bluuebunny/crossref_metadata_2025 huggingface dataset:
Inverse baseline expression pattern of the NEP/neuropeptides and NFκB/proteasome pathways in androgen-dependent and androgen-independent prostate cancer cells
Authors: Patrikidou Anna , Vlachostergios Panagiotis J , Voutsadakis Ioannis A , Hatzidaki Eleana , Valeri Rosalia-Maria , Destouni Chariklia , Apostolou Effie , Daliani Danai , Papandreou Christos N
Published: May 2011

Background

Castration-resistance in prostate cancer (PC) is a critical event hallmarking a switch to a more aggressive phenotype. Neuroendocrine differentiation and upregulation of NFκB transcriptional activity are two mechanisms that have been independently linked to this process.

Methods

We investigated these two pathways together using in vitro models of androgen-dependent (AD) and androgen-independent (AI) PC. We measured cellular levels, activity and surface expression of Neutral Endopeptidase (NEP), levels of secreted Endothelin-1 (ET-1), levels, sub-cellular localisation and DNA binding ability of NFκB, and proteasomal activity in human native PC cell lines (LnCaP and PC-3) modelling AD and AI states.

Results

At baseline, AD cells were found to have high NEP expression and activity and low secreted ET-1. In contrast, they exhibited a low-level activation of the NFκB pathway associated with comparatively low 20S proteasome activity. The AI cells showed the exact mirror image, namely increased proteasomal activity resulting in a canonical pathway-mediated NFκB activation, and minimal NEP activity with increased levels of secreted ET-1.

Conclusions

Our results seem to support evidence for divergent patterns of expression of the NFκB/proteasome pathway with relation to components of the NEP/neuropeptide axis in PC cells of different level of androgen dependence. NEP and ET-1 are inversely and directly related to an activated state of the NFκB/proteasome pathway, respectively. A combination therapy targeting both pathways may ultimately prove to be of benefit in clinical practice.
High prevalence of dhfr triple mutant and correlation with high rates of sulphadoxine-pyrimethamine treatment failures in vivo in Gabonese children
Authors: Mombo-Ngoma Ghyslain , Oyakhirome Sunny , Ord Rosalynn , Gabor Julian J , Greutélaers Katja C , Profanter Katharina , Greutélaers Benedikt , Kurth Florian , Lell Bertrand , Kun Jürgen FJ , Issifou Saadou , Roper Cally , Kremsner Peter G , Grobusch Martin P
Published: May 2011

Background

Drug resistance contributes to the global malaria burden. Plasmodium
falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) polymorphisms confer resistance to sulphadoxine-pyrimethamine (SP).

Methods

The study assessed the frequency of SP resistance-conferring polymorphisms in Plasmodium
falciparum-positive samples from two clinical studies in Lambaréné. Their role on treatment responses and transmission potential was studied in an efficacy open-label clinical trial with a 28-day follow-up in 29 children under five with uncomplicated malaria.

Results

SP was well tolerated by all subjects in vivo. Three subjects were excluded from per-protocol analysis. PCR-corrected, 12/26 (46%) achieved an adequate clinical and parasitological response, 13/26 (50%) were late parasitological failures, while 1/26 (4%) had an early treatment failure, resulting in early trial discontinuation. Of 106 isolates, 98 (92%) carried the triple mutant dhfr haplotype. Three point mutations were found in dhps in a variety of haplotypic configurations. The 437G + 540E double mutant allele was found for the first time in Gabon.

Conclusions

There is a high prevalence of dhfr triple mutant with some dhps point mutations in Gabon, in line with treatment failures observed, and molecular markers of SP resistance should be closely monitored.

Trial Registration

ClinicalTrials.gov: NCT00453856
Status of pesticide management in the practice of vector control: a global survey in countries at risk of malaria or other major vector-borne diseases
Authors: van den Berg Henk , Hii Jeffrey , Soares Agnes , Mnzava Abraham , Ameneshewa Birkinesh , Dash Aditya P , Ejov Mikhail , Tan Soo Hian , Matthews Graham , Yadav Rajpal S , Zaim Morteza
Published: May 2011

Background

It is critical that vector control pesticides are used for their acceptable purpose without causing adverse effects on health and the environment. This paper provides a global overview of the current status of pesticides management in the practice of vector control.

Methods

A questionnaire was distributed to WHO member states and completed either by the director of the vector-borne disease control programme or by the national manager for vector control. In all, 113 countries responded to the questionnaire (80% response rate), representing 94% of the total population of the countries targeted.

