bluuebunny/crossref_metadata_2025 huggingface dataset:
Kynurenic Acid Content in Selected Culinary Herbs and Spices
Authors: Turski Michal P. , Turska Monika , Kocki Tomasz , Turski Waldemar A. , Paluszkiewicz Piotr
Published: March 2015

Previous studies demonstrated that kynurenic acid (KYNA) is present in various types of food in varying concentrations. Therefore, the aim of the study was to check whether KYNA is present in culinary herbs and spices. Achieved results indicate that KYNA is present in all 19 selected culinary herbs and spices. The highest concentration of KYNA was found in basil and thyme, 14.08 and 8.87 μg/g, respectively, while the lowest content of KYNA was found in cumin and black pepper, 0.64 and 0.10 μg/g, respectively. This is the first report on the concentration of KYNA in culinary herbs and spices. The need for more detailed investigation of dietary supplementation with culinary herbs and spices containing KYNA is suggested.
Polysulfated Trehalose as a Novel Anticoagulant Agent with Dual Mode of Action
Authors: Rashid Qudsia , Abid Mohammad , Gupta Neha , Tyagi Tarun , Ashraf Mohammad Z. , Jairajpuri Mohamad Aman
Published: March 2015

Physiological hemostatic balance is a coordinated outcome of counteracting coagulation and fibrinolytic systems. An imbalance of procoagulant and anticoagulant factors may result in life threatening thromboembolism. Presently, anticoagulant administration is the first line of therapy for the treatment of these conditions and several anticoagulants have been approved, including various forms of heparin. However, the polyanionic nature and multispecificity of heparin pose several complications. Generally, the polysulfated compounds with antithrombotic potential are thought to have feasible synthetic procedures with much less bleeding, thus having favourable safety profiles. Here we report the synthesis of a novel compound, trehalose octasulfate and the assessment of its anticoagulation potential. Molecular docking of trehalose and trehalose octasulfate with antithrombin showed a specificity switch in binding affinity on sulfation, where trehalose octasulfate interacts with critical residues of AT that are either directly involved in heparin binding or in the conformational rearrangement of AT on heparin binding. Anin vitroanalysis of trehalose octasulfate demonstrated prolonged clotting time. Lead compound when intravenously injected in occlusion induced thrombotic rats showed remarkable reduction in the size and weight of the clot at a low dose. Delay in coagulation time was observed by analysing blood plasma isolated from rats preinjected with trehalose octasulfate. A decrease in Adenosine 5′-Diphosphate (ADP) induced platelet aggregation indicated a probable dual anticoagulant and antiplatelet mechanism of action. To summarize, this study presents trehalose octasulfate as a novel, effective, dual acting antithrombotic agent.
A Multiple-Kernel Relevance Vector Machine with Nonlinear Decreasing Inertia Weight PSO for State Prediction of Bearing
Authors: Fei Sheng-wei , He Yong
Published: March 2015

The scientific and accurate prediction for state of bearing is the key to ensure its safe operation. A multiple-kernel relevance vector machine (MkRVM) including RBF kernel and polynomial kernel is proposed for state prediction of bearing in this study; the proportions of RBF kernel and polynomial kernel are determined by a controlled parameter. As the selection of the parameters of the kernel functions and the controlled parameter has a certain influence on the prediction results of MkRVM, nonlinear decreasing inertia weight PSO (NDIWPSO) is used to select its kernel parameters and controlled parameter. The RBF kernel RVM model with NDIWPSO (NDIWPSO-RBFRVM) and the polynomial kernel RVM model with NDIWPSO (NDIWPSO-PolyRVM) are used, respectively, to compare with the multiple-kernel RVM model with NDIWPSO (NDIWPSO-MkRVM). The experimental results indicate that NDIWPSO-MkRVM is more suitable for the state prediction of bearing than NDIWPSO-RBFRVM and NDIWPSO-PolyRVM.
Procalcitonin Levels in Gram-Positive, Gram-Negative, and Fungal Bloodstream Infections
Authors: Leli Christian , Ferranti Marta , Moretti Amedeo , Al Dhahab Zainab Salim , Cenci Elio , Mencacci Antonella
Published: March 2015

Procalcitonin (PCT) can discriminate bacterial from viral systemic infections and true bacteremia from contaminated blood cultures. The aim of this study was to evaluate PCT diagnostic accuracy in discriminating Gram-positive, Gram-negative, and fungal bloodstream infections. A total of 1,949 samples from patients with suspected bloodstream infections were included in the study. Median PCT value in Gram-negative (13.8 ng/mL, interquartile range (IQR) 3.4–44.1) bacteremias was significantly higher than in Gram-positive (2.1 ng/mL, IQR 0.6–7.6) or fungal (0.5 ng/mL, IQR 0.4–1) infections (P<0.0001). Receiver operating characteristic analysis showed an area under the curve (AUC) for PCT of 0.765 (95% CI 0.725–0.805,P<0.0001) in discriminating Gram-negatives from Gram-positives at the best cut-off value of 10.8 ng/mL and an AUC of 0.944 (95% CI 0.919–0.969,P<0.0001) in discriminating Gram-negatives from fungi at the best cut-off of 1.6 ng/mL. Additional results showed a significant difference in median PCT values between Enterobacteriaceae and nonfermentative Gram-negative bacteria (17.1 ng/mL, IQR 5.9–48.5 versus 3.5 ng/mL, IQR 0.8–21.5;P<0.0001). This study suggests that PCT may be of value to distinguish Gram-negative from Gram-positive and fungal bloodstream infections. Nevertheless, its utility to predict different microorganisms needs to be assessed in further studies.
Retroperitoneal Lymphangioma in an Adult: A Case Report of a Rare Clinical Entity
Authors: Tripathi Mayank , Parshad Sanjeev , Karwasra Rajender Kumar , Gupta Ashish , Srivastva Saket , Sarwal Ankush
Published: March 2015

