bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficiency of Human Epiphyseal Chondrocytes with Differential Replication Numbers for Cellular Therapy Products
Authors: Nasu Michiyo , Takayama Shinichiro , Umezawa Akihiro
Published: November 2016

The cell-based therapy for cartilage or bone requires a large number of cells; serial passages of chondrocytes are, therefore, needed. However, fates of expanded chondrocytes from extra fingers remain unclarified. The chondrocytes from human epiphyses morphologically changed from small polygonal cells to bipolar elongated spindle cells and to large polygonal cells with degeneration at early passages. Gene of type II collagen was expressed in the cells only at a primary culture (Passage 0) and Passage 1 (P1) cells. The nodules by implantation of P0 to P8 cells were composed of cartilage and perichondrium. The cartilage consisted of chondrocytes with round nuclei and type II collagen-positive matrix, and the perichondrium consisted of spindle cells with type I collage-positive matrix. The cartilage and perichondrium developed to bone with marrow cavity through enchondral ossification. Chondrogenesis and osteogenesis by epiphyseal chondrocytes depended on replication number in culture. It is noteworthy to take population doubling level in correlation with pharmaceutical efficacy into consideration when we use chondrocytes for cell-based therapies.
Dispersion of Titanium Oxide Nanoparticles in Aqueous Solution with Anionic Stabilizer via Ultrasonic Wave
Authors: Tsai Wen-Bin , Kao Jui-Yang , Wu Tzong-Ming , Cheng Wen-Tung
Published: November 2016

This paper aims to reveal the effects of odium hexametaphosphate (SHMP) and polyacrylic acid (PAA) on dispersion of TiO2 (P25) nanopowder in de-ionic water through ultrasonic horn. We characterized TiO2 suspension by transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), zeta potential, and surface contact angle instruments. As shown in the results, particularly, it were noticed that (1) the SHMP has better dispersion than PAA due to electronegativity effect, resulting in that the average particle size of the dispersed titanium dioxide in de-ionic water was roughly 92 nm, and (2) the zeta potential of TiO2 suspension with SHMP can be achieved by 54 mV at pH value of 7.7, causing stronger electrostatic repulsion in the suspension solution, compared with PAA.
A Feasibility Study for Measuring Accurate Chest Compression Depth and Rate on Soft Surfaces Using Two Accelerometers and Spectral Analysis
Authors: Ruiz de Gauna Sofía , González-Otero Digna M. , Ruiz Jesus , Gutiérrez J. J. , Russell James K.
Published: November 2016

Background. Cardiopulmonary resuscitation (CPR) feedback devices are being increasingly used. However, current accelerometer-based devices overestimate chest displacement when CPR is performed on soft surfaces, which may lead to insufficient compression depth. Aim. To assess the performance of a new algorithm for measuring compression depth and rate based on two accelerometers in a simulated resuscitation scenario. Materials and Methods. Compressions were provided to a manikin on two mattresses, foam and sprung, with and without a backboard. One accelerometer was placed on the chest and the second at the manikin’s back. Chest displacement and mattress displacement were calculated from the spectral analysis of the corresponding acceleration every 2 seconds and subtracted to compute the actual sternal-spinal displacement. Compression rate was obtained from the chest acceleration. Results. Median unsigned error in depth was 2.1 mm (4.4%). Error was 2.4 mm in the foam and 1.7 mm in the sprung mattress (p<0.001). Error was 3.1/2.0 mm and 1.8/1.6 mm with/without backboard for foam and sprung, respectively (p<0.001). Median error in rate was 0.9 cpm (1.0%), with no significant differences between test conditions. Conclusion. The system provided accurate feedback on chest compression depth and rate on soft surfaces. Our solution compensated mattress displacement, avoiding overestimation of compression depth when CPR is performed on soft surfaces.
Development of a New Hybrid Biodegradable Drug-Eluting Stent for the Treatment of Peripheral Artery Disease
Authors: Lee Jung-Hee , Kim Soon-Joong , Park Se-Il , Ko Young-Guk , Choi Donghoon , Hong Myeong-Ki , Jang Yangsoo
Published: November 2016

This study aimed to develop a new biodegradable stent for peripheral artery disease (PAD) that could provide sufficient radial force to maintain long-term patency and flexibility. All self-expandable hybrid biodegradable stents were designed by using a knitting structure composed of poly-L-lactic acid (PLLA) and nitinol. Four different types of stents were implanted in 20 iliac arteries in 10 mini pigs as follows: a bare-metal stent (BMS) (group 1,n=5), a drug-free hybrid stent (group 2,n=5), a 50% (50 : 100,w/w) paclitaxel (PTX)/poly-lactide-co-glycolic acid (PLGA; fast PTX-releasing form) hybrid stent (group 3,n=5), and a 30% (30 : 100,w/w) PTX/PLGA (slow PTX-releasing form) hybrid stent (group 4,n=5). We performed follow-up angiography and intravascular ultrasonography (IVUS) at 4 and 8 weeks. In a comparison of groups 1, 2, 3, and 4, less diameter stenosis was observed in the angiographic analysis for group 4 at the 4-week follow-up (19.0%  ±  12.7% versus 39.3%  ±  18.1% versus 46.8%  ±  38.0% versus 4.8%  ±  4.2%, resp.;p=0.032). IVUS findings further suggested that the neointima of the patients in group 4 tended to be lesser than those of the others. Our new biodegradable 30% PTX/PLGA (slow-releasing form) stent showed more favorable results for patency than the other stent types.
The Microbial Hypothesis: Contributions of Adenovirus Infection and Metabolic Endotoxaemia to the Pathogenesis of Obesity
Authors: Tambo Amos , Roshan Mohsin H. K. , Pace Nikolai P.
Published: November 2016

