bluuebunny/crossref_metadata_2025 huggingface dataset:
MTHFR C677T Gene Polymorphism and Head and Neck Cancer Risk: A Meta-Analysis Based on 23 Publications
Authors: Niu Yu-Ming , Deng Mo-Hong , Chen Wen , Zeng Xian-Tao , Luo Jie
Published: January 2015

Objective.Conflicting results on the association between MTHFR polymorphism and head and neck cancer (HNC) risk were reported. We therefore performed a meta-analysis to derive a more precise relationship between MTHFR C677T polymorphism and HNC risk.Methods.Three online databases of PubMed, Embase, and CNKI were researched on the associations between MTHFR C677T polymorphism and HNC risk. Twenty-three published case-control studies involving 4,955 cases and 8,805 controls were collected. Odds ratios (ORs) with 95% confidence interval (CI) were used to evaluate the relationship between MTHFR C677T polymorphism and HNC risk. Sensitivity analysis, cumulative analyses, and publication bias were conducted to validate the strength of the results.Results.Overall, no significant association between MTHFR C677T polymorphism and HNC risk was found in this meta-analysis (T versus C: OR = 1.04, 95% CI = 0.92–1.18; TT versus CC: OR = 1.15, 95% CI = 0.90–1.46; CT versus CC: OR = 1.00, 95% CI = 0.85–1.17; CT + TT versus CC: OR = 1.01, 95% CI = 0.87–1.18; TT versus CC + CT: OR = 1.11, 95% CI = 0.98–1.26). In the subgroup analysis by HWE, ethnicity, study design, cancer location, and negative significant associations were detected in almost all genetic models, except for few significant risks that were found in thyroid cancer.Conclusion.This meta-analysis demonstrates that MTHFR C677T polymorphism may not be a risk factor for the developing of HNC.
The Ultrastructure of Secretory Cells of the Islets of Langerhans in South American Catfish Rhamdia quelen
Authors: Luchini Laura , Wicki Gustavo , Romano Luis Alberto
Published: January 2015

The present work shows that a detailed description of the ultrastructure of the secretory cells of the South American catfish Rhamdia quelen pancreatic islets is presented. Evidence is offered to support the contention that the α-granules consist of a central and an outer portion of different electron densities and solubilities, that the δ-cells are most probably morphologically altered but viable α-cells, and that the β-granules possibly possess a repeating substructure and may therefore represent an intracellular crystalline storage form of insulin.
Nelfinavir Impairs Glycosylation of Herpes Simplex Virus 1 Envelope Proteins and Blocks Virus Maturation
Authors: Gantt Soren , Gachelet Eliora , Carlsson Jacquelyn , Barcy Serge , Casper Corey , Lagunoff Michael
Published: January 2015

Nelfinavir (NFV) is an HIV-1 aspartyl protease inhibitor that has numerous effects on human cells, which impart attractive antitumor properties. NFV has also been shown to havein vitroinhibitory activity against human herpesviruses (HHVs). Given the apparent absence of an aspartyl protease encoded by HHVs, we investigated the mechanism of action of NFV herpes simplex virus type 1 (HSV-1) in cultured cells. Selection of HSV-1 resistance to NFV was not achieved despite multiple passages under drug pressure. NFV did not significantly affect the level of expression of late HSV-1 gene products. Normal numbers of viral particles appeared to be produced in NFV-treated cells by electron microscopy but remain within the cytoplasm more often than controls. NFV did not inhibit the activity of the HSV-1 serine protease nor could its antiviral activity be attributed to inhibition of Akt phosphorylation. NFV was found to decrease glycosylation of viral glycoproteins B and C and resulted in aberrant subcellular localization, consistent with induction of endoplasmic reticulum stress and the unfolded protein response by NFV. These results demonstrate that NFV causes alterations in HSV-1 glycoprotein maturation and egress and likely acts on one or more host cell functions that are important for HHV replication.
Comparing the Ratchet Effects of Cold Atoms in Periodically Symmetric and Asymmetric Optical Potentials
Authors: Arreyndip Nkongho Ayuketang , Anatole Kenfack
Published: January 2015

We consider a particle in a spatial symmetric/asymmetric potential driven by time periodic bichromatic AC fields of ratchet type. The associated time-dependent Schrödinger equation is conveniently tackled with the Floquet theory. We next proceed to investigate the ratchet effect induced by the driver, comparing the symmetric with the asymmetric cases. It turns out that the current in the asymmetric case is stronger than that of the symmetric one. Besides, we also investigate the case where the driver is a delta kicked acting on our spatial potential with more emphasis on its chaotic behaviour. Here we check that the current emerges as the phase space is mixed and that the system with asymmetric spatial potential becomes more chaotic than the symmetric one at low kicking strength.
An Effective Math Model for Eliminating Interior Resonance Problems of EM Scattering
Authors: Yun-feng Zhang , Zhong-shan Zhou , Zhi-guo Su , Rong-zhu Wang , Ze-huang Chen
Published: January 2015

