bluuebunny/crossref_metadata_2025 huggingface dataset:
Proportions of Proinflammatory Monocytes Are Important Predictors of Mortality Risk in Hemodialysis Patients
Authors: Jeng Yachung , Lim Paik Seong , Wu Ming Ying , Tseng Tien-Yu , Chen Chang Hsu , Chen Hung Ping , Wu Tsai-Kun
Published: October 2017

Despite the continuous progression in dialysis medicine, mortality and the burden of cardiovascular disease (CVD) among hemodialysis patients are still substantial. Substantial evidence suggests that proinflammatory (CD16+) monocytes contribute to the development of atherosclerosis. A cohort of 136 stable hemodialysis patients (follow-up: 6.25 year) was assessed to investigate the association between the proportion of CD16+ monocytes for all-cause and CVD mortalities. The CD16+ monocytes were associated with both mortalities after adjusting for a preexisting CVD history. Compared to the reference group (CD16+ monocytes within [15.6–18.6], the first and second quartile), patients with CD16+ monocytes above the highest quartile level (>21.5) had an adjusted hazard ratio (HR) of 30.85 (95% confidence interval [CI]: 7.12–133.8) for CVD mortality and 5.28 (2.07–13.49) for all-cause mortality, and those with CD16+ monocytes below the lowest quartile ≤15.6), had significantly elevated death risks after 3.5-year follow-up (HR [95% CI]: 10.9 [2.42–48.96] and 4.38 [1.45–13.24] for CV and all-cause mortalities, respectively). The hemodialysis patients with CD16+ monocyte level in a low but mostly covering normal range also portended a poor prognosis. The findings shed some light for nephrologists on future prospects of early recognizing immune dysfunction and improving early intervention outcomes.
Applying Two-Stage Neural Network Based Classifiers to the Identification of Mixture Control Chart Patterns for an SPC-EPC Process
Authors: Shao Yuehjen E. , Chang Po-Yu , Lu Chi-Jie
Published: October 2017

The effective controlling and monitoring of an industrial process through the integration of statistical process control (SPC) and engineering process control (EPC) has been widely addressed in recent years. However, because the mixture types of disturbances are often embedded in underlying processes, mixture control chart patterns (MCCPs) are very difficult for an SPC-EPC process to identify. This can result in problems when attempting to determine the underlying root causes of process faults. Additionally, a large number of categories of disturbances may be present in a process, but typical single-stage classifiers have difficulty in identifying large numbers of categories of disturbances in an SPC-EPC process. Therefore, we propose a two-stage neural network (NN) based scheme to enhance the accurate identification rate (AIR) for MCCPs by performing dimension reduction on disturbance categories. The two-stage scheme includes a combination of a NN, support vector machine (SVM), and multivariate adaptive regression splines (MARS). Experimental results reveal that the proposed scheme achieves a satisfactory AIR for identifying MCCPs in an SPC-EPC system.
Historical Case of Cervical Penetrating Wound: From First Aid to Surgical Intervention
Authors: Fatogoma Issa Koné , Mohamed Amadou Keïta , Siaka Soumahoro , N’faly Konaté , Kassim Diarra , Samba Karim Timbo
Published: October 2017

Objective. We report a case of cervical penetrating wound by posing the problem of its support and by analyzing the chain of survival of a patient to human sacrifice. Case Report. It was an 11-year-old boy admitted to the hosting service of cervical penetrating wound emergency occurring in a context of human sacrifice by weapon (knife). On admission, the conscious patient had a left cervical hematoma at the level of the cervical zone II and severe signs of acute anemia. The exploratory cervicotomy, carried out 12 hours after the trauma under transfusion, allowed us to highlight a section of the front edge of the sternocleidomastoid and previous jugular muscles under hyoid. We noted the presence of a linear wound of 1 cm at the level of the left internal jugular vein. The wound of the internal jugular vein has been repaired with the Prolene 4.O. The outcome was good, allowing the exit 10 days after cervicotomy. Conclusion. The causal circumstances of cervical penetrating wounds are diverse. Their importance or their severity depends on the causative circumstances dominated by aggression and attempts to autolysis. Human sacrifice, with use of the weapon, is an exceptional circumstance.
Data‐Driven Fault Diagnosis Method for Power Transformers Using Modified Kriging Model
Authors: Ding Yu , Liu Qiang
Published: October 2017

A data‐driven fault diagnosis method that combines Kriging model and neural network is presented and is further used for power transformers based on analysis of dissolved gases in oil. In order to improve modeling accuracy of Kriging model, a modified model that replaces the global model of Kriging model with BP neural network is presented and is further extended using linearity weighted aggregation method. The presented method integrates characteristics of the global approximation of the neural network technology and the localized departure of the Kriging model, which improves modeling accuracy. Finally, the validity of this method is demonstrated by several numerical computations of transformer fault diagnosis problems.
Sociotechnical Network Analysis for Power Grid Resilience in South Korea
Authors: Eisenberg Daniel A. , Park Jeryang , Seager Thomas P.
Published: October 2017