Background. Retroperitoneal lymphangioma is a rare, benign mesodermal tumor arising from the retroperitoneal lymphatics which usually presents in infancy and it is worthy to report a case when it has presented in an adult. After a thorough literature search in English we concluded that less than 200 cases of adult retroperitoneal lymphangioma have been reported so far. Apart from being a rare entity it also presents as a diagnostic dilemma and final diagnosis is often made on surgical exploration.Case Presentation. We report a case of retroperitoneal lymphangioma in a 55-year-old male who presented with abdominal distension and dull aching abdominal pain.Conclusion. Retroperitoneal lymphangiomas are rare tumors of infancy but may also present in adults where they are a diagnostic challenge. Differentiating cystic lymphangiomas from other cystic growths by imaging studies alone are often inconclusive and surgery is frequently required for definitive diagnosis and to ameliorate the symptoms.
Surgical Outcome of Medial Rectus Resection in Recurrent Exotropia: A Novel Surgical Formula
Authors: Luk Abbie Sheung-Wan , Yam Jason Cheuk-Sing , Lau Henry Hing-Wai , Yip Wilson Wai-Kuen , Young Alvin Lerrmann
Published: March 2015

Purpose. To evaluate the surgical outcomes of unilateral or bilateral medial rectus (MR) muscle resection for recurrent exotropia after bilateral lateral rectus (BLR) muscle recession based on a novel surgical formula.Methods. Forty-one consecutive patients with unilateral or bilateral MR muscle resection for recurrent exotropia after BLR muscle recession were included in this retrospective study. All surgeries were performed according to the formula: 1.0 mm MR muscle resection for every 5 prism dioptres (PD) of exotropia, with an addition of 0.5 mm to each MR muscle operated on.Results. The mean recurrent exotropia distant deviation was 28 PD ± 11.2 (range 14 to 55 PD). Overall at postoperative 1 month, 36 (88%) achieved successful outcomes, 4 (10%) had undercorrection, and 1 (2%) had overcorrection. At postoperative 6 months, 29 (71%) achieved successful outcomes, 12 (29%) had undercorrection, and none had overcorrection. Subgroup analysis showed no statistically significant difference in success rates between unilateral and bilateral MR groups.Conclusion. Unilateral or bilateral MR muscle resection using our surgical formula is a safe and effective method for calculating the amount of MR resection in moderate to large angle recurrent exotropia, with a low overcorrection rate.
Ebola Virus Disease 2013-2014 Outbreak in West Africa: An Analysis of the Epidemic Spread and Response
Authors: Cenciarelli Orlando , Pietropaoli Stefano , Malizia Andrea , Carestia Mariachiara , D’Amico Fabrizio , Sassolini Alessandro , Di Giovanni Daniele , Rea Silvia , Gabbarini Valentina , Tamburrini Annalaura , Palombi Leonardo , Bellecci Carlo , Gaudio Pasquale
Published: March 2015

The Ebola virus epidemic burst in West Africa in late 2013, started in Guinea, reached in a few months an alarming diffusion, actually involving several countries (Liberia, Sierra Leone, Nigeria, Senegal, and Mali). Guinea and Liberia, the first nations affected by the outbreak, have put in place measures to contain the spread, supported by international organizations; then they were followed by the other nations affected. In the present EVD outbreak, the geographical spread of the virus has followed a new route: the achievement of large urban areas at an early stage of the epidemic has led to an unprecedented diffusion, featuring the largest outbreak of EVD of all time. This has caused significant concerns all over the world: the potential reaching of far countries from endemic areas, mainly through fast transports, induced several countries to issue information documents and health supervision for individuals going to or coming from the areas at risk. In this paper the geographical spread of the epidemic was analyzed, assessing the sequential appearance of cases by geographic area, considering the increase in cases and mortality according to affected nations. The measures implemented by each government and international organizations to contain the outbreak, and their effectiveness, were also evaluated.
Modulation of MicroRNAs by Phytochemicals in Cancer: Underlying Mechanisms and Translational Significance
Authors: Srivastava Sanjeev K. , Arora Sumit , Averett Courey , Singh Seema , Singh Ajay P.
Published: March 2015

MicroRNAs (miRNAs) are small, endogenous noncoding RNAs that regulate a variety of biological processes such as differentiation, development, and survival. Recent studies suggest that miRNAs are dysregulated in cancer and play critical roles in cancer initiation, progression, and chemoresistance. Therefore, exploitation of miRNAs as targets for cancer prevention and therapy could be a promising approach. Extensive evidence suggests that many naturally occurring phytochemicals regulate the expression of numerous miRNAs involved in the pathobiology of cancer. Therefore, an understanding of the regulation of miRNAs by phytochemicals in cancer, their underlying molecular mechanisms, and functional consequences on tumor pathophysiology may be useful in formulating novel strategies to combat this devastating disease. These aspects are discussed in this review paper with an objective of highlighting the significance of these observations from the translational standpoint.
Cost-Effectiveness of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation with Edoxaban Compared to Warfarin in Germany
Authors: Krejczy Martin , Harenberg Job , Wehling Martin , Obermann Konrad , Lip Gregory Y. H.
Published: March 2015