It is well-known that if an E-field integral equation or an H-field integral equation is applied alone in analysis of EM scattering from a conducting body, the solution to the equation will be either nonunique or unstable at the vicinity of a certain interior frequency. An effective math model is presented here, providing an easy way to deal with this situation. At the interior resonant frequencies, the surface current density is divided into two parts: an induced surface current caused by the incident field and a resonance surface current associated with the interior resonance mode. In this paper, the presented model, based on electric field integral equation and orthogonal modal theory, is used here to filter out resonant mode; therefore, unique and stable solution will be obtained. The proposed method possesses the merits of clarity in concept and simplicity in computation. A good agreement is achieved between the calculated results and those obtained by other methods in both 2D and 3D EM scattering.
Clinical Relationship between Steatocholecystitis and Gallbladder Contractility Measured by Cholescintigraphy
Authors: Bang Chang Seok , Lee Yong Sub , Yoon Jai Hoon , Kim Youn Jeong , Kim Jin Bong , Kim Dong Joon
Published: January 2015

Objective.Contractility of gallbladder is known to be decreased in fatty gallbladder diseases. However, clinical estimation data about this relationship is still lacking. The aim of this study was to investigate the association between steatocholecystitis and contractility of gallbladder.Methods.Patients with cholecystitis (steatocholecystitis versus nonsteatocholecystitis) who underwent cholescintigraphy before cholecystectomy were retrospectively evaluated in a single teaching hospital of Korea. The association of steatocholecystitis with contractility of gallbladder, measured by preoperative cholescintigraphy, was assessed by univariable and multivariable analysis.Results.A total of 432 patients were finally enrolled (steatocholecystitis versus nonsteatocholecystitis; 75 versus 357, calculous versus acalculous cholecystitis; 316 versus 116). In the multivariable analysis, age (OR: 0.94, 95% CI: 0.90–0.99,P=0.01) and total serum cholesterol (OR: 1.02, 95% CI: 1.01–1.04,P=0.04) were related to steatocholecystitis in patients with acalculous cholecystitis. Only age (OR: 0.97, 95% CI: 0.94–0.99,P=0.004) was significantly related to steatocholecystitis in patients with calculous cholecystitis. However, ejection fraction of gallbladder reflecting contractility measured by cholescintigraphy was not related to steatocholecystitis irrespective of presence of gallbladder stone in patients with cholecystitis.Conclusion.Ejection fraction of gallbladder measured by cholescintigraphy cannot be used for the detection or confirmation of steatocholecystitis.
Longitudinal Vibrations of the Viscoelastic Moving Belt
Authors: Pang Xiaoxu , Li Junxia , Kou Ziming
Published: January 2015

The longitudinal dynamic governing equation of the viscoelastic belt with one end subjected to concentrated mass was established based on the Kelvin-Voigt viscoelastic partial-differential constitutive law. The generalized coordinate method was adopted to solve dynamic displacement and dynamic tension. And then it was reduced to be a nonhomogeneous partial-differential equation where the analytical solutions with a constant acceleration were obtained. The effects of damping coefficient, the loading radio, and the constant acceleration of the belt on the dynamic response of the belt were investigated using the established dynamic model. The results show that the longitudinal vibration frequency of the viscoelastic moving belt increases with an increasing of the mass at the end. The increasing value of the loading radio, damping coefficient, and decreasing the acceleration will lead to a deceasing in dynamic tension. Moreover, the method of solution can be applied to axially moving viscoelastic materials with different boundary conditions.
Life-Threatening Bleeding from Peristomal Varices after Cystoprostatectomy: Multimodal Approach in a Cirrhotic, Encephalopathic Patient with Severe Portal Hypertension
Authors: Staubli Sergej E. L. , Gramann Tobias , Schwab Christoph , Semela David , Hechelhammer Lukas , Engeler Daniel S. , Schmid Hans-Peter , Abt Dominik , Mordasini Livio
Published: January 2015

The bleeding of peristomal varices due to a portosystemic shunt is rare but potentially life-threatening in cirrhotic patients with portal hypertension. The scarce case reports in the literature recommend transjugular intrahepatic portosystemic shunt (TIPS) to prevent further bleeding. We report on a 72-year-old man who was referred to our hospital because of life-threatening bleeding from peristomal varices, three years after radical cystoprostatectomy for invasive bladder cancer. CT imaging showed liver cirrhosis with a prominent portosystemic shunt leading to massively enlarged peristomal varices. TIPS was taken into consideration, but not possible due to hepatic encephalopathy (HE). Medical therapy with lactulose and the nonselective beta-blocker carvedilol was initiated to treat HE and portal hypertension. In a second step, the portosystemic shunt was percutaneously embolized. Here, we present a multimodal approach to treat intractable bleeding from peristomal varices in a patient with ileal conduit urinary diversion, not suitable for TIPS.
Detecting Foreign Bodies in a Head Laceration
Authors: Fowler Thomas R. , Crellin Steven J. , Greenberg Marna Rayl
Published: January 2015