The global obesity epidemic, dubbed “globesity” by the World Health Organisation, is a pressing public health issue. The aetiology of obesity is multifactorial incorporating both genetic and environmental factors. Recently, epidemiological studies have observed an association between microbes and obesity. Obesity-promoting microbiome and resultant gut barrier disintegration have been implicated as key factors facilitating metabolic endotoxaemia. This is an influx of bacterial endotoxins into the systemic circulation, believed to underpin obesity pathogenesis. Adipocyte dysfunction and subsequent adipokine secretion characterised by low grade inflammation, were conventionally attributed to persistent hyperlipidaemia. They were thought of as pivotal in perpetuating obesity. It is now debated whether infection and endotoxaemia are also implicated in initiating and perpetuating low grade inflammation. The fact that obesity has a prevalence of over 600 million and serves as a risk factor for chronic diseases including cardiovascular disease and type 2 diabetes mellitus is testament to the importance of exploring the role of microbes in obesity pathobiology. It is on this basis that Massachusetts General Hospital is sponsoring the Faecal Microbiota Transplant for Obesity and Metabolism clinical trial, to study the impact of microbiome composition on weight. The association of microbes with obesity, namely, adenovirus infection and metabolic endotoxaemia, is reviewed.
Ectopic Pregnancy in a Cesarean Section Scar: Successful Management Using Vacuum Aspiration under Laparoscopic Supervision—Mini Review of Current Literature
Authors: Koplay Mustafa , Dogan Nasuh Utku , Sivri Mesut , Erdogan Hasan , Dogan Selen , Celik Cetin
Published: November 2016

A cesarean scar ectopic pregnancy (CSEP) is a fairly uncommon presentation wherein the conceptus is implanted deep in the myometrium and at the exact scar site of the previous cesarean section. There are various CSEP management options that range from medical treatment to surgical interventions such as dilatation and curettage, laparoscopic excision, resection by laparotomy, or, sometimes, a combination of these modalities. Establishing a diagnosis of CSEP can be challenging. Given the relatively rare incidence of CSEP, its management is controversial and current standards of therapy have been derived from data obtained from a limited number of patients. Herein, we present transvaginal ultrasonography (TVUS) imaging findings and management strategies used in a case of CSEP along with the short review of current literature.
Clinical Advancements in the Targeted Therapies against Liver Fibrosis
Authors: Bansal Ruchi , Nagórniewicz Beata , Prakash Jai
Published: November 2016

Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to liver dysfunction, is a growing cause of mortality worldwide. Hepatocellular damage owing to liver injury leads to the release of profibrotic factors from infiltrating inflammatory cells that results in the activation of hepatic stellate cells (HSCs). Upon activation, HSCs undergo characteristic morphological and functional changes and are transformed into proliferative and contractile ECM-producing myofibroblasts. Over recent years, a number of therapeutic strategies have been developed to inhibit hepatocyte apoptosis, inflammatory responses, and HSCs proliferation and activation. Preclinical studies have yielded numerous targets for the development of antifibrotic therapies, some of which have entered clinical trials and showed improved therapeutic efficacy and desirable safety profiles. Furthermore, advancements have been made in the development of noninvasive markers and techniques for the accurate disease assessment and therapy responses. Here, we focus on the clinical developments attained in the field of targeted antifibrotics for the treatment of liver fibrosis, for example, small molecule drugs, antibodies, and targeted drug conjugate. We further briefly highlight different noninvasive diagnostic technologies and will provide an overview about different therapeutic targets, clinical trials, endpoints, and translational efforts that have been made to halt or reverse the progression of liver fibrosis.
Adaptation Measurement of CAD/CAM Dental Crowns with X-Ray Micro-CT: Metrological Chain Standardization and 3D Gap Size Distribution
Authors: Tapie L. , Chiche N. , Boitelle P. , Morenton P. , Attal J.-P. , Schmitt N. , Vennat E.
Published: November 2016

Computer-Aided Design and Manufacturing systems are increasingly used to produce dental prostheses, but the parts produced suffer from a lack of evaluation, especially concerning the internal gap of the final assembly, that is, the space between the prepared tooth and the prosthesis. X-ray micro-Computed Tomography (micro-CT) is a noninvasive imaging technique enabling the internal inspection of the assembly. It has proved to be an efficient tool for measuring the gap. In this study, a critical review of the protocols using micro-CT to quantify the gap is proposed as an introduction to a new protocol aimed at minimizing errors and enabling comparison between CAD/CAM systems. To compare different systems, a standardized protocol is proposed including two reference geometries. Micro-CT is used to acquire the reference geometries. A new 3D method is then proposed and a new indicator is defined (Gap Size Distribution (GSD)). In addition, the usual 2D measurements are described and discussed. The 3D gap measurement method proposed can be used in clinical case geometries and has the considerable advantage of minimizing the data processing steps before performing the measurements.
Control Methods for Roll Instability of Articulated Steering Vehicles
Authors: Li Xuefei , Li Jian , Su Lida , Cao Yue
Published: November 2016