Results

Major gaps were evident in countries in pesticide procurement practices, training on vector control decision making, certification and quality control of pesticide application, monitoring of worker safety, public awareness programmes, and safe disposal of pesticide-related waste. Nevertheless, basic conditions of policy and coordination have been established in many countries through which the management of vector control pesticides could potentially be improved. Most countries responded that they have adopted relevant recommendations by the WHO.

Conclusions

Given the deficiencies identified in this first global survey on public health pesticide management and the recent rise in pesticide use for malaria control, the effectiveness and safety of pesticide use are being compromised. This highlights the urgent need for countries to strengthen their capacity on pesticide management and evidence-based decision making within the context of an integrated vector management approach.
Chemical stability study of vitamins thiamine, riboflavin, pyridoxine and ascorbic acid in parenteral nutrition for neonatal use
Authors: Ribeiro Daniela O , Pinto Daniela C , Lima Luis Mauricio TR , Volpato Nádia M , Cabral Lúcio M , de Sousa Valéria P
Published: May 2011

Background

The objective of this work was to study the vitamins B1, B2, B6 and C stability in a pediatric formulation containing high amounts of calcium in the presence of organic phosphate, amino acids, glucose, sodium chloride, magnesium sulfate, pediatric vitamins and trace elements under different conditions using developed and validated analytical methods.

Methods

The study was carried out during 72 h with formulations packaged in recommended storage temperature (4°C) and 25°C, with and without photoprotection.

Results

The results showed that the methodologies used for assessing the chemical stability of vitamins B1, B2, B6 and C in the formulation were selective, linear, precise and accurate. The vitamins could be considered stable in the formulation during the three days of study if stored at 4°C. When stored at 25°C vitamin C presented instability after 48 h.

Conclusion

The pediatric formulation containing high amount of calcium in the presence of organic phosphate, amino acids, glucose, sodium chloride, magnesium sulphate, pediatric vitamins and trace elements packaged in bag-type trilaminate presented a shelf life of the 72 h, when maintained under refrigeration, between 2°C and 8°C. This shelf life was measured considering the vitamins studied. Further studies are needed including all the vitamins present in this formulation.
Environmental noise exposure, early biological risk and mental health in nine to ten year old children: a cross-sectional field study
Authors: Crombie Rosanna , Clark Charlotte , Stansfeld Stephen A
Published: May 2011

Background

Previous research suggests that children born prematurely or with a low birth weight are more vulnerable to the mental health effects of ambient neighbourhood noise; predominantly road and rail noise, at home. This study used data from the Road Traffic and Aircraft Noise Exposure and Children's Cognition and Health (RANCH) study to see if this finding extends to aircraft and road traffic noise at school.

Methods

Children and their parents from schools around three European airports were selected to represent a range of aircraft and road traffic noise exposure levels. Birth weight and gestation period were merged to create a dichotomous variable assessing 'early biological risk'. Mental health was assessed using the Strengths and Difficulties Questionnaire (SDQ). Complete data were available for 1900 primary school children.

Results

Children who were 'at risk' (i.e. low birth weight or premature birth) were rated as having more conduct problems and emotional symptoms and poorer overall mental health than children not at risk. However, there was no interaction between aircraft or road traffic noise exposure at school and early biological risk.

Conclusions

Data from the RANCH study suggests that children with early biological risk are not more vulnerable to the effects of aircraft or road traffic noise at school on mental health than children without this risk; however they are more likely to have mental ill-health.
Bioactivities of berberine metabolites after transformation through CYP450 isoenzymes
Authors: Li Yi , Ren Gang , Wang Yan-Xiang , Kong Wei-Jia , Yang Peng , Wang Yue-Ming , Li Ying-Hong , Yi Hong , Li Zhuo-Rong , Song Dan-Qing , Jiang Jian-Dong
Published: May 2011

Background

Berberine (BBR) is a drug with multiple effects on cellular energy metabolism. The present study explored answers to the question of which CYP450 (Cytochrome P450) isoenzymes execute the phase-I transformation for BBR, and what are the bioactivities of its metabolites on energy pathways.

Methods

BBR metabolites were detected using LC-MS/MS. Computer-assistant docking technology as well as bioassays with recombinant CYP450s were employed to identify CYP450 isoenzymes responsible for BBR phase-I transformation. Bioactivities of BBR metabolites in liver cells were examined with real time RT-PCR and kinase phosphorylation assay.