Open wounds represent a potential area of medicolegal risk if foreign bodies are not identified prior to wound closure. The importance of imaging of lacerations was underscored by a recent case where a 20-year-old male collided with a friend’s mouth on a trampoline sustaining a simple, superficial scalp laceration. The wound was evaluated in typical fashion including irrigation and local exploration and was prepared for closure. The friend was then evaluated and noted to have multiple extensive dental fractures. An increased index of suspicion generated further evaluation of the first patient’s wound. Plain radiography obtained of the first patient’s skull was noted to have bony foreign bodies consistent with teeth, which were then removed after further exploration. Superficial wounds are common and complications arising from retained foreign bodies are a potential source of substantial morbidity and consequently medical litigation. This case serves as a reminder to be vigilant and maintain a high index of suspicion regarding the potential for foreign body.
Change-Point Analysis of Tropical Night Occurrences for Five Major Cities in Republic of Korea
Authors: Suh Myoung-Seok , Kim Chansoo
Published: January 2015

Bayesian change-point analysis is applied to detect a change-point in the occurrences of tropical night (TN) days in the 50-year time series data for five major cities in Republic of Korea. A TN day is simply defined as a day when the daily minimum temperature is greater than 25∘C. A Bayesian analysis is performed for detecting a change-point at an unknown time point in the TN day frequency time series, which is modeled by an independent Poisson random variable. The results showed that a single change occurred around 1993 for three cities (Seoul, Incheon, and Daegu). However, when we excluded the extraordinary year, 1994, a single change occurred around 1993 only in Seoul and Daegu. The average number of TN days in Seoul and Daegu increased significantly, by more than 150%, after the change-point year. The abrupt increase in TN day frequency in two cities over Republic of Korea around 1993 may be related to the significant decadal change in the East Asian summer monsoon around the mid 1990s and to rapid urbanization.
Risk Factors Associated with the Onset of Relapsing-Remitting and Primary Progressive Multiple Sclerosis: A Systematic Review
Authors: McKay Kyla A. , Kwan Vivian , Duggan Thomas , Tremlett Helen
Published: January 2015

Multiple sclerosis (MS) is a chronic central nervous system disease with a highly heterogeneous course. The aetiology of MS is not well understood but is likely a combination of both genetic and environmental factors. Approximately 85% of patients present with relapsing-remitting MS (RRMS), while 10–15% present with primary progressive MS (PPMS). PPMS is associated with an older onset age, a different sex ratio, and a considerably more rapid disease progression relative to RRMS. We systematically reviewed the literature to identify modifiable risk factors that may be associated with these different clinical courses. We performed a search of six databases and integrated twenty observational studies into a descriptive review. Exposure to Epstein-Barr virus (EBV) appeared to increase the risk of RRMS, but its association with PPMS was less clear. Other infections, such as human herpesvirus-6 and chlamydia pneumoniae, were not consistently associated with a specific disease course nor was cigarette smoking. Despite the vast literature examining risk factors for the development of MS, relatively few studies reported findings by disease course. This review exposes a gap in our understanding of the risk factors associated with the onset of PPMS, our current knowledge being predominated by relapsing-onset MS.
Development of a Machine Learning Method to Predict Membrane Protein-Ligand Binding Residues Using Basic Sequence Information
Authors: Suresh M. Xavier , Gromiha M. Michael , Suwa Makiko
Published: January 2015

Locating ligand binding sites and finding the functionally important residues from protein sequences as well as structures became one of the challenges in understanding their function. Hence a Naïve Bayes classifier has been trained to predict whether a given amino acid residue in membrane protein sequence is a ligand binding residue or not using only sequence based information. The input to the classifier consists of the features of the target residue and two sequence neighbors on each side of the target residue. The classifier is trained and evaluated on a nonredundant set of 42 sequences (chains with at least one transmembrane domain) from 31 alpha-helical membrane proteins. The classifier achieves an overall accuracy of 70.7% with 72.5% specificity and 61.1% sensitivity in identifying ligand binding residues from sequence. The classifier performs better when the sequence is encoded by psi-blast generated PSSM profiles. Assessment of the predictions in the context of three-dimensional structures of proteins reveals the effectiveness of this method in identifying ligand binding sites from sequence information. In 83.3% (35 out of 42) of the proteins, the classifier identifies the ligand binding sites by correctly recognizing more than half of the binding residues. This will be useful to protein engineers in exploiting potential residues for functional assessment.
Three Cases of Organized Hematoma of the Maxillary Sinus: Clinical Features and Immunohistological Studies for Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor 2 Expressions
Authors: Imayoshi Shoichiro , Kanazawa Takeharu , Fukushima Noriyoshi , Kikuchi Hisashi , Hasegawa Masayo , Nagatomo Takafumi , Nishino Hiroshi
Published: January 2015