This study examines the control methods for roll instability of articulated steering vehicles (ASVs) by taking wheel loaders as the research object. An eight-degrees-of-freedom nonlinear dynamics model of ASVs was built on the basis of multibody dynamics. Three methods, namely, active braking (the front and rear axles have the same braking torque), active steering, and adjusting the swing bridge (applying a control torque between the rear body and rear axle), were adopted to analyze the effects on the roll stability of ASVs through the dynamic model. The results show that active braking is conducive to the roll stability of ASVs during turning, active steering can improve the roll stability of ASVs during turning and passing over obstacles, and adjusting the swing bridge can improve the roll stability of ASVs by changing the vehicle posture and the position of the gravity center.
Larger Thyroid Volume and Adequate Iodine Nutrition in Chinese Schoolchildren: Local Normative Reference Values Compared with WHO/IGN
Authors: Mo Zhe , Lou Xiaoming , Mao Guangming , Wang Zhifang , Zhu Wenming , Chen Zhijian , Wang Xiaofeng
Published: November 2016

Objective. Thyroid volume measured by ultrasound to define goiter needs reliable local thyroid volume reference from iodine-sufficient populations. The aim of this study is to explore the reference interval for normal thyroid volume in schoolchildren aged 8–10 years from Zhejiang Province, China.Methods. A probability-proportionate-to-size sampling method was applied to select a representative sample of 1213 children aged 8–10 years in Zhejiang Province to detect the thyroid volume, salt iodine, and urine iodine.Results. Median urinary iodine concentration in involved schoolchildren was 178.30 (125.00) μg l−1, with the percentage of samples less than 100 μg l−1as 12.69% and more than 300 μg l−1as 15.25%. Thyroid volume was significantly correlated with age and anthropometric measurements independently of each other. The 97th percentile of thyroid volume in our study was larger generally than the new international reference.Conclusions. The iodine nutritional status in Zhejiang Province was at an adequate level. Despite some limitations in this study, we initially established the reference values for thyroid volume in 8–10-year-old schoolchildren in Zhejiang Province, China, as a local reference to be used for monitoring iodine deficiency disorders.
Assessment of the Number and Phenotype of Macrophages in the Human BMB Samples of CML
Authors: Song Jian-Xin , Dian Zi-Jin , Wen Yan , Mei Fen , Li Rui-Wei , Sa Ya-Lian
Published: November 2016

Macrophages have emerged as a key player in tumor biology. However, their number and phenotype in human bone marrow of biopsy (BMB) samples of chronic myeloid leukemia (CML) and their association with disease progression from an initial chronic phase (CP) to accelerated phase (AP) to advanced blast phase (BP) are still unclear. BMB samples from 127 CML patients and 30 patients with iron-deficiency anemia (IDA) as control group were analyzed by immunohistochemistry. The expression levels of CD68, CD163, and CD206 in BMB samples of CML patients were significantly higher than those in the patients of control group (P<0.01), and we observed that their positive expression was gradually elevated during the transformation of CML-CP to AP to BP (P<0.01). However, the expressions of CD68, CD163, and CD206 in released group were downregulated and contrasted to these in control group; there exists statistical significance (P<0.01). The percentage ratio of CD163 and CD206 to CD68 was pronounced to be increasing from CML-CP to AP to BP (P<0.01). Hence, the higher proportion of CD68+, CD163+ and CD206+ macrophages in BMB samples can be considered a key factor for disease progression of CML patients. Targeting macrophages, especially the M2 phenotype may help in designing therapeutic strategies for CML.
Evidence for Altered Canonical Wnt Signaling in the Trabecular Bone of Elderly Postmenopausal Women with Fragility Femoral Fracture
Authors: Bolamperti Simona , Villa Isabella , Spinello Alice , Manfredini Greta , Mrak Emanuela , Mezzadri Umberto , Ometti Marco , Fraschini Gianfranco , Guidobono Francesca , Rubinacci Alessandro
Published: November 2016

Wnt signaling, a major regulator of bone formation and homeostasis, might be involved in the bone loss of osteoporotic patients and the consequent impaired response to fracture. Therefore we analyzed Wnt-related, osteogenic, and adipogenic genes in bone tissue of elderly postmenopausal women undergoing hip replacement for either femoral fracture or osteoarthritis. Bone specimens derived from the intertrochanteric region of the femurs of 25 women with fracture (F) and 29 with osteoarthritis without fracture (OA) were analyzed. Specific miRNAs were analyzed in bone and in matched blood samples. RUNX2, BGP, and OPG showed lower expression in F than in OA samples, while OSX, OPN, BSP, and RANKL were not different. Inhibitory genes of Wnt pathway were lower in F versus OA.β-Catenin protein levels were higher in F versus OA, whereas its cotranscriptional regulator (Lef1) was lower in F group. miR-204, which targets RUNX2, and miR-130a, which inhibits PPARγ, were lower and higher, respectively, in F versus OA serum samples. The present study showed an inefficient Wnt signal transduction in F group despite higherβ-catenin protein levels, consistent with the expected overall postfracture systemic activation towards osteogenesis. This transcriptional inefficiency could contribute to the osteoporotic bone fragility.
A Perspective of the Diagnosis and Management of Congenital Tuberculosis
Authors: Saramba Manou Irmina , Zhao Dongchi
Published: November 2016