We compared the cost-utility analysis for edoxaban at both doses with that of dabigatran at both doses, rivaroxaban, and apixaban (non vitamin K antagonist oral anticoagulants, NOAC) in a German population. Data of clinical outcome events were taken from edoxaban’s ENGAGE-AF, dabigatran’s RE-LY, rivaroxaban’s ROCKET, and apixaban’s ARISTOTLE trials. The base-case analyses of a 65-year-old person with a CHADS2 score >1 gained 0.17 and 0.21 quality-adjusted life years over warfarin for 30 mg od and 60 mg od edoxaban, respectively. The incremental cost-effectiveness ratio was 50.000 and 68.000 euro per quality-adjusted life years for the higher and lower dose of edoxaban (Monte Carlo simulation). These findings were also similar to those for apixaban and more cost-effective than the other NOAC regimens. The current market costs for direct oral anticoagulants are high in relation to the quality of life gained from a German public health care insurance perspective. The willingness-to-pay threshold was lowest for 60 mg edoxaban compared to all direct oral anticoagulants and for 30 mg edoxaban compared to dabigatran and rivaroxaban.
Growth Modeling of the Maternal Cytokine Milieu throughout Normal Pregnancy: Macrophage-Derived Chemokine Decreases as Inflammation/Counterregulation Increases
Authors: Holtan Shernan G. , Chen Yiyi , Kaimal Rajani , Creedon Douglas J. , Enninga Elizabeth Ann L. , Nevala Wendy K. , Markovic Svetomir N.
Published: March 2015

Several recent studies have shown differences in the maternal immune milieu at different phases of pregnancy, but most studies have been cross-sectional or of relatively few time points. Levels of 42 cytokines were determined using a multiplex bead-based assay on archived serum from a cohort of pregnant womenN=16at median of 18 time points tested, from the first trimester through to parturition, per woman. Unconditional growth modeling was then used to determine time-dependent changes in levels of these cytokines. Macrophage-derived chemokine (MDC, aka CCL22) decreases as pregnancy progresses. IL-1β, IL-6, IL-8, IL-12p70, IL-13, IL-15, IP-10, and FLT3-ligand increase as a function of gestational weeks, and IFNα2, IL-1ra, IL-3, IL-9, IL-12p40, and soluble CD40 ligand increase as a function of trimester. As pregnancy normally progresses, a maternal shift away from a type 2-biased immune response and toward an inflammatory/counterregulatory response is observed.
Acute and Chronic Toxicity, Cytochrome P450 Enzyme Inhibition, and hERG Channel Blockade Studies with a Polyherbal, Ayurvedic Formulation for Inflammation
Authors: Dey Debendranath , Chaskar Sunetra , Athavale Nitin , Chitre Deepa
Published: March 2015

Ayurvedic plants are known for thousands of years to have anti-inflammatory and antiarthritic effect. We have recently shown that BV-9238, a proprietary formulation ofWithania somnifera, Boswellia serrata, Zingiber officinale,andCurcuma longa,inhibits LPS-induced TNF-alpha and nitric oxide production from mouse macrophage and reduces inflammation in different animal models. To evaluate the safety parameters of BV-9238, we conducted a cytotoxicity study in RAW 264.7 cells (0.005–1 mg/mL) by MTT/formazan method, an acute single dose (2–10 g/kg bodyweight) toxicity study and a 180-day chronic study with 1 g and 2 g/kg bodyweight in Sprague Dawley rats. Some sedation, ptosis, and ataxia were observed for first 15–20 min in very high acute doses and hence not used for further chronic studies. At the end of 180 days, gross and histopathology, blood cell counts, liver and renal functions were all at normal levels. Further, a modest attempt was made to assess the effects of BV-9238 (0.5 µg/mL) on six major human cytochrome P450 enzymes and3H radioligand binding assay with human hERG receptors. BV-9238 did not show any significant inhibition of these enzymes at the tested dose. All these suggest that BV-9238 has potential as a safe and well tolerated anti-inflammatory formulation for future use.
Early Life Body Fatness and Risk of Colorectal Cancer in U.S. Women and Men—Results from Two Large Cohort Studies
Authors: Zhang Xuehong , Wu Kana , Giovannucci Edward L. , Ma Jing , Colditz Graham A. , Fuchs Charles S. , Willett Walter C. , Stampfer Meir J. , Nimptsch Katharina , Ogino Shuji , Wei Esther K.
Published: March 2015

Background: The association between body fatness before adulthood and later risk of colorectal cancer remains unclear. We hypothesized that, independent of adult body fatness, early life body fatness would be associated with a higher risk of developing colorectal cancer.

Methods: We assessed body fatness during childhood and adolescence using a validated 9-level somatotype and inquired body weight in young adulthood in the Nurses' Health Study and Health Professionals Follow-up Study. We used the Cox proportional hazard regression modeling to estimate relative risks [RR, 95% confidence intervals (CI)] adjusting for adult body mass index (BMI) and other known colorectal cancer risk factors.

Results: We identified 2,100 incident colorectal cancer cases (1,292 in women and 808 in men) during 22 years of follow-up. Among women, the RR (95% CI) for childhood body fatness of level 5 or higher versus level 1 was 1.28 (1.04–1.58; Ptrend = 0.08) and for adolescent body fatness, it was 1.27 (1.01–1.60; Ptrend = 0.23). The corresponding RRs for men were 1.04 (0.82–1.31; Ptrend = 0.48) and 0.98 (0.75–1.27; Ptrend = 0.20), respectively. Results were generally similar across anatomic subsites within the colorectum. In addition, the RRs comparing BMI categories ≥27.5 to <19 kg/m2 were 1.44 (1.06–1.95, at age 18; Ptrend = 0.009) for women and 1.18 (0.84–1.65, at age 21; Ptrend = 0.57) for men.

Conclusion: Increased body fatness in early life, independent of adult obesity, might be a risk factor for colorectal cancer in women, but we observed a weaker association in men.