Objectives. Organized hematoma (OH) is a rare, nonneoplastic, hemorrhagic lesion causing mucosal swelling and bone thinning, mainly in the maxillary sinus. We aimed to clarify the clinical presentation and treatment of OH.Methods. Three cases of maxillary sinus OH and a literature review are presented.Results. Three men aged 16–40 years complained of nasal obstruction, frequent epistaxis, and/or headache. Clinical and radiological examinations revealed a maxillary sinus OH. They were cured in a piecemeal fashion via endoscopic middle meatal antrostomy. Furthermore, vascular endothelial growth factor and its receptor were expressed in the lesion.Conclusions. The pathogenesis of OH is unclear and it presents various histological and imaging findings; however, it is not difficult to rule out malignant tumors. Minimally invasive surgery such as endoscopic sinus surgery can cure it completely. Thus, it is important to determine the diagnosis using CT and MRI and to quickly provide surgical treatment.
Neuraminidase Inhibition Primes Short-Term Depression and Suppresses Long-Term Potentiation of Synaptic Transmission in the Rat Hippocampus
Authors: Savotchenko Alina , Romanov Arthur , Isaev Dmytro , Maximyuk Oleksandr , Sydorenko Vadym , Holmes Gregory L. , Isaeva Elena
Published: January 2015

Neuraminidase (NEU) is a key enzyme that cleaves negatively charged sialic acid residues from membrane proteins and lipids. Clinical and basic science studies have shown that an imbalance in NEU metabolism or changes in NEU activity due to various pathological conditions parallel with behavior and cognitive impairment. It has been suggested that the decreases of NEU activity could cause serious neurological consequences. However, there is a lack of direct evidences that modulation of endogenous NEU activity can impair neuronal function. Using combined rat entorhinal cortex/hippocampal slices and a specific inhibitor of NEU, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (NADNA), we examined the effect of downregulation of NEU activity on different forms of synaptic plasticity in the hippocampal CA3-to-CA1 network. We show that NEU inhibition results in a significant decrease in long-term potentiation (LTP) and an increase in short-term depression. Synaptic depotentiation restores LTP in NADNA-pretreated slices to the control level. These data suggest that short-term NEU inhibition produces the LTP-like effect on neuronal network, which results in damping of further LTP induction. Our findings demonstrate that downregulation of NEU activity could have a major impact on synaptic plasticity and provide a new insight into the cellular mechanism underlying behavioral and cognitive impairment associated with abnormal metabolism of NEU.
Uniqueness and Nonuniqueness in Inverse Problems for Elliptic Partial Differential Equations and Related Medical Imaging
Authors: Kwon Kiwoon
Published: January 2015

Unique determination issues about inverse problems for elliptic partial differential equations in divergence form are summarized and discussed. The inverse problems include medical imaging problems including electrical impedance tomography (EIT), diffuse optical tomography (DOT), and inverse scattering problem (ISP) which is an elliptic inverse problem closely related with DOT and EIT. If the coefficient inside the divergence is isotropic, many uniqueness results are known. However, it is known that inverse problem with anisotropic coefficients has many possible coefficients giving the same measured data for the inverse problem. For anisotropic coefficient with anomaly with or without jumps from known or unknown background, nonuniqueness of the inverse problems is discussed and the relation to cloaking or illusion of the anomaly is explained. The uniqueness and nonuniqueness issues are discussed firstly for EIT and secondly for ISP in similar arguments. Arguing the relation between source-to-detector map and Dirichlet-to-Neumann map in DOT and the uniqueness and nonuniqueness of DOT are also explained.
Occupational Health Hazards among Healthcare Workers in Kampala, Uganda
Authors: Ndejjo Rawlance , Musinguzi Geofrey , Yu Xiaozhong , Buregyeya Esther , Musoke David , Wang Jia-Sheng , Halage Abdullah Ali , Whalen Christopher , Bazeyo William , Williams Phillip , Ssempebwa John
Published: January 2015

Objective.To assess the occupational health hazards faced by healthcare workers and the mitigation measures.Methods.We conducted a cross-sectional study utilizing quantitative data collection methods among 200 respondents who worked in 8 major health facilities in Kampala.Results.Overall, 50.0% of respondents reported experiencing an occupational health hazard. Among these, 39.5% experienced biological hazards while 31.5% experienced nonbiological hazards. Predictors for experiencing hazards included not wearing the necessary personal protective equipment (PPE), working overtime, job related pressures, and working in multiple health facilities. Control measures to mitigate hazards were availing separate areas and containers to store medical waste and provision of safety tools and equipment.Conclusion.Healthcare workers in this setting experience several hazards in their workplaces. Associated factors include not wearing all necessary protective equipment, working overtime, experiencing work related pressures, and working in multiple facilities. Interventions should be instituted to mitigate the hazards. Specifically PPE supply gaps, job related pressures, and complacence in adhering to mitigation measures should be addressed.
Indigenous Starter Cultures to Improve Quality of Artisanal Dry Fermented Sausages from Chaco (Argentina)
Authors: Palavecino Prpich Noelia Z. , Castro Marcela P. , Cayré María E. , Garro Oscar A. , Vignolo Graciela M.
Published: January 2015