Tuberculosis continues to be a prevalent disease in the world and a global public health issue in many countries. The disease is more complicated in pregnant women because it imperils unborn offspring and results in congenital tuberculosis later if undiagnosed and untreated. Congenital tuberculosis is rare entity and an uncommon disease along with a high mortality rate. Congenital tuberculosis, a severe clinical type of tuberculosis caused byMycobacterium tuberculosis, is a serious and fatal disease if left untreated. Our study emphasizes that it is necessary and mandatory to consider congenital tuberculosis in the differential diagnosis of neonatal or pulmonary infections in infants, essentially in countries where the incidence of tuberculosis is high burden. Mother to neonatal transmission of disease is well known via transplacental transmission through the umbilical vein to the fetus, through the ingestion of infected amniotic fluid. Early detection is challenging, because of the nonspecific nature of the signs and symptoms in tuberculosis during pregnancy and infancy. The degree of clinical suspicion is the essential component of diagnosis. Furthermore, it generally has a difficult treatment and it should not be delayed while waiting for diagnostic test results. Prompt identification and proper treatment regimens for congenital tuberculosis strongly relate with enhanced outcomes.
A Case of Intestinal Obstruction in Pregnancy Diagnosed by MRI and Treated by Intravenous Hyperalimentation
Authors: Daimon Atsushi , Terai Yoshito , Nagayasu Yoko , Okamoto Atsuko , Sano Takumi , Suzuki Yusuke , Kanki Kazuyoshi , Fujita Daisuke , Ohmichi Masahide
Published: November 2016

Intestinal obstruction in pregnancy is rare and is mainly caused by prior pelvic surgery. We herein report a case of intestinal obstruction in a pregnant female with a history of laparoscopic myomectomy, who presented with hypogastric pain, abdominal distension, and vomiting at 26 weeks of gestation. A simple intestinal obstruction was diagnosed by MRI. Conservative treatments, including intravenous hyperalimentation and the placement of an ileus tube, were provided and her abdominal symptoms improved for 14 days. After restarting oral intake, she had no abdominal symptoms. She gave birth to a 2,146 g female infant by caesarean section at 37 weeks and 1 day of gestation. Although an area of cicatrization, which was thought to have been the starting point of the occlusion that caused the intestinal obstruction, was found, the excision of the small intestine was not necessary. Her postoperative course was uneventful. Intestinal obstruction requires a prompt diagnosis and aggressive intervention may be necessary to minimize the morbidity and mortality associated with this rare complication of pregnancy. MRI can be safely used during pregnancy to diagnose intestinal obstruction and intravenous hyperalimentation may improve the maternal and fetal prognoses.
Annealing Ant Colony Optimization with Mutation Operator for Solving TSP
Authors: Mohsen Abdulqader M.
Published: November 2016

Ant Colony Optimization (ACO) has been successfully applied to solve a wide range of combinatorial optimization problems such as minimum spanning tree, traveling salesman problem, and quadratic assignment problem. Basic ACO has drawbacks of trapping into local minimum and low convergence rate. Simulated annealing (SA) and mutation operator have the jumping ability and global convergence; and local search has the ability to speed up the convergence. Therefore, this paper proposed a hybrid ACO algorithm integrating the advantages of ACO, SA, mutation operator, and local search procedure to solve the traveling salesman problem. The core of algorithm is based on the ACO. SA and mutation operator were used to increase the ants population diversity from time to time and the local search was used to exploit the current search area efficiently. The comparative experiments, using 24 TSP instances from TSPLIB, show that the proposed algorithm outperformed some well-known algorithms in the literature in terms of solution quality.
Clinicomycological Characterization of Superficial Mycoses from a Tertiary Care Hospital in Nepal
Authors: Khadka Sundar , Sherchand Jeevan Bahadur , Pokharel Dinesh Binod , Pokhrel Bharat Mani , Mishra Shyam Kumar , Dhital Subhash , Rijal Basista
Published: November 2016

Background. Superficial mycosis is a common fungal infection worldwide, mainly caused by dermatophytes. However, the prevalence of species varies geographically. In addition, fungal treatment is best guided according to species isolated. This study was carried out to determine the clinical as well as mycological profile of superficial mycoses in a tertiary care hospital, Nepal.Methods. This was a prospective case-control laboratory based study conducted over a period of six months from January to June 2014 at Tribhuvan University Teaching Hospital, Nepal. A total of 200 specimens were collected from the patients suspected of superficial mycoses. The specimens were macroscopically as well as microscopically examined. The growth was observed up to 4 weeks.Results.Out of total 200 specimens from the patients suspected of superficial mycoses, tinea corporis 50 (25%) was most common clinical types. KOH mount was positive in 89 (44.5%) and culture was positive in 111 (55.5%).Trichophyton mentagrophytes44 (39.6%) was the most common isolate.Conclusions.The diagnostic yields of KOH mount and culture were found to be complementary to each other. Thus both the methods added with clinical findings are equally important to establish superficial mycosis.
Anticancer Activity, Antioxidant Activity, and Phenolic and Flavonoids Content of Wild Tragopogon porrifolius Plant Extracts
Authors: Al-Rimawi Fuad , Rishmawi Suzi , Ariqat Sharehan H. , Khalid Mahmoud F. , Warad Ismail , Salah Zaidoun
Published: November 2016

Tragopogon porrifolius, commonly referred to as white salsify, is an edible herb used in folk medicine to treat cancer. Samples of Tragopogon porrifolius plant grown wild in Palestine were extracted with different solvents: water, 80% ethanol, and 100% ethanol. The extracts were analyzed for their total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activity (AA). Four different antioxidant assays were used to evaluate AA of the extracts: two measures the reducing power of the extracts (ferric reducing antioxidant power (FRAP) and cupric reducing antioxidant power (CUPRAC)), while two other assays measure the scavenging ability of the extracts (2,2‐azino‐di‐(3‐ethylbenzothialozine‐sulphonic acid (ABTS)) and 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH)). Anticancer activity of the plant extracts were also tested on HOS and KHOS osteosarcoma cell lines. The results revealed that the polarity of the extraction solvent affects the TPC, TFC, and AA. It was found that both TPC and AA are highest for plant extracted with 80% ethanol, followed by water, and finally with 100% ethanol. TFC however was the highest in the following order: 80% ethanol > 100% ethanol > water. The plant extracts showed anticancer activities against KHOS cancer cell lines; they reduced total cell count and induced cell death in a drastic manner.
Mesenchymal Stem Cells as Therapeutics Agents: Quality and Environmental Regulatory Aspects
Authors: Galvez-Martin Patricia , Sabata Roger , Verges Josep , Zugaza José L. , Ruiz Adolfina , Clares Beatriz
Published: November 2016