International efforts to improve power grid resilience mostly focus on technological solutions to reduce the probability of losses by designing hardened, automated, redundant, and smart systems. However, how well a system recovers from failures depends on policies and protocols for human and organizational coordination that must be considered alongside technological analyses. In this work, we develop a sociotechnical network analysis that considers technological and human systems together to support improved blackout response. We construct corresponding infrastructure and social network models for the Korean power grid and analyze them with betweenness to identify critical infrastructures and emergency management organizations. Power grid network analysis reveals important power companies and emergency management headquarters for responding to infrastructure losses, where social network analysis reveals how information-sharing and decision-making authority shifts among these organizations. We find that separate analyses provide relevant yet incomplete recommendations for improving blackout management protocols. In contrast, combined results recommend explicit ways to improve response by connecting key owner, operator, and emergency management organizations with the Ministry of Trade, Industry, and Energy. Findings demonstrate that both technological and social analyses provide important information for power grid resilience, and their combination is necessary to avoid unintended consequences for future blackout events.
Primary Malignancy in a Supernumerary Testicle Presenting as a Large Pelvic Mass
Authors: Noroozian Justin , Farishta Daniel , Ballow Daniel , Sonstein Joseph , Orihuela Eduardo , Eyzaguirre Eduardo
Published: October 2017

Supernumerary testis, also known as polyorchidism, is a condition characterized by the presence of more than two testes. Another condition of the testes is seminoma, a common cause of testicular germ cell tumor. A 35-year-old male was transferred to our hospital with a diagnosis of abdominal mass causing abdominal pain. On physical exam, he had a palpable undescended left testicle in the left inguinal canal, which was determined to be seminoma. The mass was surgically removed, and the patient underwent chemotherapy. The report discusses his workup, treatment, and outcome. This case illustrates an unusual presentation of supernumerary testis with the extra testis harboring a seminoma. When presented with a case of testicular cancer with no tumor noted in the palpable testes, malignancy in an extranumerary testicle should be considered in the differential.
trans‐Cinnamaldehyde Inhibits Microglial Activation and Improves Neuronal Survival against Neuroinflammation in BV2 Microglial Cells with Lipopolysaccharide Stimulation
Authors: Fu Yan , Yang Pin , Zhao Yang , Zhang Liqing , Zhang Zhangang , Dong Xianwen , Wu Zhongping , Xu Ying , Chen Yongjun
Published: October 2017

Background. Microglial activation contributes to neuroinflammation and neuronal damage in neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. It has been suggested that neurodegenerative disorders may be improved if neuroinflammation can be controlled. trans‐cinnamaldehyde (TCA) isolated from the stem bark of Cinnamomum cassia possesses potent anti‐inflammatory capability; we thus tested whether TCA presents neuroprotective effects on improving neuronal survival by inhibiting neuroinflammatory responses in BV2 microglial cells. Results. To determine the molecular mechanism behind TCA‐mediated neuroprotective effects, we assessed the effects of TCA on lipopolysaccharide‐ (LPS‐) induced proinflammatory responses in BV2 microglial cells. While LPS potently induced the production and expression upregulation of proinflammatory mediators, including NO, iNOS, COX‐2, IL‐1β, and TNF‐α, TCA pretreatment significantly inhibited LPS‐induced production of NO and expression of iNOS, COX‐2, and IL‐1β and recovered the morphological changes in BV2 cells. TCA markedly attenuated microglial activation and neuroinflammation by blocking nuclear factor kappa B (NF‐κB) signaling pathway. With the aid of microglia and neuron coculture system, we showed that TCA greatly reduced LPS‐elicited neuronal death and exerted neuroprotective effects. Conclusions. Our results suggest that TCA, a natural product, has the potential of being used as a therapeutic agent against neuroinflammation for ameliorating neurodegenerative disorders.
Dynamic VaR Measurement of Gold Market with SV-T-MN Model
Authors: Li Fenglan , Wang Jie , Su Liyun , Yang Bao
Published: October 2017

VaR (Value at Risk) in the gold market was measured and predicted by combining stochastic volatility (SV) model with extreme value theory. Firstly, for the fat tail and volatility persistence characteristics in gold market return series, the gold price return volatility was modeled by SV-T-MN (SV-T with Mixture-of-Normal distribution) model based on state space. Secondly, future sample volatility prediction was realized by using approximate filtering algorithm. Finally, extreme value theory based on generalized Pareto distribution was applied to measure dynamic risk value (VaR) of gold market return. Through the proposed model on the price of gold, empirical analysis was investigated; the results show that presented combined model can measure and predict Value at Risk of the gold market reasonably and effectively and enable investors to further understand the extreme risk of gold market and take coping strategies actively.
The Role of High-Mobility Group Box-1 and Its Crosstalk with Microbiome in Rheumatoid Arthritis
Authors: Biscetti Federico , Flex Andrea , Alivernini Stefano , Tolusso Barbara , Gremese Elisa , Ferraccioli Gianfranco
Published: October 2017

Rheumatoid arthritis (RA) is a chronic, definitely disabling, and potentially severe autoimmune disease. Although an increasing number of patients are affected, a key treatment for all patients has not been discovered. High-mobility group box-1 (HMGB1) is a nuclear protein passively and actively released by almost all cell types after several stimuli. HMGB1 is involved in RA pathogenesis, but a convincing explanation about its role and possible modulation in RA is still lacking. Microbiome and its homeostasis are altered in patients with RA, and the microbiota restoration has been proposed to patients with RA. The purpose of the present review is to analyze the available evidences regarding HMGB1 and microbiome roles in RA and the possible implications of the crosstalk between the nuclear protein and microbiome in understanding and possibly treating patients affected by this harmful condition.
A Case of Advanced Glaucoma with Increased Episcleral Venous Pressure in a 17-Year-Old with Eisenmenger Syndrome
Authors: Grech Leanne , Mifsud Adrian , Caruana Maryanne , Carbonaro Francis
Published: October 2017