Lactic acid bacteria (LAB) and coagulase negative cocci (CNC) were isolated from artisanal dry sausages sampled from the northeastern region of Chaco, Argentina. In order to evaluate their performancein situand considering technological features of the isolated strains, two mixed selected autochthonous starter cultures (SAS) were designed: (i) SAS-1 (Lactobacillus sakei487 +Staphylococcus vitulinusC2) and (ii) SAS-2 (L. sakei442 +S. xylosusC8). Cultures were introduced into dry sausage manufacturing process at a local small-scale facility. Microbiological and physicochemical parameters were monitored throughout fermentation and ripening periods, while sensory attributes of the final products were evaluated by a trained panel. Lactic acid bacteria revealed their ability to colonize and adapt properly to the meat matrix, inhibiting the growth of spontaneous microflora and enhancing safety and hygienic profile of the products. Both SAS showed a beneficial effect on lipid oxidation and texture of the final products.Staphylococcus vitulinusC2, from SAS-1, promoted a better redness of the final product. Sensory profile revealed that SAS addition preserved typical sensory attributes. Introduction of these cultures could provide an additional tool to standardize manufacturing processes aiming to enhance safety and quality while keeping typical sensory attributes of regional dry fermented sausages.
In VitroSensitivity of PairedLeishmania(Viannia)braziliensisSamples Isolated before Meglumine Antimoniate Treatment and after Treatment Failure or Reactivation of Cutaneous Leishmaniasis
Authors: Baptista Cibele , Miranda Luciana de Freitas Campos , Madeira Maria de Fátima , Leon Leonor Laura Pinto , Conceição-Silva Fátima , Schubach Armando de Oliveira
Published: January 2015

This study evaluated thein vitrosensitivity of pairedLeishmania braziliensissamples isolated from the same patient before pentavalent antimonial treatment (Sample A) and after treatment failure or cutaneous leishmaniasis reactivation (Sample B) in patients undergoing intralesional administration or injections (5 mgSbV/kg/d) of meglumine antimoniate. Fourteen samples from 7 patients were studied. After 24 h of drug exposure, 50% lethal dose (LD50) values for promastigotes ranged from 0.37 mg/mL to 5.86 mg/mL for samples obtained before treatment (A) and 0.89 mg/mL to 7.80 mg/mL for samples obtained after treatment (B). After 48 h, LD50values ranged from 0.37 mg/mL to 5.75 mg/mL and 0.70 mg/mL to 7.68 mg/mL for A and B samples, respectively. After 48 h, LD50values for amastigotes ranged from 11.7 to 44.3 μg/mL for A samples and 13.7 to 52.7 μg/mL for B samples. Of 7 patients, 1 discontinued treatment and 6 were cured after retreatment with amphotericin B (4 cases) or meglumine antimoniate (2 cases). Overall the B samples had higher LD50values than A samples; however the difference was not significant. These results do not support the hypothesis that low-dose and intralesional treatments induce selection of resistant parasitesin vitroand suggest that other factors may influence therapeutic outcome in patients with poor response to initial treatment.
Polymorphic CAG Repeat and Protein Expression of Androgen Receptor Gene in Colorectal Cancer
Authors: Huang Rui , Wang Guiyu , Song Yanni , Wang Feng , Zhu Bing , Tang Qingchao , Liu Zheng , Chen Yinggang , Zhang Qian , Muhammad Shan , Wang Xishan
Published: January 2015

Although somatic alterations in CAG repeats in the androgen receptor (AR) gene have been suggested to predispose to colorectal cancer, less is known about AR in colorectal cancer carcinogenesis. Because of lack of relevant analysis on CAG repeat length and AR expression in colorectal cancer, we aimed to investigate the prognostic value of polymorphic CAG and protein expression of the AR gene in patients with colorectal cancer. A case–control study was carried out on 550 patients with colorectal cancer and 540 healthy controls to investigate whether polymorphic CAG within the AR gene is linked to increased risk for colorectal cancer. Polymorphic CAG and AR expression were analyzed to clarify their relationship with clinicopathologic and prognostic factors in patients with colorectal cancer. The study showed that the AR gene in patients with colorectal cancer had a longer CAG repeat sequence than those in the control group, as well as increased risk for colorectal cancer among females (P = 0.013), males (P = 0.002), and total colorectal cancer population (P < 0.001), respectively. AR expression exhibited a significant difference in long CAG repeat sequence among males (P < 0.001), females (P < 0.001), and total colorectal cancer study population (P < 0.001). Both long CAG repeat sequence and negative AR expression were associated with a short 5-year overall survival (OS) rate in colorectal cancer. Long CAG repeat sequences and the absence of AR expression were closely related to the development of colorectal cancer. Both long CAG and decreased AR expression were correlated with the poor 5-year OS in patients with colorectal cancer. Mol Cancer Ther; 14(4); 1066–74. ©2015 AACR.
The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models
Authors: Foster Paul , Yamaguchi Kyoko , Hsu Pin P. , Qian Fawn , Du Xiangnan , Wu Jianming , Won Kwang-Ai , Yu Peiwen , Jaeger Christopher T. , Zhang Wentao , Marlowe Charles K. , Keast Paul , Abulafia Wendy , Chen Jason , Young Jenny , Plonowski Artur , Yakes F. Michael , Chu Felix , Engell Kelly , Bentzien Frauke , Lam Sanh T. , Dale Stephanie , Yturralde Olivia , Matthews David J. , Lamb Peter , Laird A. Douglas
Published: January 2015

Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents. Mol Cancer Ther; 14(4); 931–40. ©2015 AACR.
The Genetics of Splicing in Neuroblastoma
Authors: Chen Justin , Hackett Christopher S. , Zhang Shile , Song Young K. , Bell Robert J.A. , Molinaro Annette M. , Quigley David A. , Balmain Allan , Song Jun S. , Costello Joseph F. , Gustafson W. Clay , Van Dyke Terry , Kwok Pui-Yan , Khan Javed , Weiss William A.
Published: January 2015

Regulation of mRNA splicing, a critical and tightly regulated cellular function, underlies the majority of proteomic diversity and is frequently disrupted in disease. Using an integrative genomics approach, we combined both genomic data and exon-level transcriptome data in two somatic tissues (cerebella and peripheral ganglia) from a transgenic mouse model of neuroblastoma, a tumor that arises from the peripheral neural crest. Here, we describe splicing quantitative trait loci associated with differential splicing across the genome that we use to identify genes with previously unknown functions within the splicing pathway and to define de novo intronic splicing motifs that influence splicing from hundreds of bases away. Our results show that these splicing motifs represent sites for functional recurrent mutations and highlight novel candidate genes in human cancers, including childhood neuroblastoma.

Significance: Somatic mutations with predictable downstream effects are largely relegated to coding regions, which comprise less than 2% of the human genome. Using an unbiased in vivo analysis of a mouse model of neuroblastoma, we have identified intronic splicing motifs that translate into sites for recurrent somatic mutations in human cancers. Cancer Discov; 5(4); 380–95. ©2015 AACR.

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Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage
Authors: Medina-Echeverz José , Ma Chi , Duffy Austin G. , Eggert Tobias , Hawk Nga , Kleiner David E. , Korangy Firouzeh , Greten Tim F.
Published: January 2015

Immune-stimulatory mAbs are currently being evaluated as antitumor agents. Although overall toxicity from these agents appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in the spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in the liver and spleen, serum transaminases, and liver histologies were analyzed after antibody administration. Nox2−/−, Cd40−/−, and bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid-derived suppressor cells (MDSC) was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras, we demonstrate that CD40 antibody–induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation–dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80-positive and CD40-positive liver CD11b+Gr-1+ immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14+HLA-DRlow peripheral blood mononuclear cells from patients with cancer reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced myeloid cells, caused myeloid-dependent hepatotoxicity, and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggest that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC. Cancer Immunol Res; 3(5); 557–66. ©2015 AACR.
Atazanavir-Induced Urine Crystals Demonstrated by Infrared Spectroscopic Analysis
Authors: Inagaki Isao , Adachi Mariko , Ito Hiroyasu , Yasuda Mitsuru , Tsurumi Hisashi , Deguchi Takashi , Seishima Mitsuru
Published: January 2015

Atazanavir sulfate, an azapeptide inhibitor of HIV protease, has been associated with urolithiasis. A 60-year-old man with atazanavir-induced urinary sediment crystals verified by infrared spectroscopic analysis is described. He had been receiving highly active antiretroviral therapy (HAART) for HIV infection and also had a history of urinary lithiasis and been undergoing urinalysis once every month. Needle-shaped crystals were seen in his urine sediment and infrared spectroscopic analysis revealed that these were atazanavir crystals. Because the presence of the crystals in urine do not always reveal an abnormality in the urinary test strip analysis, the urinary sediment needed to be observed microscopically in order to prevent future urolithiasis and renal failure in this HIV patient receiving atazanavir.
Comparison of Ureteroscopic Laser Lithotripsy with Laparoscopic Ureterolithotomy for Large Proximal and Mid-Ureter Stones
Authors: Kaygısız Onur , Coşkun Burhan , Kılıçarslan Hakan , Kordan Yakup , Vuruşkan Hakan , Özmerdiven Gökhun , Yavaşcaoğlu İsmet
Published: January 2015

Objectives: To compare the effectiveness and complications of ureteroscopic laser lithotripsy with laparoscopic ureter laparoscopic ureterolithotomy in mid- or proximal portion of large ureteral stones. Material and Methods: We reviewed patients with large (>15 mm) ureteral stone and those who underwent ureteroscopic laser lithotripsy (URS group) or laparoscopic ureterolithotomy (LU group). The first attempt was considered successful in patients who had residual fragments smaller than 2 mm and no conversion of the primary procedure to another. Results: Sixty patients (URS group 29, LU group 31) met inclusion criteria. FURS was used as an adjunctive procedure in one patient for URS group and in two patients for LU group in the same season. LU had a higher success rate and the first-day stone-free rate when compared with URS. Number of procedures was also significantly higher in URS group. There was no difference in stone-free rates at the first and third months, and length of hospitalization and operation were higher in the LU group. Only two patients in the LU group and one patient in the URS group had major complications. Conclusions: Laparoscopy is an effective option of large proximal and mid-ureter stone treatment; however, URS provides similar stone-free rates at three months as a minimal invasive procedure.
Impact of Antibiotic Treatment Intensity on Long-Term Sepsis-Associated Kidney Injury in a Polymicrobial Peritoneal Contamination and Infection Model
Authors: Otto Gordon P. , Grünwald Benedikt , Geis Christian , Köthe Susanne , Hurtado-Oliveros Jorge , Chung Ha-Yeun , Ekaney Michael , Bockmeyer Clemens L. , Sossdorf Maik , Busch Martin , Claus Ralf A.
Published: January 2015