Mesenchymal stem cells (MSCs) are one of the main stem cells that have been used for advanced therapies and regenerative medicine. To carry out the translational clinical application of MSCs, their manufacturing and administration in human must be controlled; therefore they should be considered as medicine: stem cell‐based medicinal products (SCMPs). The development of MSCs as SCMPs represents complicated therapeutics due to their extreme complex nature and rigorous regulatory oversights. The manufacturing process of MSCs needs to be addressed in clean environments in compliance with requirements of Good Manufacturing Practice (GMP). Facilities should maintain these GMP conditions according to international and national medicinal regulatory frameworks that introduce a number of specifications in order to produce MSCs as safe SCMPs. One of these important and complex requirements is the environmental monitoring. Although a number of environmental requirements are clearly defined, some others are provided as recommendations. In this review we aim to outline the current issues with regard to international guidelines which impact environmental monitoring in cleanrooms and clean areas for the manufacturing of MSCs.
Nivolumab in the Treatment of Hodgkin Lymphoma
Authors: Ansell Stephen M.
Published: November 2016

Despite an extensive immune infiltrate that is recruited to the tumor by malignant Reed–Sternberg cells in Hodgkin lymphoma, the antitumor immune response is ineffective and unable to eradicate the malignant cells. The ineffective immune response is in part due to PD-1 signaling that renders intratumoral immune cells anergic. Reed–Sternberg cells have been shown to upregulate expression of the PD-1 ligands, PD-L1 and PD-L2, due to either genetic alterations at chromosome 9p24.1 or Epstein–Barr virus infection, and these ligands suppress the function of PD-1+ intratumoral T cells. Blockade of PD-1 signaling has proven to be a highly successful therapeutic approach, and the use of the anti-PD-1 mAb nivolumab recently received accelerated approval by the FDA for patients with classical Hodgkin lymphoma that has relapsed or progressed after autologous stem cell transplant and posttransplantation brentuximab vedotin. Initial clinical trials using nivolumab in this patient population resulted in high response rates that were durable. Adverse events associated with nivolumab included immune-mediated adverse reactions and infusion reactions, but these were well tolerated, allowing for continued nivolumab administration. Clinical trials are now in progress to test the use of nivolumab in combination with standard chemotherapy or with novel agents with a goal of improving the outcome of patients with Hodgkin lymphoma. Clin Cancer Res; 23(7); 1623–6. ©2016 AACR.
The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target
Authors: Cardenas Mariano G. , Oswald Erin , Yu Wenbo , Xue Fengtian , MacKerell Alexander D. , Melnick Ari M.
Published: November 2016

BCL6 was initially discovered as an oncogene in B-cell lymphomas, where it drives the malignant phenotype by repressing proliferation and DNA damage checkpoints and blocking B-cell terminal differentiation. BCL6 mediates its effects by binding to hundreds of target genes and then repressing these genes by recruiting several different chromatin-modifying corepressor complexes. Structural characterization of BCL6–corepressor complexes suggested that BCL6 might be a druggable target. Accordingly, a number of compounds have been designed to bind to BCL6 and block corepressor recruitment. These compounds, based on peptide or small-molecule scaffolds, can potently block BCL6 repression of target genes and kill lymphoma cells. In the case of diffuse large B-cell lymphomas (DLBCL), BCL6 inhibitors are equally effective in suppressing both the germinal center B-cell (GCB)- and the more aggressive activated B-cell (ABC)-DLBCL subtypes, both of which require BCL6 to maintain their survival. In addition, BCL6 is implicated in an expanding scope of hematologic and solid tumors. These include, but are not limited to, B-acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non–small cell lung cancer. BCL6 inhibitors have been shown to exert potent effects against these tumor types. Moreover, mechanism-based combinations of BCL6 inhibitors with other agents have yielded synergistic and often quite dramatic activity. Hence, there is a compelling case to accelerate the development of BCL6-targeted therapies for translation to the clinical setting. Clin Cancer Res; 23(4); 885–93. ©2016 AACR.
Cytoplasmic Cyclin E Predicts Recurrence in Patients with Breast Cancer
Authors: Hunt Kelly K. , Karakas Cansu , Ha Min Jin , Biernacka Anna , Yi Min , Sahin Aysegul A. , Adjapong Opoku , Hortobagyi Gabriel N. , Bondy Melissa L. , Thompson Patricia A. , Cheung Kwok Leung , Ellis Ian O. , Bacus Sarah , Symmans W. Fraser , Do Kim-Anh , Keyomarsi Khandan
Published: November 2016

Purpose: Low molecular weight cyclin E (LMW-E) detected by Western blot analysis predicts for reduced breast cancer survival; however, it is impractical for clinical use. LMW-E lacks a nuclear localization signal that leads to accumulation in the cytoplasm that can be detected by IHC. We tested the hypothesis that cytoplasmic staining of cyclin E can be used as a predictor of poor outcome in different subtypes of breast cancer using patient cohorts with distinct clinical and pathologic features.