Eisenmenger syndrome refers to reversal of shunt and central cyanosis due to pulmonary hypertension induced by congenital heart disease with a large systemic-to-pulmonary shunt. We report a case of a 17-year-old man with Eisenmenger syndrome who presented with gradual deterioration in visual acuity and was diagnosed with advanced secondary open angle glaucoma. There have been reports of patients suffering from thrombosis due to hyperviscosity associated with this syndrome; however, to our knowledge, the association of secondary open angle glaucoma with Eisenmenger syndrome has not yet been documented.
A Review on Human Body Communication: Signal Propagation Model, Communication Performance, and Experimental Issues
Authors: Zhao Jian Feng , Chen Xi Mei , Liang Bo Dong , Chen Qiu Xia
Published: October 2017

Human body communication (HBC), which uses the human body tissue as the transmission medium to transmit health informatics, serves as a promising physical layer solution for the body area network (BAN). The human centric nature of HBC offers an innovative method to transfer the healthcare data, whose transmission requires low interference and reliable data link. Therefore, the deployment of HBC system obtaining good communication performance is required. In this regard, a tutorial review on the important issues related to HBC data transmission such as signal propagation model, channel characteristics, communication performance, and experimental considerations is conducted. In this work, the development of HBC and its first attempts are firstly reviewed. Then a survey on the signal propagation models is introduced. Based on these models, the channel characteristics are summarized; the communication performance and selection of transmission parameters are also investigated. Moreover, the experimental issues, such as electrodes and grounding strategies, are also discussed. Finally, the recommended future studies are provided.
Clustering Optimization for Out-of-Band D2D Communications
Authors: Paramonov A. , Hussain O. , Samouylov K. , Koucheryavy A. , Kirichek R. , Koucheryavy Y.
Published: October 2017

Significant increase in multimedia traffic challenges 5G networks in terms of capacity and correspondent QoS parameters. Device-to-device communication paradigm has already become an integral part of 3GPP standards; nevertheless it has not yet been widely deployed due to many different reasons. D2D is expected to leverage implementation of many qualitatively new services and to efficiently accomplish it D2D devices are supposed to form clusters. Due to practical limitations, current D2D implementations are mostly out-of-band and use Wi-Fi Direct. In this paper, we propose a novel model for throughput optimization in out-of-band D2D clusters. We delivered numerical results for different typical cluster member distributions and revealed key functional dependencies. Further, for the first time we compare clustering algorithms for out-of-band D2D and identify effective clustering algorithm that increases network resource utilization rate.
Development of a Rapid and Simple Method to Remove Polyphenols from Plant Extracts
Authors: Ranatunge Imali , Adikary Subshini , Dasanayake Piumi , Fernando Chamira Dilanka , Soysa Preethi
Published: October 2017

Polyphenols are secondary metabolites of plants, which are responsible for prevention of many diseases. Polyvinylpolypyrrolidone (PVPP) has a high affinity towards polyphenols. This method involves the use of PVPP column to remove polyphenols under centrifugal force. Standards of gallic acid, epigallocatechin gallate, vanillin, and tea extracts(Camellia sinensis)were used in this study. PVPP powder was packed in a syringe with different quantities. The test samples were layered over the PVPP column and subjected to centrifugation. Supernatant was tested for the total phenol content. The presence of phenolic compounds and caffeine was screened by HPLC and measuring the absorbance at 280. The antioxidant capacity of standards and tea extracts was compared with the polyphenol removed fractions using DPPH scavenging assay. No polyphenols were found in polyphenolic standards or tea extracts after PVPP treatment. The method described in the present study to remove polyphenols is simple, inexpensive, rapid, and efficient and can be employed to investigate the contribution of polyphenols present in natural products to their biological activity.
Controlled Assembly of Nanorod TiO2 Crystals via a Sintering Process: Photoanode Properties in Dye-Sensitized Solar Cells
Authors: Vafaei Saeid , Manseki Kazuhiro , Horita Soki , Matsui Masaki , Sugiura Takashi
Published: October 2017

We present for the first time a synthetic method of obtaining 1D TiO2 nanorods with sintering methods using bundle-shaped 3D rutile TiO2 particles (3D BR-TiO2) with the dimensions of around 100 nm. The purpose of this research is (i) to control crystallization of the mixture of two kinds of TiO2 semiconductor nanocrystals, that is, 3D BR-TiO2 and spherical anatase TiO2 (SA-TiO2) on FTO substrate via sintering process and (ii) to establish a new method to create photoanodes in dye-sensitized solar cells (DSSCs). In addition, we focus on the preparation of low-cost and environmentally friendly titania electrode by adopting the “water-based” nanofluids. Our results provide useful guidance on how to improve the photovoltaic performance by reshaping the numerous 3D TiO2 particles to 1D TiO2-based electrodes with sintering technique.
Use of Personal Protective Equipment among Building Construction Workers in Kampala, Uganda
Authors: Izudi Jonathan , Ninsiima Viola , Alege John Bosco
Published: October 2017

