bluuebunny/crossref_metadata_2025 huggingface dataset:
Corrosion Behavior of Austenitic Stainless Steel in Supercritical CO2 Containing O2 and H2O
Authors: Teeter Lucas , Huerta Nicolas , Dogan Omer , Ziomek-Moroz Margaret , Oleksak Richard , Oryshchyn Danylo , Disenhof Corinne , Baltrus John P , Tucker Julie
Published: October 2016

The corrosion behavior of 347H stainless steel was investigated in supercritical CO2 (sCO2) containing H2O and O2 simulating heat exchanger conditions that would exist in direct sCO2 power cycles. Thermodynamic properties of oxygenated sCO2 aqueous systems related to the corrosion phenomena was determined using NIST developed software REFPROP. The exposure tests of the corrosion samples were performed at a pressure of 80 bar and two temperatures, 50 °C and 248 °C up to 1500 hours. The samples were exposed to oxygenated H2O-containing CO2, and oxygenated sCO2-containing H2O. The corrosion rate of the alloys was determined by mass change measurements. The surface microstructure and composition of the corrosion films were investigated using X-ray diffraction (XRD), scanning electron microscopy (SEM) equipped with energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy (XPS). The XRD results for the corrosion products on the sample surfaces formed in the oxygenated CO2-containg H2O and water-containing CO2 and O2 at 248°C revealed the presence of Fe2O3 and Fe3O4,-rich phase, respectively. The XPS results revealed that the samples had thicker films after exposure to 0.01 O2/ 0.04 H2O ratio in CO2 at 248°C than at 50°C. The outer film layer contained Fe and O and the inner layer Cr and O at 248°C. Mostly Cr and O were found at 50°C.
The Effect of Nickel Alloy Corrosion under Cathodic Protection inside High Temperature Molten Salt Systems
Authors: Tavakoli Bahareh Alsadat , Shimpalee Sirivatch , Weidner John W. , Garcia-Diaz Brenda L. , Martinez-Rodriguez Michael J. , Olson Luke Christopher
Published: October 2016

One way to potentially reduce the costs of concentrated solar power (CSP) systems is to operate the central receiver at high temperatures which allow for more efficient thermodynamic power conversion cycles. Molten salts are one potential heat transfer fluid that can operate efficiently at these temperatures, but their use will introduce other technological challenges, such as corrosion reactions. Cathodic protection may mitigate corrosion of metal surfaces by shifting the potential of the alloy below its oxidation potential. The behavior of molten salt (CSP) systems under cathodic protection can be obtained by developing a 3-D model. A simplified model was designed for a thermosiphon vessel. This thermosiphon vessel exposed the alloy coupons to isothermal and non-isothermal conditions expected in concentrated solar power (CSP) plants. The model compared the corrosion rates for the cases with and without cathodic protection. Results were in good agreement with experimental values with less than 5% error.
The Development of Novel Sound-Absorbing and Anti-Corrosion Nanocomposite Coating
Authors: Huang Chien-Yu , Tsai Pei-Ying , Gu B E , Hu W C , Jhao J S , Jhuang Gao-Shu , Lee Yueh-Lien
Published: October 2016

The effects of addition of graphene on the corrosion protection and acoustic absorption performance of PU coatings have been studied in this paper. The corrosion properties of the coatings were characterized by electrochemical impedance spectroscopy, potentiodynamic polarization curves, and salt spray testing. The acoustic absorption coefficient (α) was measured over the frequency range of 1–8 kHz by two-microphone impedance tube filled with water. The preliminary experimental results showed that PU/graphene nanocomposite coating exhibited a relatively high and stable impedance value during exposure to a 3.5 wt% NaCl for 168 hours, suggesting the presence of graphene can effectively improve corrosion resistance of the PU coating. Also, it was observed that PU/graphene nanocomposite coating had higher acoustic absorption coefficient and exhibited good absorption performance in the frequency range of 1000 Hz and 8000 Hz as the graphene content is 4 wt%.
Advanced Process Control for Variability Control in Chemical Mechanical Polishing Process
Authors: Koli Dinesh R , Wan Hsiang Liang Rachel , Kim Hong Jin , Solan Robert
Published: October 2016

With transistors scaling towards sub 14nm nodes, FIN-field effect transistors (FINFETs) have been the preferred design architecture to meet device requirements. The gate last/replacement metal gate (RMG) integration scheme forms the core design for FINFETs due to the advantages in thermal budgets. Chemical Mechanical Planarization (CMP) plays a key role in this integration scheme with various CMP steps supporting dummy poly gate formation, poly removal and replacement metal gate formation. And the final gate height after metal gate CMP process typically determines device resistance. Therefore, one of major requirements of metal gate CMP is to control gate height as tightly as possible for every wafer. In this paper, two fold approaches are introduced to achieve this. Integrated advanced process control (iAPC) method improves wafer to wafer variation, and zonal iAPC provides additional within wafer variation improvement. The concept of iAPC is to use data collected from each wafer and to adjust polishing time (and zone pressure for zonal iAPC case) to achieve final gate height. Using these two approaches, gate height control of less than 5nm has been demonstrated.
Mechanisms and Development of Ceria-Based, Fast Oxide Slurries
Authors: Urban Nathaniel D , Dickmann Dan , Her Bob , Santora Brian
Published: October 2016