Experimental Design: We evaluated the subcellular localization of cyclin E in breast cancer specimens from 2,494 patients from 4 different cohorts: 303 from a prospective study and 2,191 from retrospective cohorts [NCI, MD Anderson Cancer Center (MDA), and the United Kingdom (UK)]. Median follow-up times were 8.0, 10.1, 13.5, and 5.7 years, respectively.

Results: Subcellular localization of cyclin E on IHC was associated with full-length (nuclear) and low molecular weight isoforms (cytoplasmic) of cyclin E on Western blot analysis. In multivariable analysis, cytoplasmic cyclin E staining was associated with the greatest risk of recurrence compared with other prognostic factors across all subtypes in three (NCI, MDA, and UK) of the cohorts. In the MDA cohort, cytoplasmic cyclin E staining outperformed Ki67 and all other variables as prognostic factors.

Conclusions: Cytoplasmic cyclin E identifies patients with the highest likelihood of recurrence consistently across different patient cohorts and subtypes. These patients may benefit from alternative therapies targeting the oncogenic isoforms of cyclin E. Clin Cancer Res; 23(12); 2991–3002. ©2016 AACR.
Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities
Authors: Slyepchenko Anastasiya , Maes Michael , Jacka Felice N. , Köhler Cristiano A. , Barichello Tatiana , McIntyre Roger S. , Berk Michael , Grande Iria , Foster Jane A. , Vieta Eduard , Carvalho André F.
Published: November 2016

Background: Persistent low-grade immune-inflammatory processes, oxidative and nitrosative stress (O&NS), and hypothalamic-pituitary-adrenal axis activation are integral to the pathophysiology of major depressive disorder (MDD). The microbiome, intestinal compositional changes, and resultant bacterial translocation add a new element to the bidirectional interactions of the gut-brain axis; new evidence implicates these pathways in the patho-aetiology of MDD. In addition, abnormalities in the gut-brain axis are associated with several chronic non-communicable disorders, which frequently co-occur in individuals with MDD, including but not limited to irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), obesity, and type 2 diabetes mellitus (T2DM). Methods: We searched the PubMed/MEDLINE database up until May 1, 2016 for studies which investigated intestinal dysbiosis and bacterial translocation (the ‘leaky gut') in the pathophysiology of MDD and co-occurring somatic comorbidities with an emphasis on IBS, CFS, obesity, and T2DM. Results: The composition of the gut microbiota is influenced by several genetic and environmental factors (e.g. diet). Several lines of evidence indicate that gut-microbiota-diet interactions play a significant pathophysiological role in MDD and related medical comorbidities. Gut dysbiosis and the leaky gut may influence several pathways implicated in the biology of MDD, including but not limited to immune activation, O&NS, and neuroplasticity cascades. However, methodological inconsistencies and limitations limit comparisons across studies. Conclusions: Intestinal dysbiosis and the leaky gut may constitute a key pathophysiological link between MDD and its medical comorbidities. This emerging literature opens relevant preventative and therapeutic perspectives.
Precuneal Thickness and Depression in Parkinson Disease
Authors: Zanigni Stefano , Sambati Luisa , Evangelisti Stefania , Testa Claudia , Calandra-Buonaura Giovanna , Manners David Neil , Terlizzi Rossana , Poda Roberto , Oppi Federico , Lodi Raffaele , Cortelli Pietro , Tonon Caterina ,   on behalf of the BoProPark Study Group
Published: November 2016

Background: Depression-related gray matter changes in Parkinson disease (PD) patients have been reported, although studies investigating cortical thickness in early-stage disease are lacking. Objective: We aimed to evaluate cortical changes related to depression in early-stage PD patients with an extensive neuropsychological evaluation. Methods: 17 PD patients and 22 healthy controls underwent a 1.5-T brain MR protocol, and voxel-wise differences in cortical thickness among patients with (n = 6) and without (n = 11) depression and controls were evaluated using FreeSurfer software. Results: Cortical thickness was increased in the precuneus bilaterally in PD patients with depression compared to the other groups (number of vertices >100; p < 0.001, uncorrected) with a direct correlation with the Beck Depression Inventory score (p < 0.001, uncorrected). Conclusion: Precuneal cortical thickening is evident in PD patients with mild-moderate depression even in the early stages of the disease. This finding may reflect the early involvement of this region in the development of PD-related depression.
Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency
Authors: Grimberg Adda , DiVall Sara A. , Polychronakos Constantin , Allen David B. , Cohen Laurie E. , Quintos Jose Bernardo , Rossi Wilma C. , Feudtner Chris , Murad Mohammad Hassan ,   on behalf of the Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society
Published: November 2016

Background/Aims: On behalf of the Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society, we sought to update the guidelines published in 2003 on the use of growth hormone (GH). Because idiopathic short stature (ISS) remains a controversial indication, and diagnostic challenges often blur the distinction between ISS, GH deficiency (GHD), and primary IGF-I deficiency (PIGFD), we focused on these three diagnoses, thereby adding recombinant IGF-I therapy to the GH guidelines for the first time. Methods: This guideline was developed following the GRADE approach (Grading of Recommendations, Assessment, Development, and Evaluation). Results: This guideline provides recommendations for the clinical management of children and adolescents with growth failure from GHD, ISS, or PIGFD using the best available evidence. Conclusion: The taskforce suggests that the recommendations be applied in clinical practice with consideration of the evolving literature and the risks and benefits to each individual patient. In many instances, careful review highlights areas that need further research.
Drug-Induced Liver Injury Associated with Complementary and Alternative Medicines
Authors: Takahashi Koji , Kanda Tatsuo , Yasui Shin , Haga Yuki , Kumagai Junichiro , Sasaki Reina , Wu Shuang , Nakamoto Shingo , Nakamura Masato , Arai Makoto , Yokosuka Osamu
Published: November 2016