Background. 270 million workplace accidents occur annually. In Uganda, Kampala district has the highest workplace injury and fatality rates. However, information on personal protective equipment (PPE)—hand gloves, hardhats, overalls, safety boots, earplugs, safety harness with lanyard, and face shields—utilization among building construction workers remains scarce. We assessed PPE utilization and determinants among building construction workers in Kampala, Uganda. Methods. This cross-sectional study involved 385 respondents. Data collected by structured questionnaire was double-entered in EpiData and analyzed in STATA at 5% significance level. Independent determinants of PPE use were established by a stepwise backward logistic regression analysis. Results. 305 (79.2%) respondents were males, 290 (75.3%) were 18–30 years, 285 (74.0%) completed secondary education, and 197 (51.2%) were temporary employees. 60 (15.6%) respondents used PPE. Female sex (adjusted odds ratio (AOR) = 6.64; 95% CI: 1.55–28.46; P=0.011), temporary (AOR = 0.05; 95% CI: 0.01–0.27; P<0.001) and casual (AOR = 0.01; 95% CI: 0.001–0.071; P<0.001) employment, and previous knowledge of safety measures (AOR = 100.72; 95% CI: 26.00–390.16; P<0.001) were associated with PPE use. Conclusion. PPE use was low in Kampala, Uganda. Building construction companies should implement measures of the Uganda Occupational Health and Safety Act.
Antidyslipidemic, Anti‐Inflammatory, and Antioxidant Activities of Aqueous Leaf Extract of Dioscoreophyllum cumminsii (Stapf) Diels in High‐Fat Diet‐Fed Rats
Authors: Ibitoye O. B. , Ghali U. M. , Adekunle J. B. , Uwazie J. N. , Ajiboye T. O.
Published: October 2017

Dioscoreophyllum cumminsii (Stapf) Diels leaves are widely used in the treatment of diabetes, obesity, and cardiovascular related complications in Nigeria. This study investigates the anti‐inflammatory and antiobesity effect of aqueous extract of Dioscoreophyllum cumminsii leaves in high‐fat diet‐ (HFD‐) induced obese rats. HFD‐fed rats were given 100, 200, and 400 mgkg−1 body weight of aqueous extract of Dioscoreophyllum cumminsii leaves for 4 weeks starting from 9th week of HFD treatment. D. cumminsii leaves aqueous extract reversed HFD‐mediated decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose 6‐phosphate dehydrogenase. Moreover, HFD‐mediated elevation in the levels of conjugated dienes, lipid hydroperoxides, malondialdehyde, protein carbonyl, and DNA fragmentation in rats liver was lowered. HFD‐mediated alterations in serum total cholesterol, triacylglycerol, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, and very low‐density lipoprotein cholesterol were significantly reversed by the extract. The treatment of HFD‐fed rats reduced the levels of insulin, leptin, protein carbonyl, fragmented DNA, and tumour necrosis factor‐α and interleukin‐ (IL‐) 6 and IL‐ 8 and increased the adiponectin level. This study showed that aqueous extract of Dioscoreophyllum cumminsii leaves has potential antiobesity and anti‐inflammatory effects through modulation of obesity‐induced inflammation, oxidative stress, and obesity‐related disorder in HFD‐induced obese rats.
Renoprotective Effects of Total Glucosides from Paeony against Nephrotoxicity Induced by Total Alkaloids from Semen Strychni
Authors: Lv Mingming , Zhang Meiyu , Cheng Yezhe , Zhang Kexia , Hou Chenzhi , Chen Xiaohui
Published: October 2017

Semen Strychni have been shown to have therapeutic effect in improving blood circulation, relieving rheumatic pain, and treating cancer. However, Semen Strychni could cause severe nephrotoxicity. The present study was designed to evaluate whether treatment with total glucosides from paeony (TGP) has renoprotective effect against nephrotoxicity induced by total alkaloids from Semen Strychni (TAS). The levels of blood urea nitrogen (BUN) and creatinine (Cr) were determined and histopathological changes were also examined to evaluate renal injury. Moreover, a HPLC‐MS method was developed and validated to investigate the comparative toxicokinetics of strychnine and brucine in rats plasma after oral administration of TAS and pretreatment with TGP. Results demonstrated that the levels of BUN and Cr were significantly increased (p < 0.05) in TAS group, together with tubule epithelium cloudy swelling, degeneration, and glomerular atrophy in rats’ kidneys. The TAS‐induced kidney damage was alleviated after pretreatment with TGP. Besides, Tmax of strychnine and brucine were increased and T1/2 of strychnine and brucine were decreased after pretreatment with TGP. The toxicokinetics study showed that pretreatment with TGP could attenuate the absorption of strychnine and brucine, as well as accelerate their elimination. These results suggest that TGP possesses renoprotective effects.
A Versatile Coexistence Decision-Making System for Efficient TV Whitespace Sharing among Whitespace Objects
Authors: Raza M. Asif , Iqbal Zafar , Byun Sang-Seon , Kang Hyunduk , Lee Heung-No
Published: October 2017

A coexistence decision-making (CDM) system for efficient TV whitespace (TVWS) sharing among whitespace objects (WSOs) is introduced in this paper. The proposed system is considered versatile in functionality as it jointly takes care of three distinct channel allocation features: (a) optimizing system quality of service (QoS) performance metrics, (b) improving TVWS utility, and (c) satisfying WSO channel demands. Regarding system QoS performance metrics, the TVWS sharing problem is defined as an optimization problem with an aim to maximize the system throughput and minimize unfairness in allocation. Supporting the WSOs channel demands in a TVWS sharing problem is a multifold task which requires elaborate consideration in different aspects of the system performance. To this end, the variations of the SNR of wireless frequency channels which result in variable throughput gain of the WSOs are also taken care of in the proposed CDM system. A fast channel allocation algorithm is then designed that implements the TVWS sharing mechanism in a reasonable amount of time. Additionally, the proposed algorithm improves the TVWS utility by promoting a novel frequency reuse method by exploiting the inter-WSO interference information. Simulation results show the superiority of the proposed algorithm over existing TVWS sharing algorithms.
Two Reliable Methods for Solving the (3 + 1)‐Dimensional Space‐Time Fractional Jimbo‐Miwa Equation
Authors: Sirisubtawee Sekson , Koonprasert Sanoe , Khaopant Chaowanee , Porka Wanassanun
Published: October 2017