Recent developments in vertical integration schemes including 3D-NAND flash memory have introduced a significant need for fast oxide slurries (1). Specifically, the new staircase CMP process requires exceptionally large step heights to be polished in a timely manner. Balancing low defectivity and high planarization efficiency with extremely fast bulk oxide removal rates is a difficult but crucial set of requirements. Ceria-based slurries with fine-tuned chemistries are well suited to meet these challenges. Mechanisms for ceria-based slurries polishing behavior on oxide surfaces have been the subject of investigation for a number of years now. A careful examination of these proposed mechanisms can drive the design and development of next generation fast oxide slurries.
Fluorescence Correlation Spectroscopic Studies of Particle Properties for Colloidal Ceria Abrasives Used in Chemical-Mechanical Planarization
Authors: Schorr Donald K. , Smith Madison A. , Rawat Ashwani K. , Carver Colin T. , Mansour Moinpour , Remsen Edward E.
Published: October 2016

The application of fluorescence correlation spectroscopy (FCS) in the characterization of ceria abrasives used in chemical-mechanical planarization (CMP) slurries is described. A fluorescent dye, Rhodamine 110 (R110), is used for this purpose. R110 adsorption on ceria particles is found to be pH-dependent and colloidal ceria dispersions differing in mean hydrodynamic diameter are analyzed. A Langmuir isotherm is generated for R110 adsorption on ceria, and the magnitude of the Langmuir constant is found to be four-times smaller than the corresponding constant for R110 adsorption on colloidal silica CMP abrasives. R110-labeled ceria particles are generated to quantitatively determine the particle size distribution (PSD) of abrasive ceria dispersions. The Maximum Entropy Method is used reduce the FCS autocorrelation function of R110-labeled ceria particle dispersions thereby producing a PSD. These findings indicate that ceria size distributions containing particles as small as 5 to 10 nm in diameter can be readily characterized using FCS.
Nano-Sized Chemical Release Capsules Enable High Planarization Efficiency CMP Processes
Authors: Ihnfeldt Robin , Javery Kerry , Nguyen Kathy , Nguyen Mary
Published: October 2016

As semiconductor device sizes decrease, next generation CMP slurries must achieve planarization on increasingly more complicated material surfaces with higher aspect ratio structures. While incremental improvements to CMP performance using the traditional homogenous mixtures of abrasives and chemical components continue to be obtained, new approaches to CMP slurry formulations are needed to meet future device requirements. GE&R has developed novel techniques to economically synthesize CMP slurries containing nano-capsules. Nano-capsules use typical metal oxide nanoparticles, where the pores of the particle are loaded with a chemical payload, and then coated with a polymer to encapsulate the chemical payload. When the nano-capsule contacts the wafer surface during CMP, the polymer coating is torn away and the chemical payload is released only in a localized area. A variety of metal oxide base particles (including GE&R silica) and different chemical payloads are possible, opening the door for improved selectivity mechanisms and high planarity processes.
Divergent functions of endotrophin on different cell populations in adipose tissue
Authors: Zhao Yueshui , Gu Xue , Zhang Ningyan , Kolonin Mikhail G. , An Zhiqiang , Sun Kai
Published: October 2016

Endotrophin is a cleavage product of collagen 6 (Col6) in adipose tissue (AT). Previously, we demonstrated that endotrophin serves as a costimulator to trigger fibrosis and inflammation within the unhealthy AT milieu. However, how endotrophin affects lipid storage and breakdown in AT and how different cell types in AT respond to endotrophin stimulation remain unknown. In the current study, by using a doxycycline-inducible mouse model, we observed significant upregulation of adipogenic genes in the white AT (WAT) of endotrophin transgenic mice. We further showed that the mice exhibited inhibited lipolysis and accelerated hypertrophy and hyperplasia in WAT. To investigate the effects of endotrophin in vitro, we incubated different cell types from AT with conditioned medium from endotrophin-overexpressing 293T cells. We found that endotrophin activated multiple pathological pathways in different cell types. Particularly in 3T3-L1 adipocytes, endotrophin triggered a fibrotic program by upregulating collagen genes and promoted abnormal lipid accumulation by downregulating hormone-sensitive lipolysis gene and decreasing HSL phosphorylation levels. In macrophages isolated from WAT, endotrophin stimulated higher expression of the collagen-linking enzyme lysyl oxidase and M1 proinflammatory marker genes. In the stromal vascular fraction isolated from WAT, endotrophin induced upregulation of both profibrotic and proinflammatory genes. In conclusion, our study provides a new perspective on the effect of endotrophin in abnormal lipid accumulation and a mechanistic insight into the roles played by adipocytes and a variety of other cell types in AT in shaping the unhealthy microenvironment upon endotrophin treatment.
Use of Aldosterone Antagonist to Treat Diarrhea and Hypokalemia of Ogilvie’s Syndrome
Authors: Ram Pradhum , Goyal Abhinav , Lu Marvin , Sloan Joshua , McElhaugh William
Published: October 2016