A 24-year-old man was admitted due to acute hepatitis with unknown etiology. After his condition and laboratory data gradually improved with conservative therapy, he was discharged 1 month later. Two months after his discharge, however, liver dysfunction reappeared. After his mother accidentally revealed that he took complementary and alternative medicine, discontinuation of the therapy caused his condition to improve. Finally, he was diagnosed with a recurrent drug-induced liver injury associated with Japanese complementary and alternative medicine. It is important to take the medical history in detail and consider complementary and alternative medicine as a cause of liver disease.
Evaluation of Isolation Methods for Circulating Tumor Cells (CTCs)
Authors: Kallergi Galatea , Politaki Eleni , Alkahtani Saad , Stournaras Christos , Georgoulias Vassilis
Published: November 2016

Background: Detection of CTCs is a poor prognostic factor for many cancer types; however, their very low frequency represents an obstacle for their detection. The objective of the current study was to compare the performance of commonly used methods for CTCs isolation. Methods: The evaluated methods using spiking experiments of MCF7, SKBR3 and MDA MB-231 breast cancer cell lines were (i) ficoll density gradient separation (DGS), (ii) red blood cell lysis (Erythrolysis) isolation, (iii) positive immunomagnetic selection (EpCAM Dynal beads), (iv) two different negative immunomagnetic separation systems (Dynal vs Miltenyi CD45 beads) as well as (v) the Cell Search platform and (vi) the ISET system. Results: The recovery rates of Erythrolysis and DGS were 39% and 24%, respectively. Magnetic isolations are ranked from the worse to the best recovery rate as follows:, Myltenyi-anti-CD45 microbeads (24%); Dynal-anti-EpCAM beads (75%); Dynabeads-anti-CD45 (97%). CTCs isolation from blood samples using the CellSearch and ISET systems revealed that the recovery rate for Cell Search and ISET was 52% and 95%, respectively. Conclusions: Dynal-anti-CD45 beads have the best recovery rate compared to other magnetic methods. Furthermore the recovery rate of ISET was higher compared to Cell Search, especially for the more aggressive MDA-MB 231 cell line.
Renal Denervation Attenuates Multi-Organ Fibrosis and Improves Vascular Remodeling in Rats with Transverse Aortic Constriction Induced Cardiomyopathy
Authors: Wang Kai , Lu Dasheng , Zhang Bin , Wang Shengchan , Liu Qian , Zhang Qi , Geng Jie , Shan Qijun
Published: November 2016

Background/Aims: To investigate the effects of renal denervation (RDN) on multi-organ fibrosis and vascular remodeling in cardiomyopathy. Methods: Thirty-six male Sprague-Dawley rats underwent transverse aortic constriction (TAC). Five weeks later, 28 surviving TAC rats were randomly assigned to three groups: (1) RDN, (2) Sham, (3) Carvedilol. Six male Sham TAC rats served as the Control. Ten weeks after TAC, samples were collected. Results: TAC rats showed an increased diastolic interventricular septal thickness at week 5. At 10 weeks, Masson staining showed that left ventricular and renal glomerular fibrosis were significantly reduced in RDN compared with Sham group. In comparison to Sham group, hepatic perivascular fibrosis was attenuated in both RDN and Carvedilol group, so were the media thickness and the media/lumen of aorta. The plasma levels of B-type natriuretic peptide (BNP), Cystatin C (Cys-C), Alanine Transaminase, angiotensin II (Ang II), transforming growth factor beta 1 (TGF-β1), and malondialdehyde increased, and total superoxide dismutase (T-SOD) decreased in Sham but not in RDN group, compared with Control group. Both RDN and Carvedilol reduced the Cys-C and TGF-β1 levels, and restored T-SOD concentration, compared with Sham group. While only RDN lowered the plasma levels of BNP and Ang II. No significant effects of RDN on blood pressure (BP) and heart rate (HR) were oberved. Conclusions: RDN can attenuate multi-organ fibrosis and improve vascular remodeling independent of BP and HR change in TAC-induced cardiomyopathy. These effects of RDN may be associated with the direct inhibition of renin-angiotensin-aldosterone system and oxidative stress.
Contribution of Common Variants in GABRG2, RELN and NRG3 and Interaction Networks to the Risk of Hirschsprung Disease
Authors: Wang Yang , Wang Jun , Zhou Ying , Wei Zhiyun , Xiao Yongtao , Zhou Kejun , Wen Jie , Yan Junkai , Cai Wei
Published: November 2016