We investigate methods for obtaining exact solutions of the (3 + 1)‐dimensional nonlinear space‐time fractional Jimbo‐Miwa equation in the sense of the modified Riemann‐Liouville derivative. The methods employed to analytically solve the equation are the (G′/G, 1/G)‐expansion method and the novel (G′/G)‐expansion method. To the best of our knowledge, there are no researchers who have applied these methods to obtain exact solutions of the equation. The application of the methods is simple, elegant, efficient, and trustworthy. In particular, applying the novel (G′/G)‐expansion method to the equation, we obtain more exact solutions than using other existing methods such as the (G′/G)‐expansion method and the exp(−Φ(ξ))‐expansion method. The exact solutions of the equation, obtained using the two methods, can be categorized in terms of hyperbolic, trigonometric, and rational functions. Some of the results obtained by the two methods are new and reported here for the first time. In addition, the obtained exact explicit solutions of the equation characterize many physical meanings such as soliton solitary wave solutions, periodic wave solutions, and singular multiple‐soliton solutions.
Resveratrol and Montelukast Alleviate Paraquat‐Induced Hepatic Injury in Mice: Modulation of Oxidative Stress, Inflammation, and Apoptosis
Authors: El-Boghdady Noha A. , Abdeltawab Nourtan F. , Nooh Mohammed M.
Published: October 2017

Paraquat (PQ) is one of the most used herbicide worldwide. Its cytotoxicity is attributed to reactive radical generation. Resveratrol (Res) and montelukast (MK) have anti‐inflammatory and antioxidant properties. The protective effects of Res, MK, or their combination against PQ‐induced acute liver injury have not been investigated before. Therefore, we explored the protective potential of Res and/or MK against PQ hepatic toxicity in a mouse model. Mice were randomly assigned to five groups: group I served as the normal control and group II received a single dose of PQ (50 mg/kg, i.p.). Groups III, IV, and V received PQ plus oral Res (5 mg/kg/day), MK (10 mg/kg/day), and Res/MK combination, respectively. Res and/or MK reduced PQ‐induced liver injury, evidenced by normalization of serum total protein, ALT, and AST. Res and/or MK significantly reversed PQ‐induced oxidative stress markers glutathione and malondialdehyde. Res and/or MK significantly reduced PQ‐induced inflammation reflected in TNF‐α levels. Furthermore, Res and/or MK reversed PQ‐induced apoptosis assessed by differential expression of p53, Bax, and Bcl-2. Histopathologic examination supported the biochemical findings. Although Res and MK displayed antioxidative, anti‐inflammatory, and antiapoptotic activities, their combination was not always synergistic.
ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms
Authors: Couts Kasey L. , Bemis Judson , Turner Jacqueline A. , Bagby Stacey M. , Murphy Danielle , Christiansen Jason , Hintzsche Jennifer D. , Le Anh , Pitts Todd M. , Wells Keith , Applegate Allison , Amato Carol , Multani Pratik , Chow-Maneval Edna , Tentler John J. , Shellman Yiqun G. , Rioth Matthew J. , Tan Aik-Choon , Gonzalez Rene , Medina Theresa , Doebele Robert C. , Robinson William A.
Published: October 2017

Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK (ALKATI) was reported in 11% of melanomas but the response of melanomas expressing ALKATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 of 45 (24.4%) melanomas. Ten melanomas express wild-type (wt) ALK and/or ALKATI and one mucosal melanoma expresses multiple novel EML4-ALK fusion variants. Melanoma cells expressing different ALK variants were tested for response to ALK inhibitors. Whereas the melanoma expressing EML4-ALK were sensitive to ALK inhibitors in vitro and in vivo, the melanomas expressing wt ALK or ALKATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALKATI was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate ALK fusions occur in malignant melanomas and respond to targeted therapy, whereas melanomas expressing ALKATI do not respond to ALK inhibitors. Targeting ALK fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt ALK or ALKATI. Mol Cancer Ther; 17(1); 222–31. ©2017 AACR.
Theranostic Radiolabeled Anti-CD20 sdAb for Targeted Radionuclide Therapy of Non-Hodgkin Lymphoma
Authors: Krasniqi Ahmet , D'Huyvetter Matthias , Xavier Catarina , Van der Jeught Kevin , Muyldermans Serge , Van Der Heyden José , Lahoutte Tony , Tavernier Jan , Devoogdt Nick
Published: October 2017