Ogilvie’s syndrome (OS) is a functional obstruction of the bowel due to an autonomic imbalance. It often presents with diarrhea and is associated with hypokalemia. We present a case of a 70-year-old male who developed severe abdominal distension, watery diarrhea, and persistent hypokalemia status after left hip arthroplasty after suffering from a femoral neck fracture due to a fall and was diagnosed with OS. The persistent hypokalemia was slow to improve despite aggressive repletion because of the high potassium losses in the stool. This is most likely mediated through the increased expression of BK channels in the colonic mucosa. Aldosterone is theorized to have a role in the regulation of BK channels. Spironolactone was subsequently given and resulted in marked improvement of the diarrhea and hypokalemia. Thus, this case suggests a novel therapeutic approach for the treatment of Ogilvie’s syndrome-associated diarrhea and hypokalemia.
A Conservative Esthetic Approach Using Enamel Recontouring and Composite Resin Restorations
Authors: Mathias Paula , da Silva Emily Vivianne Freitas , Aguiar Thaiane Rodrigues , Andrade Aline Silva , Azevedo Juliana
Published: October 2016

Conservative clinical solutions, predictable esthetic, and immediate outcomes are important concepts of restorative dentistry. The aim of this case study was to recognize the selective enamel removal as an interesting conservative alternative to achieve optimal esthetic results and discuss the clinical protocol. This clinical report described an alternative esthetic and conservative treatment to transform the long and sharp aspect of the maxillary canines with a slightly aggressive aspect into features of slightly curved teeth with delicate lines. An accurate diagnostic and esthetic analysis of the smile was initially performed. The selective enamel removal was performed, and direct composite restoration was strategically placed. Clinical assessment showed good esthetic outcomes, enabling a smile harmony with an immediate, simple, and lower-cost technique. Practitioners should be exposed to conservative approaches to create esthetic smiles based on the selective enamel removal technique combined with composite resin.
A Case of Metastatic Melanoma in the Ureter
Authors: Macneil James , Hossack Tania
Published: October 2016

Advances in the treatment of melanoma are resulting in patients living for extended periods after being diagnosed with metastatic disease. Metastases to the ureter are rare, but they have been described in the literature on a number of occasions. In this case report, we describe a patient with established metastatic melanoma who, whilst taking and responding to immunomodulatory therapy, was found to have an obstructive mass in the middle of his left ureter. Rather than performing either a nephroureterectomy or partial resection of the ureter, we opted to perform an endoscopic resection of the melanoma. Follow-up imaging at 12 months shows no evidence of local disease recurrence. We submit that primary endoscopic management of metastatic melanoma in the ureter is a viable alternative to a radical approach.
Coordinated Learning by Model Difference Identification in Multiagent Systems with Sparse Interactions
Authors: Zhang Qi , Jiao Peng , Yin Quanjun , Sun Lin
Published: October 2016

Multiagent Reinforcement Learning (MARL) is a promising technique for agents learning effective coordinated policy in Multiagent Systems (MASs). In many MASs, interactions between agents are usually sparse, and then a lot of MARL methods were devised for them. These methods divide learning process into independent learning and joint learning in coordinated states to improve traditional joint state-action space learning. However, most of those methods identify coordinated states based on assumptions about domain structure (e.g., dependencies) or agent (e.g., prior individual optimal policy and agent homogeneity). Moreover, situations that current methods cannot deal with still exist. In this paper, a modified approach is proposed to learn where and how to coordinate agents’ behaviors in more general MASs with sparse interactions. Our approach introduces sample grouping and a more accurate metric of model difference degree to identify which states of other agents should be considered in coordinated states, without strong additional assumptions. Experimental results show that the proposed approach outperforms its competitors by improving the average agent reward per step and works well in some broader scenarios.
Macrophage Activation Syndrome Associated with Adult-Onset Still’s Disease Successfully Treated with Anakinra
Authors: Kumar Aswini , Kato Hiroshi
Published: October 2016

Macrophage activation syndrome (MAS) is a potentially fatal complication of Adult-Onset Still’s disease (Still’s disease). Whereas an increasing body of evidence supports interleukin-1 (IL-1) blockade as a promising treatment for Still’s disease, whether it is therapeutic for MAS associated with Still’s disease remains unclear. We report a 34-year-old Caucasian man with one-decade history of TNF-blockade-responsive seronegative arthritis who presented with abrupt onset of fever, serositis, bicytopenia, splenomegaly, hepatitis, and disseminated intravascular coagulation. Striking hyperferritinemia was noted without evidence of infection, malignancy, or hemophagocytosis on bone marrow biopsy. NK cells were undetectable in the peripheral blood, whereas soluble IL-2 receptor was elevated. His multiorgan disease resolved in association with methylprednisolone pulse therapy, Anakinra, and a tapering course of prednisone. This case reinforces the notion that Still’s disease is inherently poised to manifest MAS as one of the clinical phenotypes by shedding light on the role of IL-1 underlying both Still’s disease and related MAS.
Joining of Metal-Plastics-Hybrid Structures Using Laser Radiation by Considering the Surface Structure of the Metal
Authors: Hopmann Christian , Kreimeier Suveni , Keseberg Jan , Wenzlau Carsten
Published: October 2016