Impact: Our findings support the growing evidence that early life body fatness affects the risk of colorectal cancer many decades later. Cancer Epidemiol Biomarkers Prev; 24(4); 690–7. ©2015 AACR.
Significance of Circulating Tumor Cells in Metastatic Triple-Negative Breast Cancer Patients within a Randomized, Phase II Trial: TBCRC 019
Authors: Paoletti Costanza , Li Yufeng , Muñiz Maria C. , Kidwell Kelley M. , Aung Kimberly , Thomas Dafydd G. , Brown Martha E. , Abramson Vandana G. , Irvin William J. , Lin Nancy U. , Liu Minetta C. , Nanda Rita , Nangia Julie R. , Storniolo Anna M. , Traina Tiffany A. , Vaklavas Christos , Van Poznak Catherine H. , Wolff Antonio C. , Forero-Torres Andres , Hayes Daniel F.
Published: March 2015

Purpose: Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). We tested whether EpCAM-based capture system (CellSearch) is effective in patients with triple-negative (TN) MBC, and whether CTC apoptosis and clustering enhances the prognostic role of CTC.

Experimental Design: CTC enumeration and apoptosis were determined using the CXC CellSearch kit at baseline and days 15 and 29 in blood drawn from TN MBC patients who participated in a prospective randomized phase II trial of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without tigatuzumab. Association between levels of CTC and patient outcomes was assessed using logistic regression, Kaplan–Meier curves, and Cox proportional hazards modeling.

Results: Nineteen of 52 (36.5%), 14 of 52 (26.9%), and 13 of 49 (26.5%) patients who were evaluable had elevated CTC (≥5 CTC/7.5 mL whole blood) at baseline and at days 15 and 29, respectively. Patients with elevated versus not elevated CTC at each time point had worse progression-free survival (PFS; P = 0.005, 0.0003, 0.0002, respectively). The odds of clinical benefit response for those who had elevated versus low CTC at baseline and days 15 and 29 were 0.25 (95% CI: 0.08–0.84; P = 0.024), 0.19 (95% CI: 0.05–0.17; P = 0.014), and 0.06 (95% CI: 0.01–0.33; P = 0.001), respectively. There was no apparent prognostic effect comparing CTC apoptosis versus non-apoptosis. Presence of CTC cluster at day 15 and day 29 was associated with shorter PFS.

Conclusions: CTC were detected using CellSearch assay in approximately one-third of TN MBC patients. Elevated CTC at baseline and days 15 and 29 were prognostic, and reductions in CTC levels reflected response. Clin Cancer Res; 21(12); 2771–9. ©2015 AACR.

See related article by Forero-Torres et al., p. 2722
Monoclonal Antibodies Targeting LecLex-Related Glycans with Potent Antitumor Activity
Authors: Chua Jia Xin , Vankemmelbeke Mireille , McIntosh Richard S. , Clarke Philip A. , Moss Robert , Parsons Tina , Spendlove Ian , Zaitoun Abid M. , Madhusudan Srinivasan , Durrant Lindy G.
Published: March 2015

Purpose: To produce antitumor monoclonal antibodies (mAbs) targeting glycans as they are aberrantly expressed in tumors and are coaccessory molecules for key survival pathways.

Experimental Design: Two mAbs (FG88.2 and FG88.7) recognizing novel tumor-associated Lewis (Le) glycans were produced by immunizations with plasma membrane lipid extracts of the COLO205 cell line.

Results: Glycan array analysis showed that both mAbs bound LecLex, di-Lea, and LeaLex, as well as Lea-containing glycans. These glycans are expressed on both lipids and proteins. Both mAbs showed strong tumor reactivity, binding to 71% (147 of 208) of colorectal, 81% (155 of 192) of pancreatic, 54% (52 of 96) of gastric, 23% (62 of 274) of non–small cell lung, and 31% (66 of 217) of ovarian tumor tissue in combination with a restricted normal tissue distribution. In colorectal cancer, high FG88 glyco-epitope expression was significantly associated with poor survival. The mAbs demonstrated excellent antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), in addition to direct tumor cell killing via a caspase-independent mechanism. Scanning electron microscopy revealed antibody-induced pore formation. In addition, the mAbs internalized, colocalized with lysosomes, and delivered saporin that killed cells with subnanomolar potency. In vivo, the mAbs demonstrated potent antitumor efficacy in a metastatic colorectal tumor model, leading to significant long-term survival.

Conclusions: The mAbs direct and immune-assisted tumor cell killing, pan-tumor reactivity, and potent in vivo antitumor efficacy indicate their potential as therapeutic agents for the treatment of multiple solid tumors. In addition, internalization of saporin conjugates and associated tumor cell killing suggests their potential as antibody drug carriers. Clin Cancer Res; 21(13); 2963–74. ©2015 AACR.
The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase
Authors: Song Liang-Nian , Silva Jose , Koller Antonius , Rosenthal Andrew , Chen Emily I. , Gelmann Edward P.
Published: March 2015

NKX3.1 is a prostate-specific homeodomain protein and tumor suppressor whose expression is reduced in the earliest phases of prostatic neoplasia. NKX3.1 expression is not only diminished by genetic loss and methylation, but the protein itself is a target for accelerated degradation caused by inflammation that is common in the aging prostate gland. NKX3.1 degradation is activated by phosphorylation at C-terminal serine residues that mediate ubiquitination and protein turnover. Because NKX3.1 is haploinsufficient, strategies to increase its protein stability could lead to new therapies. Here, a high-throughput screen was developed using an siRNA library for kinases that mediate NKX3.1 degradation. This approach identified several candidates, of which DYRK1B, a kinase that is subject to gene amplification and overexpression in other cancers, had the greatest impact on NKX3.1 half-life. Mechanistically, NKX3.1 and DYRK1B were shown to interact via the DYRK1B kinase domain. In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine 185, a residue critical for NKX3.1 steady-state turnover. Lastly, small-molecule inhibitors of DYRK1B prolonged NKX3.1 half-life. Thus, DYRK1B is a target for enzymatic inhibition in order to increase cellular NKX3.1.