Anti-CD20 radioimmunotherapy is an effective approach for therapy of relapsed or refractory CD20pos lymphomas, but faces limitations due to poor tumor penetration and undesirable pharmacokinetics of full antibodies. Camelid single-domain Ab fragments (sdAb) might circumvent some of the limitations of radiolabeled full antibodies. In this study, a set of hCD20-targeting sdAbs was generated, and their capacity to bind hCD20 was evaluated in vitro and in vivo. A lead sdAb, sdAb 9079, was selected on the basis of its specific tumor targeting and significant lower kidney accumulation compared with other sdAbs. SdAb 9079 was then radiolabeled with 68Ga and 177Lu for PET imaging and targeted therapy. The therapeutic potential of 177Lu-DTPA-sdAb was compared with that of 177Lu-DTPA-rituximab and unlabeled rituximab in mice bearing hCD20pos tumors. Radiolabeled with 68Ga, sdAb 9079 showed specific tumor uptake, with very low accumulation in nontarget organs, except kidneys. The tumor uptake of 177Lu-DTPA-sdAb 9079 after 1.5 h was 3.4 ± 1.3% ID/g, with T/B and T/M ratios of 13.3 ± 4.6 and 32.9 ± 15.6. Peak tumor accumulation of 177Lu-DTPA-rituximab was about 9 times higher, but concomitantly with high accumulation in nontarget organs and very low T/B and T/M ratios (0.8 ± 0.1 and 7.1 ± 2.4). Treatment of mice with 177Lu-DTPA-sdAb 9079 significantly prolonged median survival compared with control groups and was as effective as treatment with rituximab or its 177Lu-labeled variant. Taken together, sdAb 9079 displays promising features as a theranostic drug to treat CD20pos lymphomas. Mol Cancer Ther; 16(12); 2828–39. ©2017 AACR.
Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression
Authors: Rusan Maria , Li Kapsok , Li Yvonne , Christensen Camilla L. , Abraham Brian J. , Kwiatkowski Nicholas , Buczkowski Kevin A. , Bockorny Bruno , Chen Ting , Li Shuai , Rhee Kevin , Zhang Haikuo , Chen Wankun , Terai Hideki , Tavares Tiffany , Leggett Alan L. , Li Tianxia , Wang Yichen , Zhang Tinghu , Kim Tae-Jung , Hong Sook-Hee , Poudel-Neupane Neermala , Silkes Michael , Mudianto Tenny , Tan Li , Shimamura Takeshi , Meyerson Matthew , Bass Adam J. , Watanabe Hideo , Gray Nathanael S. , Young Richard A. , Wong Kwok-Kin , Hammerman Peter S.
Published: October 2017

Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.

Significance: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies. Cancer Discov; 8(1); 59–73. ©2017 AACR.

See related commentary by Carugo and Draetta, p. 17.

This article is highlighted in the In This Issue feature, p. 1
Assoziationen statt Kausalitäten: zur Empfehlung von Vitamin-D-Einnahme gegen Allergien
Authors: Traidl-Hoffmann Claudia
Published: October 2017

Hintergrund: Vitamin D hat verschiedene immunologische Funktionen. Die Daten zur Beziehung zwischen Vitamin-D-Status und Allergien sind umstritten. Methoden: Wir untersuchten den Zusammenhang zwischen Serumkonzentrationen von 25-Hydroxyvitamin D (25-OHD) und Allergien im Kindesalter. Die Studienpopulation (n = 819) war Teil einer randomisierten, doppelblinden, Placebo-kontrollierten Studie, in der Mütter, bei deren Kindern ein hohes Allergierisiko bestand, in den letzten 4 Wochen der Schwangerschaft eine Probiotika-Mischung (oder Placebo) einnahmen und ihr Kind dies nach der Geburt 6 Monate lang erhielt. Die Probanden wurden 5 Jahre lang im Hinblick auf das Auftreten von Sensibilisierung und allergischen Symptomen beobachtet und im Alter von 3 und 6 Monaten, 2 und 5 Jahren sowie im Falle allergischer Symptome medizinisch untersucht. Die 25-OHD-Spiegel wurden in Proben von Nabelschnurblut (NSB) (n = 724) und in Serumproben, die im Alter von 2 Jahren genommen wurden, (n = 369) gemessen. Die Daten wurden in Terzile (T1-T3) und Quartile (Q1-Q4) kategorisiert. Die Beziehung zwischen 25-OHD-Spiegeln und Sensibilisierung bzw. Allergie wurde mit einer multivablen logistischen Regressionsanalyse ausgewertet. Ergebnisse: 25-OHD-Spiegel in T2 im NSB waren mit einem höheren Risiko einer Sensibilisierung im Alter von 2 Jahren und allergischen Erkrankungen im Alter von 5 Jahren verbunden. Bei den im Alter von 2 Jahren genommenen Serumproben waren 25-OHD-Spiegel in Q3 mit einem höheren Sensibilisierungsrisiko und IgE-vermittelten Allergien im Alter von 5 Jahren verbunden. Schlussfolgerung: Die 25-OHD-Spiegel im frühen Kindesalter sind mit dem Auftreten von Allergien assoziiert, jedoch scheint der Zusammenhang nichtlinear zu sein.
Die Systemtherapie des fortgeschrittenen Melanoms im Jahr 2016
Authors: Heppt Markus Vincent , Dietrich Cecilia , Graf Saskia , Ruzicka Thomas , Tietze Julia , Berking Carola
Published: October 2017