Background: Hirschsprung disease (HSCR) is a complex and heterogeneous disorder, characterized by a deficit in enteric nervous system. Genome-wide studies implied GABRG2, RELN and NRG3 might be involved in HSCR etiology. Here, we aimed to assess genetic variants in GABRG2, RELN and NRG3 that may confer susceptibility to HSCR and explore genetic interaction networks in HSCR. Methods: Using a strategy that combined case-control study and gene-gene interaction analysis with the MassArray system, we evaluated 24 polymorphisms within GABRG2, RELN and NRG3 in 104 HSCR cases and 151 normal controls of Han Chinese origin. Results: We observed that seven polymorphisms showed statistically significant differences between HSCR subjects and normal controls. For each of the three genes, the haplotypes which combined eight markers were the most significant. Moreover, we recruited SNPsyn, GO enrichment and MDR analyses to interrogate the interactions among GABRG2, RELN, NRG3 and our previous identified PTCH1 gene. Significant interaction networks were found among GABRG2, RELN, and PTCH1. Conclusion: We provide a first indication that common variants of GABRG2, RELN and NRG3 and the GABRG2-RELN-PTCH1 interaction networks might confer altered susceptibility to HSCR in the Han Chinese population, suggesting a potential mechanism underlying HSCR pathogenesis.
Inhibition of the JAK2/STAT3/SOSC1 Signaling Pathway Improves Secretion Function of Vascular Endothelial Cells in a Rat Model of Pregnancy-Induced Hypertension
Authors: Luo Jian-Ying , Fu Dan , Wu Ya-Qin , Gao Ying
Published: November 2016

Background/Aims: The present study aimed to investigate the effects of the JAK2/STAT3/SOSC1 signaling pathway on the secretion function of vascular endothelial cells (VECs) in a rat model of pregnancy-induced hypertension (PIH). Methods: A PIH rat model was established. Forty-eight pregnant Sprague-Dawley female rats were selected and assigned into four groups: the normal group (normal non-pregnant rats), the non-PIH group (pregnant rats without PIH), the PIH group (pregnant rats with PIH) and the AG490 group (pregnant rats with PIH treated with AG490). Systolic blood pressure (SBP) and urinary protein (UP) were measured. The expressions of JAK2/STAT3/SOSC1 signaling pathway-related proteins in placenta tissues were detect by Western blotting. Radioimmunoassay was applied to detect serum levels of nitric oxide (NO), super oxide dismutase (SOD), placental growth factor (PGF), thromboxane B2 (TXB2) and endothelin (ET). Enzyme-linked immunosorbent assay (ELISA) was used to determine serum levels of interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α). Results: Compared with the normal and non-PIH groups, the PIH and AG490 groups had higher SBP and UP levels at 17th and 25th day of pregnancy. The expressions of p/t-JAK2, p/t-STAT3 and SOSC1 in the PIH and AG490 groups were higher than those in the non-PIH group, while the expressions of p/t-JAK2, p/t-STAT3 and SOSC1 in the AG490 group were lower than those in the PIH group. Compared with the non-PIH group, serum levels of ET, TXB2, IL-6 and TNF-α were increased in the PIH and AG490 groups, while serum levels of NO, SOD, 6-keto-PGF1a and IL-10 levels were reduced. Furthermore, the AG490 had lower serum levels of ET, TXB2, IL-6 and TNF-α and higher serum levels of NO, SOD, 6-keto-PGF1a and IL-10 than those in the PIH group. Conclusion: Our study provides evidence that inhibition of the JAK2/STAT3/SOSC1 signaling pathway could improve the secretion function of VECs in PIH rats.
Contribution of p38 MAPK to the Ameliorating Effect of Enriched Environment on the Cognitive Deficits Induced by Chronic Cerebral Hypoperfusion
Authors: Li Yu-Wang , Li Qing-Yun , Wang Jin-Hua , Xu Xiao-Lin
Published: November 2016

Background/Aims: An enriched environment (EE) ameliorates learning and memory impairments induced by chronic cerebral hypoperfusion, and the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway exerts both beneficial and deleterious effects on the nervous system during the progression of ischemia. Methods: The present study investigated whether p38 MAPK participates in the process by which EE exposure ameliorates the cognitive deficits induced by chronic cerebral hypoperfusion. Results: EE exposure significantly enhanced the cognitive performance of vascular dementia (VD) model rats, and p38 MAPK protein decreased in parallel with cognitive improvements. Inhibition of p38 MAPK function by its selective inhibitor SB203580 improved the cognition index of VD rats and upregulated p38 MAPK expression with p38 MAPK antisense oligodeoxynucleotides. This impaired cognition in VD rats could not be rescued by EE exposure. Conclusion: p38 MAPK participates in the process by which EE exposure ameliorates cognitive deficits induced by chronic cerebral hypoperfusion.
CD44 and CD44v6 are Correlated with Gastric Cancer Progression and Poor Patient Prognosis: Evidence from 42 Studies
Authors: Fang Min , Wu Junrong , Lai Xin , Ai Huaying , Tao Yifeng , Zhu Bo , Huang Lingsha
Published: November 2016

Background/Aims: The prognostic power of the levels of total CD44 and its isoform CD44v6 for patients with gastric cancer (GC) remains controversial. Therefore, our study aims to generalize the clinicopathological and prognostic significance of these two proteins in GC. Methods: A literature search of the PubMed, Web of Science and Embase databases was conducted to identify eligible studies. The odds ratio (OR) with a 95% confidence interval (CI) was used to assess the effects. Results: In all, 42 studies including 6,229 patients were included in this analysis. Total CD44 was mentioned in 21 papers, and the results showed that CD44 was positively correlated with the T category, the N category, distant metastasis, lymphatic invasion and TNM stage. Moreover, patients with CD44 overexpression had a lower 5-year overall survival (OS) rate (OR = 3.35, 95%CI = 1.83-6.13). CD44v6 was mentioned in 24 studies, with results that were similar to those for total CD44. However, total CD44 or CD44v6 expression was not correlated with tumor size and histological grade. Conclusion: High CD44 or CD44v6 expression levels were correlated with cancer progression and poor prognosis in patients with GC. Both CD44 and CD44v6 may be useful diagnostic or prognostic biomarkers for GC.