Implications: DYRK1B is a promising and novel kinase target for prostate cancer treatment mediated by enhancing NKX3.1 levels. Mol Cancer Res; 13(5); 913–22. ©2015 AACR.
Five-Year Cervical (Pre)Cancer Risk of Women Screened by HPV and Cytology Testing
Authors: Uijterwaal Margot H. , Polman Nicole J. , Van Kemenade Folkert J. , Van Den Haselkamp Sander , Witte Birgit I. , Rijkaart Dorien , Berkhof Johannes , Snijders Peter J.F. , Meijer Chris J.L.M.
Published: March 2015

Primary human papillomavirus (HPV)–based cervical screening will be introduced in the Netherlands in 2016. We assessed the 5-year cervical (pre)cancer risk of women with different combinations of HPV and cytology test results. Special attention was paid to risks for cervical intraepithelial neoplasia grade 3 and 2 or more (CIN3+/2+) of HPV-positive women with a negative triage test, because this determines the safety of a 5-year screening interval for HPV-positive, triage test–negative women. In addition, age-related effects were studied. A total of 25,553 women were screened by HPV testing and cytology in a screening setting. Women were managed on the presence of HPV and/or abnormal cytology. Five-year cumulative incidences for CIN3+/2+ were calculated. Five-year CIN3+(2+) risk was 10.0% (17.7%) among HPV-positive women. When stratified by cytology, the CIN3+(CIN2+) risk was 7.9% (12.9%) for women with normal cytology and 22.2% (45.3%) for women with equivocal or mildly abnormal (i.e., BMD) cytology. For HPV-negative women, the 5-year CIN3+(2+) risk was 0.09% (0.21%). Additional triage of HPV-positive women with normal cytology by repeat cytology at 12 months showed a 5-year CIN3+(2+) risk of 4.1% (7.0%). HPV-non 16/18-positive women with normal cytology at baseline had comparable risks of 3.5% (7.9%). HPV-non 16/18-positive women with normal baseline cytology and normal repeat cytology had a 5-year CIN3+ risk of 0.42%. No age-related effects were detected. In conclusion, HPV-positive women with normal cytology and a negative triage test, either repeat cytology after 12 months or baseline HPV 16/18 genotyping, develop a non-negligible CIN3+ risk over 5 years. Therefore, extension of the screening interval over 5 years only seems possible for HPV screen–negative women. Cancer Prev Res; 8(6); 502–8. ©2015 AACR.
Population Biobanking and International Collaboration
Authors: Zawati Ma''n H. , Knoppers Bartha , Thorogood Adrian
Published: March 2015

Population-based biobanks promise to be important resources for genetic research. However, the study of normal genomic variation across populations requires the collection of data and biological samples from individuals on a large scale. While international collaboration has become both a scientific and an ethical imperative, international sharing of data and samples poses many challenges. Significant variation persists among the legal and ethical norms governing population biobanks in different jurisdictions. Many of these norms do not clearly provide for international access. To illustrate these problems, we collected and compared applicable legislative instruments, as well as ethical guidelines issued by national, regional, and international bodies. In addition, harmonization is faced with important limitations and may not be sufficient to ensure effective international sharing. Population biobanks are therefore looking for new ways to promote sharing and improve interoperability. The formation of biobank networks and the development of common governance tools are two approaches that are setting the groundwork for international collaboration in genetic research.
Paediatric Biobanks: Opinions, Feelings and Attitudes of Parents towards the Specimen Donation of Their Sick Children to a Hypothetical Biobank
Authors: Salvaterra Elena , Locatelli Federica , Strazzer Sandra , Borgatti Renato , D''angelo Grazia , Lenzi Leonardo
Published: March 2015

Over the last years, the storing of biological materials from children for research purposes in biobanks has become the subject of an intense debate in the scientific and ethical communities on a global level. Paediatric biobanks are an important resource for the development of translational research. At the same time, paediatric biobanks are ethically ‘sensitive' due to the unique issues they raise. In this study, we explore opinions, feelings and attitudes of parents towards the specimen donation of their sick children to a hypothetical biobank. According to a qualitative methodology based on focus groups, we analysed parents' views, perceptions and inclinations towards typical ethical, legal and social aspects of paediatric biobanks such as proxy consent, minor assent, privacy protection and return of results. Our study confirms the need for specific policies dedicated to paediatric biobanks by highlighting how the nature of the disease affecting children may influence the parents' opinions and decisions towards the enrolment of their children in biobank-based research studies.
Is Watching Television a Realistic Leisure Option for People with Dementia
Authors: Gústafsdóttir Margrét
Published: March 2015

Background: Watching television is a common leisure activity, not least among older people. However, watching television may become difficult when it is disturbed by symptoms of dementia. Method: A total of 284 questionnaires were handed out to relatives of people with dementia in Iceland, in the Memory Clinic of the University Hospital and in specialized units for people with dementia (6 day-care units and 8 units within nursing homes). The response rate was just below 58%. Results: Watching television was shown to play a less important role in the course of the daily life of people with dementia as soon as the symptoms of the disease became evident, and it increasingly became less relevant. So, this previous leisure activity left an ever-growing void of time to fill. However, watching television may provide an important social context for contact and togetherness during the progress of the disease, as watching television with someone close to them was important for the individuals with dementia. Conclusion: It is not a viable option for people with dementia to watch television on their own, but they may enjoy watching television while sharing this activity with a person close to them. This may even provide quality time.
Biobanking Trends, Challenges, and Opportunities
Authors: Mackenzie Fiona
Published: March 2015