Results

In rat experiments, 4 major metabolites of BBR, berberrubine (M1), thalifendine (M2), demethyleneberberine (M3) and jatrorrhizine (M4) were identified in rat's livers using LC-MS/MS (liquid chromatography-tandem mass spectrometry). In the cell-free transformation reactions, M2 and M3 were detectable after incubating BBR with rCYP450s or human liver microsomes; however, M1 and M4 were below detective level. CYP2D6 and CYP1A2 played a major role in transforming BBR into M2; CYP2D6, CYP1A2 and CYP3A4 were for M3 production. The hepatocyte culture showed that BBR was active in enhancing the expression of insulin receptor (InsR) and low-density-lipoprotein receptor (LDLR) mRNA, as well as in activating AMP-activated protein kinase (AMPK). BBR's metabolites, M1-M4, remained to be active in up-regulating InsR expression with a potency reduced by 50-70%; LDLR mRNA was increased only by M1 or M2 (but not M3 and M4) with an activity level 35% or 26% of that of BBR, respectively. Similarly, AMPK-α phosphorylation was enhanced by M1 and M2 only, with a degree less than that of BBR.

Conclusions

Four major BBR metabolites (M1-M4) were identified after phase-I transformation in rat liver. Cell-free reactions showed that CYP2D6, CYP1A2 and CYP3A4 seemed to be the dominant CYP450 isoenzymes transforming BBR into its metabolites M2 and M3. BBR's metabolites remained to be active on BBR's targets (InsR, LDLR, and AMPK) but with reduced potency.
Improved ground-state modulation characteristics in 1.3 μm InAs/GaAs quantum dot lasers by rapid thermal annealing
Authors: Zhao Hanxue , Yoon Soon Fatt , Ngo Chun Yong , Wang Rui
Published: May 2011

We investigated the ground-state (GS) modulation characteristics of 1.3 μm InAs/GaAs quantum dot (QD) lasers that consist of either as-grown or annealed QDs. The choice of annealing conditions was determined from our recently reported results. With reference to the as-grown QD lasers, one obtains approximately 18% improvement in the modulation bandwidth from the annealed QD lasers. In addition, the modulation efficiency of the annealed QD lasers improves by approximately 45% as compared to the as-grown ones. The observed improvements are due to (1) the removal of defects which act as nonradiative recombination centers in the QD structure and (2) the reduction in the Auger-related recombination processes upon annealing.
Lentiviral vector-mediated stable expression of sTNFR-Fc in human macrophage and neuronal cells as a potential therapy for neuroAIDS
Authors: Cao Shengbo , Wu Chengxiang , Yang Yongbo , Sniderhan Lynn F , Maggirwar Sanjay B , Dewhurst Stephen , Lu Yuanan
Published: May 2011

Background

Human immunodeficiency virus type 1 (HIV-1) infection frequently causes neurologic disease, which is the result of viral replication and activation of macrophages and microglia in the CNS, and subsequent secretion of high levels of neurotoxic products, including tumor necrosis factor-α (TNF-α). We therefore hypothesized that a soluble TNF-α antagonist might have potential utility as a neuroprotective effecter molecule, and conducted proof-of-concept studies to test this hypothesis.

Methods

To develop novel therapeutics for the treatment of neuroAIDS, we constructed and characterized a soluble TNF receptor (sTNFR)-Fc fusion protein with the goal of neutralizing TNF-α, and tested the stability of expression of this gene following delivery by a lentiviral vector.

Results

High-titer lentiviral vectors were prepared, allowing efficient transduction of macrophage/glial and neuronal cell lines, as well as primary rat cerebellar neurons. Efficient, stable secretion of sTNFR-Fc was demonstrated in supernatants from transduced cell lines over 20 passages, using both western blot and ELISA. Biological activity of the secreted sTNFR-Fc was confirmed by TNF-specificin vitroprotein binding and functional blocking assays. Finally, the secreted protein was shown to protect neuronal cells from TNF-α, HIV-1 Tat-, and gp120-mediated neurotoxicity.

Conclusions

These results demonstrate that lentiviral vector mediated expression of sTNFR-Fc may have potential as a novel therapy for neuroAIDS.
Trafficking of some old world primate TRIM5α proteins through the nucleus
Authors: Diaz-Griffero Felipe , Gallo Daniel E , Hope Thomas J , Sodroski Joseph
Published: May 2011

Background

TRIM5α and TRIMCyp are cytoplasmic proteins that bind incoming retroviral capsids and mediate early blocks to viral infection. TRIM5 proteins form cytoplasmic bodies, which are highly dynamic structures. So far, TRIM5 proteins have been found only in the cytoplasm of cells. Interestingly, other proteins from the TRIM family localize to the nucleus. Therefore, we tested the possibility that TRIM5 proteins traffic to the nucleus and the impact of this trafficking on retroviral restriction.