Background/Aims: Long-term kidney affections after sepsis are poorly understood. Animal models for investigating kidney damage in the late phase of disease progression are limited. The aim of this study was to investigate the impact of two antibiotic regimes on persistence of kidney injury after peritonitis. Methods: Kidney damage was investigated 65 days after polymicrobial peritoneal contamination and infection (PCI) sepsis induction in C57BL/6 mice. Short-term antibiotic therapy (STA, 4 days) was compared to long-term (LTA, 10 days) treatment using plasma creatinine, plasma and urine neutrophil gelatinase-associated lipocalin (NGAL), urine albumin/creatinine ratio and renal histology. Results: Sepsis resulted in mortality rates of 68.2% (STA) and 61.0% (LTA). Surviving STA animals showed the most pronounced kidney damage indicated by significantly elevated levels of creatinine and acute tubular damage (ATD), whereas NGAL was significantly increased in LTA survivors only. A creatinine level above 0.3 mg/dl was used to define kidney injury, found in 21.4% of STA animals and 7.8% of LTA animals. While animals with kidney injury demonstrated significantly higher ATD scores and persistent tubular damage, no significant differences were found for plasma or urine NGAL levels or urine albumin/creatinine ratios. Conclusion: Prolonged antibiotic treatment reduced the rate of ongoing peritonitis-induced kidney injury in a C57BL/6 mouse model. Plasma or urine NGAL levels were not able to identify animals with or without persistent kidney injury. The kidney injury after the PCI mouse model represents prototypic clinical findings and should be used for further studies investigating disease mechanisms.
Recto-Bartholin's Duct Fistula: A Case Report
Authors: Kim Young Sun , Han Hyo Sang , Seo Min Woo , Kim Woo Suk , Lee Jin Hyung , Park Nae Kyeong , Sang Jae Hong
Published: January 2015

Bartholin's duct cysts, the most common growths in the vulva, occur in the labia majora. The cyst may become infected, and an abscess may develop in the gland. Rectovaginal fistula is a rare complication and its formation is secondary to Bartholin's cyst; only 4 cases have been reported in the literature so far. In this case, the fistula was located between the rectum and a Bartholin's duct, rather than the vagina and the rectum. We present the first case of a recto-Bartholin's duct fistula, performed surgical excision and fistulectomy. Postoperative treatment with antibiotics resulted in the complete resolution of all lesions at the 3-month follow-up.
A Phase II Trial of Combined Chemotherapy with Oral S-1 and 24-Hour Infusions of Irinotecan plus Bevacizumab in Patients with Metastatic Colorectal Cancer
Authors: Sadahiro Sotaro , Suzuki Toshiyuki , Tanaka Akira , Okada Kazutake , Saito Gota , Kamijo Akemi
Published: January 2015

Objectives: Protracted low-dose infusion of irinotecan has been suggested to enhance antitumor activity. A phase II study was conducted to evaluate the safety and efficacy of oral S-1 combined with 24-hour infusion of irinotecan and intravenous bevacizumab for metastatic colorectal cancer (MCRC). Methods: The subjects were 79 patients with MCRC; 57 were chemotherapy naïve. Irinotecan (125 mg/m2) was administered as a 24-hour infusion on days 1 and 15, S-1 (80 mg/m2) was administered orally on days 1-14, and bevacizumab (5.0 mg/kg) was given on days 1 and 15. The treatment was repeated every 4 weeks. Results: Median follow-up was 20.0 months, and the mean number of cycles was 7. The overall response rate was 79.7% (95% CI, 69.2-88.0), 86.0% (95% CI, 74.2-93.7) for first-line and 63.6% (95% CI, 40.7-82.8) for second-line treatment. The median progression-free survival was 16.4 months (95% CI, 13.9-21.0) for first-line and 9.4 months (95% CI, 4.9-16.5) for second-line treatment. The median overall survival was not reached. Grade 3-4 toxicities were neutropenia (43%), leukopenia (20.3%), anorexia (19.0%), and diarrhea (10.1%). Toxicity was tolerable. Conclusions: Combination chemotherapy with oral S-1 and biweekly 24-hour infusions of irinotecan plus bevacizumab appears to be highly active and well tolerated both as first-line and second-line chemotherapy for MCRC.
18F-Fluorodeoxyglucose Uptake Level-Based Lymph Node Staging in Oropharyngeal Squamous Cell Cancer - Role of Molecular Marker Expression on Diagnostic Outcome
Authors: Sadick Maliha , Weiss Christel , Piniol Rafael , Frey Sabine , Hoermann Karl , Schoenberg Stefan O. , Sadick Haneen
Published: January 2015