Objectives: To review the different interests and needs of industry and academic users of human biomaterials. Methods: A review of the current literature and interviews with involved parties. Questionnaires were e-mailed to assess current attitudes towards biobanking and opinions of trends and implications for the future. The organisations included commercial biobanks, charitable foundations, academic biobanks, and hospital sites. Results: Biobanks have the potential to have a critical impact across several industrial sectors, and their future success will depend on satisfying the differing needs of each group. There is a growing need for greater collaboration between researchers and biobanks, and if the involvement of industry is not sought by biobanks to create conditions that support the effective use of resources, there is a risk that samples will not be collected or used to the best advantage. Conclusions: It is evident that industry can play a vital role in the innovation process of biobanking, both in terms of the collecting and processing methods and the nature of the disease and sample types collected. With this feedback, biobanks can be utilised effectively to advance research to the benefits of all to the best advantage.
The Uniqueness of Biobanks for Neurological and Psychiatric Diseases: Potentials and Pitfalls
Authors: Ravid Rivka
Published: March 2015

Objectives: Central nervous system (CNS) biobanks are facing difficult and specific challenges due to the sensitive issue of collecting specimens of the CNS, and especially the brain. At present, there is no global network/central database to serve researchers, clinicians and pharma companies, or to supply the special specimens and the accompanying data in sufficient numbers and detail, respectively. The main challenge/objective is to standardize and harmonize all the facets involved in CNS biobanking in order to maximize efficient sample collection. Methods: Since the number of CNS biospecimens stored in existing biobanks is relatively limited and the accompanying data are not always readily available and hard to identify, we propose using optimal procedures for handling and storage of these specimens, and the global standardization of the cliniconeuropathological diagnostic criteria. Results: One of the prominent achievements of the current global activity in brain tissue biobanks (BTB-banks) is the development of an inventory of international standards, available specimens and concomitant data, and national registries. Conclusions: Taking into consideration the huge variety of the specimens stored in different repositories and the enormous differences in medicolegal systems and ethics regulations in different countries, we strongly recommend that healthcare systems and institutions who host BTB-banks make efforts to secure adequate funding for the infrastructure and daily activities. BTB-banks will refine standard operating procedures and their internal guides of best practices/codes of conduct. This in turn will enable the BTB-banks to share the collected specimens and data with the largest possible number of researchers, aiming at maximal scientific spin-off and advance of public health research.
LEP -2548G>A Polymorphism of the Leptin Gene and Its Influence on the Lipid Profile in Obese Individuals
Authors: Ferreira-Julio Maysa Araujo , Pinhel Marcela Souza , Quinhoneiro Driele Cristina Gomes , Nicoletti Carolina Ferreira , Brandão Antonio Carlos , Nonino Carla Barbosa , Pinheiro Jr Sidney , Oliveira Bruno Affonso Parenti , Gregório Michele Lima , Andrade Days Oliveira , Cortes-Oliveira Cristiana , Souza Dorotéia Silva
Published: March 2015

Background/Aim: We studied the molecular pathogenesis of obesity, involving complex interactions between environmental and genetic factors, with a focus on the leptin gene. It was our aim to characterize the LEP -2548G>A leptin polymorphism and lipid profile in obese and normal-weight individuals. Methods: A total of 212 individuals were divided into the study group including 136 obese patients (body mass index, BMI ≥30) and the control group with 76 normal-weight individuals (BMI >18.5 and ≤24.9). DNA was amplified by polymerase chain reaction and restriction fragment length polymorphism. The lipid profile was analyzed by enzymatic colorimetric methods. The level of significance was set at p < 0.05. Results: There was a prevalence of the GA genotype in both groups. However, comparative group analysis showed an association of the recessive model (AA+GA) with increased triglycerides (TG) and decreased high-density lipoprotein cholesterol (HDL-C) levels in the study group. Conclusion: This study did not confirm an association between obesity and the LEP -2548G>A polymorphism. However, AA+GA genotypes, in the presence of obesity, seem to contribute to a reduction in HDL-C and an increase in TG compared with normal-weight individuals. This should be confirmed in further studies.
Abnormal Cochlear Potentials in Friedreich's Ataxia Point to Disordered Synchrony of Auditory Nerve Fiber Activity
Authors: Santarelli Rosamaria , Cama Elona , Pegoraro Elena , Scimemi Pietro
Published: March 2015

Background: Friedreich's ataxia (FRDA) is a degenerative disorder caused by mutations of the FXN gene. Sensorineural hearing loss is one of the clinical features of FRDA, and the majority of hearing-impaired patients have shown evidence of auditory neuropathy. Objective: This study characterizes the cochlear receptor and auditory nerve potentials in a patient with FRDA who had the clinical profile of auditory neuropathy. The aim was to investigate the site of the lesion and the pathophysiological mechanisms behind the hearing dysfunction. Methods: Using transtympanic electrocochleography, both receptor (cochlear microphonic, CM, and summating potential, SP) and auditory nerve potentials were recorded in response to trains of clicks with stimulation intensities from 60 to 120 dB SPL. The results were compared with recordings obtained from two groups of subjects, i.e. 20 normally hearing controls and 19 subjects with cochlear hearing loss. Results: The results showed that the synchronized neural response seen in both normally hearing and hearing-impaired subjects was lacking in our patient, replaced by a prolonged, low-amplitude negative potential that decreased in both amplitude and duration for rapid stimulation rates, consistent with adaptation of neural sources. CMs were recorded with a normal amplitude, consistent with preserved outer hair cell function. SP peak latency was within normal limits, whereas SP amplitude was comparable with that of subjects with cochlear hearing loss, consistent with inner hair cell loss. Conclusion: These findings suggest that underlying auditory neuropathy in FRDA is a disordered synchrony in auditory nerve fiber discharge, possibly resulting from auditory nerve fiber degeneration and inner hair cell loss.
Alteration in Downstream Hypoxia Gene Signaling in Neonatal Glutathione Peroxidase Overexpressing Mouse Brain after Hypoxia-Ischemia
Authors: Sheldon R. Ann , Sadjadi Raha , Lam Matthew , Fitzgerald Russell , Ferriero Donna M.
Published: March 2015