Lightweight construction is a central technology in today’s industrial production. One way to achieve the climate goals is the production of hybrid compounds of metal and plastic. The manufacturing process for these hybrid parts can be divided into in-mold assembly and postmold assembly. The postmold assembly includes thermal joining by laser, which is applied in the context of this paper. For the investigations, four plastics (MABS, PA6.6-GF35, PP, and PC), which differ in their properties, and three metals (unalloyed steel, stainless steel, and aluminum) are combined and analyzed. These materials have been used, since they have a huge significance in the automotive industry. Preliminary studies showed that an adhesive bond between the two materials is achieved using metal with a structured surface. According to these studies, three structuring processes for metals (selective laser melting (SLM), NRX, and a welded metallic tissue) are tested. The quality of the material/structure combinations is tested in tensile-shear-tests, microscopy images, and alternating climate tests. Compounds with SLM-Structure achieve highest strength, while compounds with aluminum are much more complex to manufacture.
A Persistent Structured Hierarchical Overlay Network to Counter Intentional Churn Attack
Authors: Kaur Ramanpreet , Sangal Amrit Lal , Kumar Krishan
Published: October 2016

The increased use of structured overlay network for a variety of applications has attracted a lot of attention from both research community and attackers. However, the structural constraints, open nature (anybody can join and anybody may leave), and unreliability of its participant nodes significantly affect the performance of these applications and make it vulnerable to a variety of attacks such as eclipse, Sybil, and churn. One attack to compromise the service availability in overlay network is intentional churn (join/leave) attack, where a large number of malicious users will join and leave the overlay network so frequently that the entire structure collapses and becomes unavailable. The focus of this paper is to provide a new robust, efficient, and scalable hierarchical overlay architecture that will counter these attacks by providing a structure that can accommodate the fleeting behaviour of nodes without causing much structural inconsistencies. The performance evaluation showed that the proposed architecture has more failure resilience and self-organization as compared to chord based architecture. Experimental results have demonstrated that the effect of failures on an overlay is proportional to the size of failure.
Typing Method for the QUB11a Locus ofMycobacterium tuberculosis: IS6110Insertions and Tandem Repeat Analysis
Authors: Maeda-Mitani Eriko , Murakami Koichi , Oishi Akira , Etoh Yoshiki , Sera Nobuyuki , Fujimoto Shuji
Published: October 2016

QUB11a is used as a locus for variable number of tandem repeats (VNTR) analysis ofMycobacterium tuberculosisBeijing lineage. However, amplification of QUB11a occasionally produces large fragments (>1,400 bp) that are not easily measured by capillary electrophoresis because of a lack of the typical stutter peak patterns that are used for counting repeat numbers. IS6110insertion may complicate VNTR analysis of large QUB11a fragments inM. tuberculosis. We established a method for determining both tandem repeat numbers and IS6110insertion in the QUB11a locus ofM. tuberculosisusing capillary electrophoresis analysis andBsmBI digestion. All 29 large QUB11a fragments (>1,200 bp) investigated contained IS6110insertions and varied in the number of repeats (18 patterns) and location of IS6110insertions. This method allows VNTR analysis with high discrimination.
Diabetes Mellitus as Hub for Tuberculosis Infection: A Snapshot
Authors: Pal Rahul , Ansari Moiz A. , Hameed Saif , Fatima Zeeshan
Published: October 2016

Tuberculosis (TB) still remains the thorn in the flesh of efficient therapeutics affecting one-third of global population annually. There are several factors that enhance the susceptibility to TB infections including malnutrition, smoking, and immunocompromised conditions such as AIDS. In the recent years, growing body of evidence has gained considerable prominence which suggests that Diabetes Mellitus (DM) is individual risk factor leading to complicated TB infections. In this article the authors have attempted to summarize the link of type 2 DM with TB, the mechanistic action of how DM sensitizes for developing the active TB infection from the latent infection, and problems faced during treatment followed by possible preventive measures. We have tried to give account of the alterations that occurred in DM making a person more prone to develop TB.
Fetal Right Ventricular Diverticulum Detected by Prenatal Ultrasound Screening
Authors: Katsura Daisuke , Hayashi Kaori , Tsuji Shunichiro , Ono Tetsuo , Ishiko Akiko , Takahashi Kentaro , Murakami Takashi
Published: October 2016

Prenatal ultrasound screening has allowed for the detection of in utero cardiac abnormalities. Specifically, distinction is possible between ventricular diverticula and aneurysms, which is important because each condition has a different clinical outcome. We report the case of a 35-year-old, gravida 1, para 1 woman, with no significant past medical history, who underwent routine prenatal ultrasound screening at 32 weeks’ gestation. A four-chamber ultrasound of the fetal heart combined with M-mode echocardiography showed abnormal dilatation of the right ventricular chamber measuring 2.2 cm × 1.0 cm but with normal contractility. Delivery was performed at full term by cesarean section, and a right ventricular diverticulum was confirmed by postnatal cardiac computed tomography. The baby developed normally with no cardiac sequelae during followup. This case demonstrates the importance of making a correct diagnosis of ventricular diverticula by prenatal ultrasound when abnormal dilatation of the fetal ventricle is identified during routine screening. Because evaluating the wall contractility by M-mode ultrasound leads to evaluating whether it has the myocardium, we conclude that M-mode echocardiography is effective for the purpose of prenatal cardiac diagnosis and can distinguish between ventricular aneurysms and functioning ventricular diverticula.
Successful Use of Tocilizumab in a Patient with Coexisting Rheumatoid Arthritis and Ulcerative Colitis
Authors: Szeto Matthew Chak Hin , Yalçın Metin Devrim , Khan Abdul , Piotrowicz Andrzej
Published: October 2016