Das Melanom ist eine häufige Form von Hautkrebs mit hoher Tendenz zur Metastasenbildung. Tyrosinkinase-Inhibitoren, die zielgerichtet in den MAPK (mitogen-activated protein kinase)-Signaltransduktionsweg eingreifen, sowie die Immun-Checkpoint-Blockade haben in jüngster Zeit die Behandlung des nicht-resezierbaren und des metastasierten Melanoms revolutioniert. Doch erworbene Resistenzen und primäres Nichtansprechen auf diese Therapien machen neuartige Behandlungsstrategien und Kombinationsansätze erforderlich. Das Ziel dieser Übersichtsarbeit ist es, einen kurzen und aktuellen Überblick über das klinische Management des Melanoms und die gegenwärtige Studiensituation zu geben. Die Arbeit enthält Zusammenfassungen der relevantesten Studien zu BRAF- und MEK-Inhibitoren sowie zu Antikörpern gegen CTLA-4 (T-lymphocyte-associated protein 4) und PD-1 (programmed cell death protein 1). Während die meisten Wirkstoffe schon in Monotherapie eine gute antitumorale Wirksamkeit zeigen, sind durch Kombinationstherapien mit zugelassenen und in der Entwicklung befindlichen Wirkstoffen weitere Verbesserungen erzielt worden. Wir besprechen hier laufende Studien und evaluieren Ansätze, die künftig eine noch höhere Wirksamkeit bei geringerer Toxizität gewährleisten könnten. Übersetzung aus Oncol Res Treat 2016;39:635-642 (DOI:10.1159/000448904)
Parasitic Hematuria: Six Cases in a Row in a Single Centre in Spain
Authors: Ballesta Martínez Begoña , Rodríguez Talavera Jonathan , Amador Robayna Adrián , Carrión Valencia Almudena , Orribo Morales Nuria , García García Lorena , Santa Cruz Pérez Melania , Ravina Pisaca Manuel Felipe
Published: October 2017

Most cases of urogenital parasitosis are registered in Africa. However, migration movements and travellers moving from developed to developing countries are responsible for leading to an increased incidence of genitourinary infections caused by parasites in the western world including Spain having serious economic and health implications. The importance of its early detection and treatment also results from its potential risk for infertility, susceptibility for HIV infection and the development of bladder cancer. The most common presentation symptom is terminal haematuria, and when diagnosed, praziquantel is the treatment of choice. We report a series of 6 cases of urinary schistosomiasis that happened in a single centre in Spain and reminds the importance of having the infection in mind in certain cases of haematuria study.
An Open-Label Randomized Multicenter Study Assessing the Noninferiority of a Caffeine-Based Topical Liquid 0.2% versus Minoxidil 5% Solution in Male Androgenetic Alopecia
Authors: Dhurat Rachita , Chitallia Jill , May Theodor W. , Jayaraaman Ammani M. , Madhukara Jithendriya , Anandan Subbu , Vaidya Pradyumna , Klenk Adolf
Published: October 2017

Background: Androgenetic alopecia is a condition with a high prevalence worldwide and affects both males and females. Currently, only 2 approved treatments exist: finasteride (males only) and minoxidil 2 or 5% solution (males and females). Methods: We conducted a randomized, open-label, multicenter noninferiority study to determine whether a caffeine-based 0.2% topical liquid would be no less effective than minoxidil 5% solution in males (n = 210) with androgenetic alopecia. The primary end point was the percentage change in the proportion of anagen hairs from baseline to 6 months using a frontal and occipital trichogram. Results: At 6 months, the group of the 5% minoxidil solution showed a mean improvement in anagen ratio of the trichogram of 11.68%, and the group of the 0.2% caffeine solution had an anagen improvement of 10.59%. The difference of mean values between both groups was 1.09%. The statistical analysis was performed and reported in accordance with the CONSORT Guidelines 2010 for reporting of noninferiority and equivalence randomized trials. Conclusion: A caffeine-based topical liquid should be considered as not inferior to minoxidil 5% solution in men with androgenetic alopecia.
Bladder Metastases from Breast Cancer: Managing the Unexpected. A Systematic Review
Authors: Sanguedolce Francesca , Landriscina Matteo , Ambrosi Antonio , Tartaglia Nicola , Cianci Pasquale , Di Millo Marcello , Carrieri Giuseppe , Bufo Pantaleo , Cormio Luigi
Published: October 2017

Breast cancer (BrC) has the highest incidence among females world over and it is one of the most common causes of death from cancer overall. Its high mortality is mostly due to its propensity to rapidly spread to other organs through lymphatic and blood vessels in spite of proper treatment. Bladder metastases from BrC are rare, with 50 cases having been reported in the last 60 years. This review aims to discuss some critical points regarding this uncommon condition. First, we performed a systematic review of the literature in order to draw a clinical and pathological profile of this entity. On this basis, its features in terms of diagnostic issues, imaging techniques, and survival are critically examined. Most bladder metastases from BrC are secondary lobular carcinoma, which mimic very closely the rare variant of urothelial cancer with lobular carcinoma-like features (uniform cells with an uncohesive single-cell, diffusely invasive growth pattern); thus, immunohistochemistry is mandatory to arrive at a correct diagnosis. This article summarizes the current knowledge regarding the incidence, clinical presentation, diagnosis, prognosis, and treatment of bladder metastases in patients with BrC.
The Androgen Receptor Promotes Cellular Proliferation by Suppression of G-Protein Coupled Estrogen Receptor Signaling in Triple-Negative Breast Cancer
Authors: Shen Yan , Yang Fang , Zhang Wenwen , Song Wei , Liu Yuxiu , Guan Xiaoxiang
Published: October 2017