We have previously shown that glutathione peroxidase (GPx) overexpressing mice (hGPx-tg) have reduced brain injury after neonatal hypoxia-ischemia (HI) as a consequence of reduced hydrogen peroxide accumulation. However, this protection is reversed with hypoxia preconditioning, raising the question of the roles of the genes regulated by hypoxia-inducible factor-1α (HIF-1α) and their transcription products, such as erythropoietin (EPO), in both the initial protection and subsequent reversal of protection. hGPx-tg and their wild-type (WT) littermates underwent the Vannucci procedure of HI brain injury at postnatal day 9 - left carotid artery ligation followed by exposure to 10% oxygen for 50 min. Brain cortices and hippocampi were subsequently collected 0.5, 4 and 24 h later for the determination of protein expression by Western blot for GPx, HIF-1α, HIF-2α, EPO, EPO receptor, ERK1/2, phospho-ERK1/2, spectrin 145/150 (as a marker of calpain-specific necrotic cell death), and spectrin 120 (as a marker of apoptotic cell death mediated via caspase-3). As expected, the GPx overexpressing mouse cortex had approximately 3 times the GPx expression as WT naïve. Also, GPx expression remained higher in the GPx overexpressing brain than WT at all time points after HI (0.5, 4, 24 h). HIF-1α was not significantly changed in hGPx-tg as a consequence of HI but decreased in the WT cortex 4 h after HI. HIF-2α decreased in the WT hippocampus after HI. EPO was higher in the GPx overexpressing cortex and hippocampus 30 min after HI compared to WT, but the EPO receptor was unchanged by HI. ERK1/2 phosphorylation increased in the hippocampus at 4 h after HI and in the cortex at 24 h after HI in both WT and hGPx-tg. Spectrin 145/150 was increased in the WT cortex at 4 and 24 h after HI, and spectrin 120 increased 24 h after HI, perhaps reflecting greater injury in the WT brain, especially at 24 h when brain injury is more evident. The effect of GPx overexpression does not appear to upregulate the HIF pathway, yet EPO was upregulated, perhaps via ERK. This might explain, in part, why cell death takes a necrotic or apoptotic path. This may also be an explanation for why the GPx overexpressing brain cannot be preconditioned. This information may prove valuable in the development of therapies for neonatal HI brain injury.
Urinary C-Peptide/Creatinine Ratio Can Distinguish Maturity-Onset Diabetes of the Young from Type 1 Diabetes in Children and Adolescents: A Single-Center Experience
Authors: Yılmaz Agladioglu Sebahat , Sagsak Elif , Aycan Zehra
Published: March 2015

Background: The urinary C-peptide/creatinine ratio (UCPCR) and fasting C-peptide level can assess beta-cell function in clinical practice. In the present study, the use of the UCPCR and fasting C-peptide levels was investigated in the differential diagnosis between maturity-onset diabetes of the young (MODY) and type 1 diabetes mellitus (T1DM). Methods: Twenty-seven patients with genetically confirmed MODY by next-generation sequence analysis and 42 children with T1DM were included. C-peptide levels were measured after an overnight fast before breakfast, and urine samples were collected 2 h after a standard lunch in the hospital. Results: The UCPCR in the T1DM group was 0.17 ± 0.5 nmol/mmol, and in the MODY group it was 1.27 ± 1.03 nmol/mmol (p = 0.001). The receiver operating characteristic (ROC) curves showed excellent discrimination (area under the curve 0.93). A UCPCR ≥0.22 nmol/mmol yielded a 96.3% sensitivity and an 85.7% specificity. The fasting C-peptide level in the T1DM group was lower than that in the MODY group (p = 0.001). The fasting C-peptide cutoff determined by ROC curve analysis was 0.62 ng/ml, with a sensitivity of 93% and a specificity of 90% for discriminating between MODY and T1DM. Conclusions: We showed that the UCPCR and fasting C-peptide levels in children and adolescents can distinguish patients with MODY from patients with T1DM with high specificity and sensitivity. A value of UCPCR ≥0.22 nmol/mmol may indicate further genetic testing for MODY.
Use of the Prostate Health Index for the Detection of Aggressive Prostate Cancer at Radical Prostatectomy
Authors: Mearini Luigi , Nunzi Elisabetta , Ferri Carla , Bellezza Guido , Lolli Carolina , Porrozzi Carlo , Porena Massimo
Published: March 2015