Tocilizumab is an interleukin-6 receptor inhibitor licensed for moderate to severe rheumatoid arthritis (RA). We report a case of Tocilizumab monotherapy for severe active RA in a patient with coexisting ulcerative colitis (UC). The patient was intolerant to multiple disease-modifying drugs, so Tocilizumab monotherapy was commenced. We found clinical improvement in both RA and UC. There was no major adverse event after 2 years. Manufacturer advised caution in using Tocilizumab in patient with gastrointestinal ulceration due to an increased risk of bowel perforation. However, alternative treatments such as glucocorticoid and nonsteroidal anti-inflammatory drugs may carry a higher bowel perforation risk. The presence of gastrointestinal ulceration therefore should not constitute an absolute contraindication for Tocilizumab therapy. Future studies of registry data will inform clinician of the Tocilizumab-related risk of gastrointestinal toxicity in “real-life” settings. Contrary to previous case report, we found Tocilizumab therapy to have a positive effect on UC. Laboratory studies supported a role for interleukin-6 in the pathophysiology of UC. Further clinical trial to evaluate the therapeutic role of Tocilizumab in UC would be warranted.
Modification of Mechanical Properties, Polymerization Temperature, and Handling Time of Polymethylmethacrylate Cement for Enhancing Applicability in Vertebroplasty
Authors: Tai Ching-Lung , Lai Po-Liang , Lin Wei-De , Tsai Tsung-Tin , Lee Yen-Chen , Liu Mu-Yi , Chen Lih-Huei
Published: October 2016

Polymethylmethacrylate (PMMA) bone cement is a popular bone void filler for vertebroplasty. However, the use of PMMA has some drawbacks, including the material’s excessive stiffness, exothermic polymerization, and short handling time. This study aimed to create an ideal modified bone cement to solve the above-mentioned problems. Modified bone cements were prepared by combining PMMA with three different volume fractions of castor oil (5%, 10%, and 15%). The peak polymerization temperatures, times to achieve the peak polymerization temperature, porosities, densities, modulus and maximum compression strengths of standard (without castor oil), and modified cements were investigated following storage at ambient temperature (22°C) or under precooling conditions (3°C). Six specimens were tested in each group of the aforementioned parameters. Increasing castor oil content and precooling treatment effectively decreased the peak polymerization temperatures and increased the duration to achieve the peak polymerization temperature (P<0.05). Furthermore, the mechanical properties of the material, including density, modulus, and maximum compression strength, decreased with increasing castor oil content. However, preparation temperature (room temperature versus precooling) had no significant effect (P>0.05) on these mechanical properties. In conclusion, the addition of castor oil to PMMA followed by precooling created an ideal modified bone cement with a low modulus, low polymerization temperature, and long handling time, enhancing its applicability and safety for vertebroplasty.
Electromagnetic-Thermal Integrated Design Optimization for Hypersonic Vehicle Short-Time Duty PM Brushless DC Motor
Authors: Li Quanwu , Dou Manfeng , Tan Bo , Zhang Haitao , Zhao Dongdong
Published: October 2016

High reliability is required for the permanent magnet brushless DC motor (PM-BLDCM) in an electrical pump of hypersonic vehicle. The PM-BLDCM is a short-time duty motor with high-power-density. Since thermal equilibrium is not reached for the PM-BLDCM, the temperature distribution is not uniform and there is a risk of local overheating. The winding is a main heat source and its insulation is thermally sensitive, so reducing the winding temperature rise is the key to the improvement of the reliability. In order to reduce the winding temperature rise, an electromagnetic-thermal integrated design optimization method is proposed. The method is based on electromagnetic analysis and thermal transient analysis. The requirements and constraints of electromagnetic and thermal design are considered in this method. The split ratio and the maximum flux density in stator lamination, which are highly relevant to the windings temperature rise, are optimized analytically. The analytical results are verified by finite element analysis (FEA) and experiments. The maximum error between the analytical and the FEA results is 4%. The errors between the analytical and measured windings temperature rise are less than 8%. It can be proved that the method can obtain the optimal design accurately to reduce the winding temperature rise.
Metabolite and Microbiome Interplay in Cancer Immunotherapy
Authors: Johnson Caroline H. , Spilker Mary E. , Goetz Laura , Peterson Scott N. , Siuzdak Gary
Published: October 2016

The role of the host microbiome has come to the forefront as a potential modulator of cancer metabolism and could be a future target for precision medicine. A recent study revealed that in colon cancer, bacteria form polysaccharide matrices called biofilms at a high frequency in the proximal colon. Comprehensive untargeted and stable isotope–assisted metabolomic analysis revealed that the bacteria utilize polyamine metabolites produced from colon adenomas/carcinomas to build these protective biofilms and may contribute to inflammation and proliferation observed in colon cancer. This study highlighted the importance of finding the biological origin of a metabolite and assessing its metabolism and mechanism of action. This led to a better understanding of host and microbial interactions, thereby aiding therapeutic design for cancer. In this review, we will discuss methodologies for identifying the biological origin and roles of metabolites in cancer progression and discuss the interactions of the microbiome and metabolites in immunity and cancer treatment, focusing on the flourishing field of cancer immunotherapy. Cancer Res; 76(21); 6146–52. ©2016 AACR.
History of Gestational Diabetes Mellitus and Risk of Incident Invasive Breast Cancer among Parous Women in the Nurses' Health Study II Prospective Cohort
Authors: Powe Camille E. , Tobias Deirdre K. , Michels Karin B. , Chen Wendy Y. , Eliassen A. Heather , Manson JoAnn E. , Rosner Bernard , Willett Walter C. , Hu Frank B. , Zhang Cuilin , Rich-Edwards Janet W. , Rexrode Kathryn M.
Published: October 2016

Background: Type II diabetes is associated with breast cancer in epidemiologic studies. Pregnancy also modifies breast cancer risk. We hypothesized that women with a history of gestational diabetes mellitus (GDM), which shares pathogenesis and risk factors with type II diabetes, would have greater invasive breast cancer risk than parous women without a history of GDM.