Background: A prospective study was performed to assess standard uptake value (SUV)-level based 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) lymph node staging in 33 patients with oropharyngeal squamous cell cancer (OSCC) out of a total of 99 patients with head-and-neck squamous cell cancer (HNSCC) and the role of nodal molecular marker expression in diagnostic outcome prediction. Methods: Preoperative nodal PET/CT staging in 123 lymph nodes was correlated with postoperative lymph node histology, which served as gold standard. Tissue samples were prepared for immunohistochemistry of the excised lymph nodes. Results: The negative and positive predictive values (NPV and PPV) of PET for correct lymph node assessment were 100% and 93%, respectively. There was a significant association between SUVmax and lymph node histology (p < 0.0001) and a significant linear correlation between SUVmax and nodal size (Pearson's correlation coefficient r = 0.61336, p < 0.0001). The molecular marker E-Cadherin was significantly overexpressed in lymph node metastases (p < 0.0001). Benign lymph nodes showed significant 2-fold Bcl2 overexpression (p < 0.0001). However, the molecular marker expression profiles were inhomogeneous and did not allow valuable diagnostic outcome prediction. Conclusions: SUV level-based 18F-FDG-PET/CT lymph node assessment in OSCC still has to be considered as the most established and reliable staging tool. Lymph node molecular marker expression profiles need to be investigated further as they currently do not sufficiently contribute to therapy decision-making.
Accuracy of Unenhanced Computerized Tomography Interpretation by Urologists in Patients with Acute Flank Pain
Authors: Sancak Eyup Burak , Resorlu Mustafa , Celik Orcun , Resorlu Berkan , Gulpinar Murat Tolga , Akbas Alpaslan , Karakan Tolga , Bayrak Omer , Kabar Mucahit , Eroglu Muzaffer , Ozdemir Huseyin
Published: January 2015

Purpose: The aim was to compare the findings of non-contrast computerized tomography (NCCT) evaluated by urology specialists with the findings of experienced radiologists, who are accepted as a standard reference for patients who present with acute flank pain. Materials and Methods: Five hundred patients evaluated with NCCT were included in the study. The NCCT images of these patients were evaluated by both radiologists and urology specialists in terms of the presence of calculus, size of calculus, the location of calculus, the presence of hydronephrosis, and pathologies other than calculus, and the results were compared. Results: The evaluations of urology specialists and standard reference radiology specialists are consistent with each other in terms of the presence of calculus (kappa [κ]: 0.904), categorical stone size (κ: 0.81), the location of calculus (κ: 0.88), and hydronephrosis (κ: 0.94). However, the evaluations of urology specialists in detecting pathologies other than calculus, which may cause acute flank pain or accompany renal colic, were found to be inadequate (κ: 0.37). The false-negative rate of detecting pathologies outside of the urinary system by the urology specialists is calculated as 0.86. Conclusion: Although the urology specialists can evaluate the findings related to calculus sufficiently with NCCT, they may not discover pathologies outside of the urinary system.
Primary Tumor Standardized Uptake Value Predicts Survival in Head and Neck Squamous Cell Carcinoma
Authors: Zhang Baitao , Geng Jiangqiao , Nie Fang , Li Xiaoming
Published: January 2015

Background: The purpose of this study was to determine whether the pretreatment primary tumor standardized uptake value (SUV), as measured by positron emission tomography (PET), can add prognostic information for predicting survival in patients with head and neck squamous cell carcinoma (HNSCC). Materials and Methods: 7 articles were identified by searching electronic databases. Statistical analysis was performed with RevMan 4.2.2. SUV measurement and SUV threshold for defining high SUV were studied dependently. For each publication, we first obtained an estimate of the relative risk (RR) for comparing patients with a low or a high SUV. Subsequently, we aggregated the individual RRs into a combined RR, using a fixed-effect model. Publication bias was assessed using a funnel plot. Results: The study included 7 clinical trials dedicated to HNSCC, involving 674 patients who underwent fluoro-2-deoxy-D-glucose-PET scanning before treatment. The combined RR from the 7 reports for the survival was 0.53 (95% confidence interval: 0.46-0.62). The funnel plot showed symmetrical distribution, indicating no evidence of any substantial publication bias. Conclusion: Our meta-analysis indicates that patients with HNSCC who have a primary tumor with a high SUV have poor survival; this should be further confirmed in a meta-analysis based on individual patient data.
Opportunities for Intervention Strategies for Weight Management: Global Actions on Fluid Intake Patterns
Authors: Lafontan Max , Visscher Tommy L.S. , Farpour-Lambert Nathalie , Yumuk Volkan
Published: January 2015

Summary: Water is an essential nutrient for all physiological functions and particularly important for thermoregulation. About 60% of our body weight is made of water. Under standard conditions (18-20 °C and moderate activity), water balance is regulated within 0.2 % of body weight over a 24-hour period. Water requirement varies between individuals and according to environmental conditions. Concerning considerations related to obesity, the health impact of fluid intake is commonly overlooked. Fluid intake advices are missing in most of food pyramids offered to the public, and water requirements and hydration challenges remain often neglected. The purpose of this paper is to emphasize and discuss the role of water consumption in the context of other important public health measures for weight management. Attention will be focused on fluid intake patterns and hydration-related questions in the context of global interventions and/or physical activity programs settled in weight management protocols.