Introduction: In current study, we compared the accuracy of the PSA isoform p2PSA and its derivatives, the percentage of p2PSA to free PSA (%p2PSA) and the Prostate Health Index (PHI) in the detection of prostate cancer (PC) characteristics at the ﬁnal pathology with respect to reference standards. Materials and Methods: This was an observational prospective study evaluating 43 consecutive PC patients treated with laparoscopic/robotic radical prostatectomy (RP). Logistic regression models were ﬁtted to test the predictors of pT3 stage, pathologic Gleason score ≥8 or Gleason score upgrading, margin status, lymph node invasion, and the presence of high-risk disease (pT3 disease and/or Gleason score ≥8 and/or positive lymph node). The comparative base model included tPSA, clinical stage, biopsy Gleason score, and percentage of positive core. Results: Seventeen patients (39.5%) were affected by pT3 disease or had a pathologic Gleason score ≥8; positive margins were detected in 12 patients (27.9%), lymph node invasion was found in 2 patients (4.7%), and 15 patients (34.8%) harbored high-risk disease. In the univariate analysis, p2PSA, %p2PSA, and PHI were signiﬁcant predictors of pT3 disease, pathologic Gleason score, and the presence of high-risk disease (all p < 0.05), whereas only PHI was an independent predictor of pT3 disease, margin status, and presence of high-risk disease, increasing the accuracy of a base multivariable model by 6.3% (p < 0.05) and 4.2% (p < 0.05) for the prediction of pT3 and high-risk disease, respectively. Conclusions: p2PSA and its derivatives, primarily PHI, were signiﬁcant predictors of unfavorable PC characteristics as detected at the ﬁnal pathology, thus improving the clinical performance of standard prognostic factors for aggressive disease.
Neural Tube Defects in Jarcho-Levin Syndrome: Study of Twenty-Eight Cases
Authors: Alatas Ibrahim , Canaz Huseyin , Akkoyun Nesrin , Er Ali , Demirhan Ozkan , Kizilay Deniz , Emel Erhan
Published: March 2015

Jarcho-Levin syndrome (JLS) is a congenital disorder consisting of various vertebral and costal anomalies. Congenital heart defects, abdominal wall malformations, urogenital and anal abnormalities, multiple skeletal anomalies, upper limb anomalies, spina bifida, and inguinal, umbilical and diaphragmatic hernias can be seen as components of JLS. Spina bifida appears to be a common finding in reported JLS cases. We retrospectively reviewed the medical records, plain X-rays and MRIs of patients with spina bifida between 2010 and 2014 and discussed the results.
Evaluation of the Utility of in utero Treatment of Twin Anemia-Polycythemia Sequence
Authors: Sananès Nicolas , Veujoz Marine , Severac Francois , Barthoulot Maël , Meyer Nicolas , Weingertner Anne-Sophie , Kohler Monique , Guerra Fernando , Gaudineau Adrien , Nisand Israël , Favre Romain
Published: March 2015

Objective: The aim of this study is to evaluate the interest in the in utero treatment of twin anemia-polycythemia sequence (TAPS). Methods: The obstetrical and neonatal data on all cases of TAPS followed up in our institution between 2006 and 2013 were reviewed. Statistical analyses were conducted using Bayesian methods. Results: Twenty cases of TAPS were included. Laser therapy or intrauterine transfusion (IUT) was performed on the donor twin in 9 cases. Eleven cases were included in the ‘nontreated' group (managed expectantly or diagnosed at birth). The gestational age at diagnosis was lower in the group with treated TAPS [difference (diff) = -22.20 days (-57.13, 14.28), probability (Pr) (diff >0) = 10.6%]. The rate of preterm premature rupture of membranes was higher in the group with treated TAPS [diff = 22.5% (-14, 57), Pr (diff >0) = 89%], but overall mortality was similar. The interval between diagnosis and delivery was longer [diff = 44.37 days (9.41, 77.90), Pr (diff >0) = 99.2%], the TAPS resolution rate was higher [diff = 49.9% (12, 81), Pr (diff >0) = 99.4%], and the neonatal transfusion rate was lower [diff = -30.5% (-60, 0), Pr (diff >0) = 2.6%] in the treated group. Conclusion: In utero treatment for TAPS is associated with a higher resolution rate of TAPS and a longer time between diagnosis and birth, but overall mortality is the same as with expectant management.
Pregnancy during Ustekinumab Treatment for Severe Psoriasis
Authors: Rocha Katiucia , Piccinin Mariana Carolina , Kalache Luciana F. , Reichert-Faria Adriane , Silva de Castro Caio César
Published: March 2015

We report the case of a 25-year-old patient who became pregnant during ustekinumab therapy. Treatment was suspended immediately after pregnancy had been confirmed. The patient had an uneventful pregnancy and her child is currently 14 months old, with adequate development to her age. Four reports of pregnancy during ustekinumab treatment have been reported and one resulted in miscarriage.
Pasireotide in Acromegaly: An Overview of Current Mechanistic and Clinical Data
Authors: Samson Susan L.
Published: March 2015

Background: Acromegaly is an insidious neuroendocrine disorder caused by hypersecretion of growth hormone (GH) by a somatotroph adenoma. Somatostatin receptor ligands (SRLs) are recommended as first-line medical therapy in patients for whom surgery has failed or is contraindicated. There are 5 known somatostatin receptor subtypes (SSTRs), 2 of which, i.e. SSTR2 and SSTR5, are expressed by a majority of somatotroph adenomas. The currently available SRLs, i.e. octreotide and lanreotide, primarily bind to SSTR2. Pasireotide (SOM230) is a new multireceptor-targeted SRL which has a broader binding profile and an increased affinity for SSTR1, 2, 3, and 5. Methods: PubMed searches were performed to identify all of the available published English language data on pasireotide with regard to the mechanism of action, in vitro effects, and clinical data. Results: Preclinical studies have demonstrated that pasireotide has a broader range of functional activity than octreotide. Recently, the efficacy of pasireotide in attenuating GH and insulin-like growth factor 1 (IGF-1) levels in patients with acromegaly has been evaluated in phase III clinical trials. Pasireotide demonstrated superiority over octreotide in achieving biochemical control (i.e. GH ≤2.5 µg/l and age- and sex-matched IGF-1 normalization) in patients with acromegaly, as well as significant efficacy in treating patients who were previously inadequately controlled on the maximum allowed doses of octreotide and lanreotide. Pasireotide-induced hyperglycemia was the most concerning adverse event but was reversible upon discontinuation of pasireotide. Conclusion: The clinical data support pasireotide as a promising new therapy for the treatment of acromegaly, and the long-acting formulation was recently approved in the US and Europe for the treatment of acromegaly.