Methods: We conducted a prospective analysis among parous women in the Nurses' Health Study II, with mean age 35 years in 1989. Multivariate Cox proportional hazards models were used to compare risks of incident invasive breast cancer in women with and without a history of GDM.

Results: Among 86,972 women studied, 5,188 women reported a history of GDM and 2,377 developed invasive breast cancer (100 with history of GDM, 2,277 without GDM) over 22 years of prospective follow-up. History of GDM was inversely associated with incident invasive breast cancer [HR, 0.68; 95% confidence interval (CI), 0.55–0.84; P = 0.0004], compared with no history of GDM, after adjustment for body mass index, reproductive history, and other breast cancer risk factors. Findings were similar by menopausal status, although observed person-time was predominantly premenopausal (premenopausal: HR, 0.73; 95% CI, 0.56–0.96; P = 0.03; postmenopausal: HR, 0.63; 95% CI, 0.43–0.92; P = 0.02). Restricting to women undergoing mammography screening modestly attenuated the relationship (HR, 0.74; 95% CI, 0.57–0.96; P = 0.02).

Conclusions: Among a large cohort of U.S. women, history of GDM was not associated with an elevated risk of subsequent invasive breast cancer.

Impact: Our findings highlight the need to further investigate GDM's role in breast cancer development. Cancer Epidemiol Biomarkers Prev; 26(3); 321–7. ©2016 AACR.
Preclinical Therapeutic Synergy of MEK1/2 and CDK4/6 Inhibition in Neuroblastoma
Authors: Hart Lori S. , Rader JulieAnn , Raman Pichai , Batra Vandana , Russell Mike R. , Tsang Matthew , Gagliardi Maria , Chen Lucy , Martinez Daniel , Li Yimei , Wood Andrew , Kim Sunkyu , Parasuraman Sudha , Delach Scott , Cole Kristina A. , Krupa Shiva , Boehm Markus , Peters Malte , Caponigro Giordano , Maris John M.
Published: October 2016

Purpose: Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition.

Experimental Design: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies.

Results: Sensitivity to binimetinib and ribociclib was inversely related (r = −0.58, P = 0.009). MYCN amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs.

Conclusions: Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS–MAPK signaling. Clin Cancer Res; 23(7); 1785–96. ©2016 AACR.
Diagnostic Utility of Systematic Aquaporin-4 Antibodies Determination in the First Event of Immune-Mediated Optic Neuritis
Authors: Carnero Contentti Edgar , De Virgiliis Mariana , Hryb Javier Pablo , Leguizamon Felisa , Celso Julia , Di Pace José Luis , Perassolo Mónica
Published: October 2016

Background: Antibodies against aquaporin-4 (AQP4-ab) have diagnostic and prognostic value. However, little is known to date about their utility in the first event of optic neuritis (ON). Objective: To evaluate the utility of systematic AQP4-ab determination in a retrospective cohort of patients with a first onset of ON. Patients and Methods: All patients (n = 42) were tested for AQP4-ab in the following context: typical ON (TON) and atypical ON (AON). Clinical, radiological and biochemical data were collected; patients with TON vs. AON and AQP4-ab positive vs. negative were compared. Results: The proportion of AQP4-ab seropositive patients was 40% in the TON group vs. 40.9% in the AON group. Visual acuity (VA) at baseline was poor in AON patients (p = 0.02) and these patients were associated with worse VA outcome (p < 0.001) at 6 months compared with TON patients, with a median follow-up of 3.27 ± 1.79 years. Brain MRI with dissemination in space criteria (p < 0.001), spinal cord partial lesions (p < 0.001) and oligoclonal bands (p = 0.02) were associated with the initial stages of TON. VA severity, number of myelitis attacks and ON relapses did not differ significantly between seropositive and seronegative patients. AQP4-ab were detected only in neuromyelitis optica spectrum disorders patients. Conclusion: This study showed a high seropositivity for AQP4-ab in TON patients, suggesting that it could diagnostic utility at the onset of ON.
Complete and Sustained Response with a Doublet Chemotherapy Protocol in an 81-Year-Old Patient with Metastatic Breast Cancer
Authors: Puty Taynah Cascaes , Brito Gabriel S.A. , Dias Mariana S. , Miranda Henrique C. , Chaves Juliana R. , Freitas Heryvelton L. , Carvalho Luís E.W.
Published: October 2016

