiponectin in obese individuals. To prospectively evaluate multiple myeloma risk in relation to adiponectin levels overall and stratified by body mass index and other characteristics, we conducted a pooled investigation of pre-diagnosed peripheral blood samples from 624 multiple myeloma cases and 1,246 individually matched controls from seven cohorts participating in the Multiple Myeloma Cohort Consortium. Analysis of circulating analyte levels measured by ELISA revealed that higher total adiponectin levels were associated with reduced multiple myeloma risk overall [highest quartile vs. lowest: OR, 0.64; 95% confidence interval (CI) 0.47–0.85; Ptrend = 0.001]. This association was apparent among cases diagnosed six or more years after blood collection (OR, 0.60; 95% CI, 0.40–0.90; Ptrend = 0.004) and was similar in magnitude for men and women (OR, 0.59 and 0.66, respectively). Interestingly, we observed strong associations among subjects who were overweight (OR, 0.41; 95% CI, 0.26–0.65) or obese (OR, 0.41; 95% CI, 0.17–0.98) but not among those with normal weight (OR, 1.20; 95% CI, 0.73–2.00; overweight/obese vs. normal weight, Pinteraction = 0.04). Our findings provide the strongest epidemiologic evidence to date that adiponectin protects against multiple myeloma development, particularly among overweight and obese individuals, and offer a method for risk assessment in this susceptible population of heavier patients. Cancer Res; 76(7); 1935–41. ©2016 AACR.