Background/Aims: The targeted therapy for triple-negative breast cancer (TNBC) is still challenging due to poor understanding on its molecular etiology. The androgen receptor (AR) has recently emerged as a prognostic and treatment-predictive marker in breast cancer. However, the role of AR in TNBC remained elusive. Methods: Immunohistochemistry (IHC) was used to detect AR and G-protein coupled estrogen receptor (GPER) expression in tissue microarrays of 165 TNBC patients. Microarray analysis of mRNAs was performed to identify downstream regulators of AR. TNBC cells were cultured with dihydrotestosterone (DHT) alone or in combination with AR knockdown performed with AR shRNA. Cell viability and colony formation were assessed. Western blotting and qRT-PCR were used to examine protein and mRNA expression, respectively. The potential mechanism of AR-mediated GPER suppression was identified by Chromatin immunoprecipitation (ChIP) assay. AR and GPER expressions were also assessed in nude mouse xenografts by IHC. Results: IHC staining showed that the expression of AR was positively associated with tumor size, lymph node metastasis and high-grade tumor in TNBC patients. AR activation triggered by DHT suppressed GPER expression, to promote cell growth of TNBC. G-1, a GPER agonist, inhibited DHT-stimulated proliferation. Further experiments illustrated that AR suppressed GPER activation via binding directly to the promoter of GPER. Moreover, a negative correlation between AR and GPER was observed in MDA-MB-231 tumor cell xenografts and TNBC patient samples. Conclusions: The suppression of GPER via AR may be involved in the positive actions towards the TNBC progression, making it a promising therapeutic target for TNBC treatment.
Pharmaceutical care in Brazil’s primary health care
Authors: Araújo Patricia Sodré , Costa Ediná Alves , Guerra Junior Augusto Afonso , Acurcio Francisco de Assis , Guibu Ione Aquemi , Álvares Juliana , Costa Karen Sarmento , Karnikowski Margô Gomes de Oliveira , Soeiro Orlando Mario , Leite Silvana Nair
Published: October 2017

OBJECTIVE: To characterize the activities of clinical nature developed by pharmacists in basic health units and their participation in educational activities aiming at health promotion. METHODS: This article is part of the Pesquisa Nacional sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos – Serviços, 2015 (PNAUM – National Survey on Access, Use and Promotion of Rational Use of Medicines – Services, 2015), a cross-sectional and exploratory study, of evaluative nature, consisting of a survey of information in a representative sample of cities, stratified by the Brazilian regions that constitute domains of study, and a subsample of primary health care services. The interviewed pharmacists (n=285) were responsible for the delivery of medicines and were interviewed in person with the use of a script. The characterization of the activities of clinical nature was based on information from pharmacists who declared to perform them, and on participation in educational activities aiming at health promotion, according to information from all pharmacists. The results are presented in frequency and their 95% confidence intervals. RESULTS: From the interviewed subjects, 21.3% said they perform activities of clinical nature. Of these, more than 80% considered them very important; the majority does not dispose of specific places to perform them, which hinders privacy and confidentiality in these activities. The main denominations were “pharmaceutical guidance” and “pharmaceutical care.” The registration of activities is mainly made in the users’ medical records, computerized system, and in a specific document filed at the pharmacy, impairing the circulation of information among professionals. Most pharmacists performed these activities mainly along with physicians and nurses; 24.7% rarely participated in meetings with the health team, and 19.7% have never participated. CONCLUSIONS: Activities of clinical nature performed by pharmacists in Brazil are still incipient. The difficulties found point out to the professionals’ improvisation and effort. The small participation in educational activities of health promotion indicates little integration of pharmacists with the health team and of pharmaceutical services with other health actions
Infrastructure of pharmacies of the primary health care in the Brazilian Unified Health System:
Authors: Leite Silvana Nair , Manzini Fernanda , Álvares Juliana , Guerra Junior Augusto Afonso , Costa Ediná Alves , Acurcio Francisco de Assis , Guibu Ione Aquemi , Costa Karen Sarmento , Karnikowski Margô Gomes de Oliveira , Soeiro Orlando Mário , Farias Mareni Rocha
Published: October 2017

OBJECTIVE: To characterize the infrastructure of the primary health care pharmacies of the Brazilian Unified Health System, aiming at humanizing the offered services. METHODS: This is a cross-sectional study, of quantitative approach, from data obtained in the Pesquisa Nacional de Acesso, Utilização e Promoção do Uso Racional de Medicamentos – Serviços, 2015 (PNAUM – National Survey on Access, Use and Promotion of Rational Use of Medicines – Services, 2015). Information on 1,175 pharmacies/dispensing units were gathered from direct observation and assessment of dispensing units installations conducted by trained researchers who used a standardized form. The analyzed variables refer to the physical structure of pharmacies or medicine dispensing units of the health units under research. RESULTS: The pharmacy area was greater than 14 m2 in 40.3% of the sampled units, highlighting those from Midwest (56.9%) and Southeast (56.2%) regions and those of Northeast, with only 23.3%. About 80.2% units had waiting rooms with chairs for patients, 31.8% of them had dispensing areas inferior to 5m2 , while in 46.2% these areas were superior to 10m2 . Bars were found in service counters in 23.8% of health units, thus separating the patient from the professional; 44.1% had internet access. In most units, the area of medicine storage had no refrigerator or freezer for their exclusive storage and 13.7% had a specific room for pharmaceutical consultation. CONCLUSION: Aiming at achieving care humanization and improving working conditions for professionals, the structuring of the environment of pharmacy services is necessary. This would contribute to the better qualification of pharmacy services, comprising more than medicine delivery. Data on the Northeast region indicated less favorable conditions to the development of adequate dispensing services. Based on the panorama pointed out, we suggest the expansion of stimulus concerning the physical structure of pharmaceutical services, considering regional specificities