Metastatic breast cancer (MBC) entails an overall 5-year survival of approximately 25%. The choice of therapy is influenced by expression of the HER2 gene and hormone receptors, by a disease-free interval, and by age. The use of paclitaxel combined with gemcitabine (doublet protocol) has shown efficacy as first-line treatment for MBC in either initial or maintenance therapy when compared to monotherapy with paclitaxel. There is evidence showing that the doublet protocol is a good alternative to maintenance therapy in women under 50 years old. Nevertheless, there is a lack of information concerning individuals above that age. We report the case of an 81-year-old patient presenting with recurrence of MBC, with lung and skin metastases both positive for hormone receptor and negative for HER2. We implemented a therapy based on the combination of gemcitabine and paclitaxel for 12 cycles, when complete response was achieved. Currently, 16 months after this achievement, the patient is receiving maintenance treatment under the doublet protocol, presenting acceptable parameters of toxicity since the beginning of treatment, which shows satisfactory tolerability and management of chemotherapy in an elderly patient. We suggest that the maintenance treatment protocol with a doublet might be an alternative with a satisfactory response in patients with MBC.
Tetrahydrocannabinol:Cannabidiol Oromucosal Spray for Multiple Sclerosis-Related Resistant Spasticity in Daily Practice
Authors: Vermersch Patrick , Trojano Maria
Published: October 2016

Background: Tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex®) is an add-on therapy for moderate-to-severe multiple sclerosis (MS)-related drug-resistant spasticity (MSS). Aim: The MOVE-2 EU study collected data from everyday clinical practice concerning the effectiveness and tolerability of THC:CBD. Methods: This was an observational, prospective, multicentre, non-interventional study. Patients with resistant MSS prescribed add-on THC:CBD oromucosal spray according to approved labelling, were followed for 3 months. After 1 month, only responders (≥20% improvement in spasticity) continued treatment. The main endpoints were the evolution of MSS and associated symptoms, quality of life (QoL) and tolerability. Results: Four hundred and thirty three patients (55% female) were recruited (98% in Italy). The mean duration of MSS was 7.4 years and baclofen was used by 78.1% of participants. Three hundred and forty nine participants continued with THC:CBD oromucosal spray after 1 month, and 281 after 3 months. THC:CBD mean dosage was 6 sprays/day. MSS scores and spasticity-related symptoms (spasms, fatigue, pain, sleep quality and bladder dysfunction) were significantly improved by THC:CBD at 3 months, as were activities of daily living, and QoL (EQ-5D VAS). Adverse events, none of which were severe or serious, were reported by 10.4% of patients. Conclusions: In everyday clinical practice, THC:CBD oromucosal spray provided symptomatic relief of MSS and related troublesome symptoms.
Intrathecal Methotrexate and Craniospinal Radiotherapy Can Be an Effective Treatment of Carcinomatous Meningitis in Patients with Breast Cancer: Case Reports
Authors: Meissner Magdalena , Addeo Alfredo
Published: October 2016

Introduction: Carcinomatous meningitis in breast cancer occurs as a complication in up to 5% of all cases. It is a very devastating diagnosis, with a median patient survival of about 3 months. Treatment is very controversial, and different modalities of treatment have been used but none of them show significant benefit for overall survival. Case Reports: We report 2 cases of carcinomatous meningitis in breast cancer patients. They received a similar treatment of a combination of intrathecal (IT) methotrexate followed by craniospinal radiotherapy. Both patients survived for many years after treatment and are in complete clinical and radiological remission. Conclusion: Meningeal metastasis from breast cancer can be very effectively treated with IT and/or systemic chemotherapy followed by craniospinal radiotherapy. Further studies are needed to determine the effectiveness of this sequential combination of chemotherapy with radiotherapy.
A Case of Primary Small-Cell Carcinoma of the Bladder
Authors: Ono Ashita , Hirasawa Yosuke , Yamashina Mitsumasa , Kaburagi Naoto , Mima Takashi , Sugihara Toru , Hamada Riu , Gondo Tatsuo , Ohori Makoto , Nagao Toshitaka , Ohno Yoshio
Published: October 2016

Primary small-cell carcinoma arising from the bladder (SmCCB) is uncommon. It differs from urothelial carcinoma (UC), the most common type of bladder cancer, with respect to its cell of origin, biology, and prognosis. Biologically, prostatic SmCCB is much more aggressive than UC, and the prognosis for cases with distant metastasis is especially poor. We report here a case of primary SmCCB (cT3bN1M0) treated with radical cystectomy.
Prevalence of Late-Onset Hypogonadism in Men with Localized and Metastatic Renal Cell Carcinoma
Authors: Ralla Bernhard , Magheli Ahmed , Wolff Ingmar , Erber Barbara , Goranova Irena , Friedersdorff Frank , Hinz Stefan , Kempkensteffen Carsten , Miller Kurt , Busch Jonas
Published: October 2016

Background: Cancer-related fatigue is a common symptom in patients with renal cell carcinoma (RCC) and can be similar to the fatigue found in late-onset hypogonadism (LOH). The aim of this study was to investigate the prevalence of LOH in patients with localized RCC (loRCC) and metastatic RCC (mRCC) disease under targeted therapy (TT) and compare the results to findings of epidemiologic studies. Methods: A total of 51 mRCC patients under TT and 33 patients with loRCC undergoing nephrectomy were included. Total testosterone (tT) levels and clinical signs of LOH were recorded (testicular volume, body-mass index (BMI), hip-to-waist ratio, International Index of Erectile Function, IIEF-5, Androgen Deficiency in the Aging Male, ADAM, and quality of life questionnaire-C30). LOH was defined according to current guidelines. Results: Morning tT and calculated free testosterone levels showed no significant difference in patients with mRCC and loRCC (p = 0.551 and p = 0.430). A significant difference was found for clinical signs and symptoms including the ADAM score (p = 0.003), hip-to-waist ratio (p = 0.017) and testicular volume (p < 0.001). IIEF-5 score and BMI were not significantly different. The prevalence of LOH according to the current EAU definition was 13.7 and 15.2% for the mRCC and loRCC cohort, respectively (p = 0.302). Conclusions: LOH was present in a significant proportion of RCC patients. Prevalence rates of LOH were higher in patients with RCC compared to patients without cancer.
Prognostic Benefit of Cardiac Magnetic Resonance Over Transthoracic Echocardiography for the Assessment of Ischemic and Nonischemic Dilated Cardiomyopathy Patients Referred for the Evaluation of Primary Prevention Implantable Cardioverter–Defibrillator Therapy
Authors: Pontone Gianluca , Guaricci Andrea I. , Andreini Daniele , Solbiati Anna , Guglielmo Marco , Mushtaq Saima , Baggiano Andrea , Beltrama Virginia , Fusini Laura , Rota Cristina , Segurini Chiara , Conte Edoardo , Gripari Paola , Dello Russo Antonio , Moltrasio Massimo , Tundo Fabrizio , Lombardi Federico , Muscogiuri Giuseppe , Lorenzoni Valentina , Tondo Claudio , Agostoni Piergiuseppe , Bartorelli Antonio L. , Pepi Mauro
Published: October 2016

Background—

The aim of this study was to determine the prognostic benefit of cardiac magnetic resonance (CMR) over transthoracic echocardiography (TTE) in ischemic cardiomyopathy and nonischemic dilated cardiomyopathy patients evaluated for primary prevention implantable cardioverter–defibrillator therapy.

Methods and Results—

We enrolled 409 consecutive ischemic and dilated cardiomyopathy patients (mean age: 64±12 years; 331 men). All patients underwent TTE and CMR, and left ventricle end-diastolic volume, left ventricle end-systolic volume, and left ventricle ejection fraction (LVEF) were evaluated. In addition, late gadolinium enhancement was also assessed. All patients were followed up for major adverse cardiac events (MACE) defined as a composite end point of long runs of nonsustained ventricular tachycardia, sustained ventricular tachycardia, aborted sudden cardiac death, or sudden cardiac death. The median follow-up was 545 days. CMR showed higher left ventricle end-diastolic volume (mean difference: 43±22.5 mL), higher left ventricle end-systolic volume (mean difference: 34±20.5 mL), and lower LVEF (mean difference: −4.9±10%) as compared to TTE (
P
<0.01). MACE occurred in 103 (25%) patients. Patients experiencing MACE showed higher left ventricle end-diastolic volume, higher left ventricle end-systolic volume, and lower LVEF with both imaging modalities and higher late gadolinium enhancement per-patient prevalence as compared to patients without MACE. At multivariable analysis, CMR-LVEF ≤35% (hazard ratio=2.18 [1.3–3.8]) and the presence of late gadolinium enhancement (hazard ratio=2.2 [1.4–3.6]) were independently associated with MACE (
P
<0.01). A model based on CMR-LVEF ≤35% or CMR-LVEF ≤35% plus late gadolinium enhancement detection showed a higher performance in the prediction of MACE as compared to TTE-LVEF resulting in net reclassification improvement of 0.468 (95% confidence interval, 0.283–0.654;
P
<0.001) and 0.413 (95% confidence interval, 0.23–0.63;
P
<0.001), respectively.

Conclusions—

CMR provides additional prognostic stratification as compared to TTE, which may have direct impact on the indication of implantable cardioverter–defibrillator implantation.
Novel Angiographic Classification of Each Vascular Lesion in Chronic Thromboembolic Pulmonary Hypertension Based on Selective Angiogram and Results of Balloon Pulmonary Angioplasty
Authors: Kawakami Takashi , Ogawa Aiko , Miyaji Katsumasa , Mizoguchi Hiroki , Shimokawahara Hiroto , Naito Takanori , Oka Takashi , Yunoki Kei , Munemasa Mitsuru , Matsubara Hiromi
Published: October 2016

Background—

Balloon pulmonary angioplasty (BPA) is an alternative therapy for patients with chronic thromboembolic pulmonary hypertension who are ineligible for standard therapy, pulmonary endarterectomy. Although there are several classifications of vascular lesions, these classifications are based on the features of the specimen removed during pulmonary endarterectomy. Because organized thrombi are not removed during balloon pulmonary angioplasty, we attempted to establish a new classification of vascular lesions based on pulmonary angiographic images. We evaluated the success and complication rate of BPA in accordance with the location and morphology of thromboembolic lesions.

Methods and Results—

We reviewed 500 consecutive procedures (1936 lesions) of BPA in 97 patients with chronic thromboembolic pulmonary hypertension and investigated the outcomes of BPA based on the lesion distribution and the angiographic characteristics of the thromboembolic lesions, as follows: type A, ring-like stenosis lesion; type B, web lesion; type C, subtotal lesion; type D, total occlusion lesion, and type E, tortuous lesion. The success rate was higher, and the complication rate was lower in ring-like stenosis and web lesions. The total occlusion lesions had the lowest success rate. Tortuous lesions were associated with a high complication rate and should be treated only by operators with extensive experience with BPA.

Conclusions—

We modified the previous angiographic classification and established a new classification for each vascular lesion. We clarified that the outcome and complication rate of the BPA are highly dependent on the lesion characteristics.