Results

Here we report that the TRIM5α proteins of two Old World primates, humans and rhesus monkeys, are transported into the nucleus and are shuttled back to the cytoplasm by a leptomycin B-sensitive mechanism. In leptomycin B-treated cells, these TRIM5α proteins formed nuclear bodies that also contained TRIM19 (PML). Deletion of the amino terminus, including the linker 1 (L1) region, resulted in TRIM5α proteins that accumulated in nuclear bodies. Leptomycin B treatment of TRIM5α-expressing target cells only minimally affected the restriction of retrovirus infection.

Conclusions

We discovered the ability of human and rhesus TRIM5α to shuttle into and out of the nucleus. This novel trafficking ability of TRIM5α proteins could be important for an as-yet-unknown function of TRIM5α.
Defining neurotrauma in administrative data using the International Classification of Diseases Tenth Revision
Authors: Chen Amy Y , Colantonio Angela
Published: May 2011

Background

It is essential to use a definition that is precise and accurate for the surveillance of traumatic brain injuries (TBI) and spinal cord injuries (SCI). This paper reviews the International Classification of Diseases 10th revision (ICD-10) definitions used internationally to inform the definition for neurotrauma surveillance using administrative data in Ontario, Canada.

Methods

PubMed, Web of Science, Medline and the grey literature were searched for keywords "spinal cord injuries" or "brain injuries" and "international classification of diseases". All papers and reports that used an ICD-10 definition were included. To determine the ICD-10 codes for inclusion consensus across papers and additional evidence were sought to look at the correlation between the condition and brain or spinal injuries.

Results

Twenty-four articles and reports were identified; 15 unique definitions for TBI and 7 for SCI were found. The definitions recommended for use in Ontario by this paper are F07.2, S02.0, S02.1, S02.3, S02.7, S02.8, S02.9, S06, S07.1, T90.2, and T90.5 for traumatic brain injuries and S14.0, S14.1, S24.0, S24.1, S34.1, S34.0, S34.3, T06.0, T06.1 and T91.3 for spinal cord injuries.

Conclusions

Internationally, inconsistent definitions are used to define brain and spinal cord injuries. An abstraction study of data would be an asset in understanding the effects of inclusion and exclusion of codes in the definition. This paper offers a definition of neurotrauma for surveillance in Ontario, but the definition could be applied to other countries that have mandated administrative data collection.
Immunogenicity and safety of virus-like particle of the porcine encephalomyocarditis virus in pig
Authors: Jeoung Hye-Young , Lee Won-Ha , Jeong WooSeog , Shin Bo-Hye , Choi Hwan-Won , Lee Hee Soo , An Dong-Jun
Published: May 2011

Background

In this study, porcine encephalomyocarditis virus (EMCV) virus-like particles (VLPs) were generated using a baculovirus expression system and were tested for immunogenicity and protective efficacy in vivo.

Results

VLPs were successfully generated from Sf9 cells infected with recombinant baculovirus and were confirmed to be approximately 30-40 nm by transmission electron microscopy (TEM). Immunization of mice with 0.5 μg crude protein containing the VLPs resulted in significant protection from EMCV infection (90%). In swine, increased neutralizing antibody titers were observed following twice immunization with 2.0 μg crude protein containing VLPs. In addition, high levels of neutralizing antibodies (from 64 to 512 fold) were maintained during a test period following the second immunization. No severe injection site reactions were observed after immunization and all swine were healthy during the immunization period

Conclusion

Recombinant EMCV VLPs could represent a new vaccine candidate to protect against EMCV infection in pig farms.
Claudin-1 required for HCV virus entry has high potential for phosphorylation and O-glycosylation
Authors: Ahmad Waqar , Shabbiri Khadija , Ijaz Bushra , Asad Sultan , Sarwar Muhammad T , Gull Sana , Kausar Humera , Fouzia Kiran , Shahid Imran , Hassan Sajida
Published: May 2011

HCV is a leading cause of hepatocellular carcinoma and cirrhosis all over the world. Claudins belong to family of tight junction's proteins that are responsible for establishing barriers for controlling the flow of molecules around cells. For therapeutic strategies, regulation of viral entry into the host cells holds a lot of promise. During HCV infection claudin-1 is highly expressed in liver and believed to be associated with HCV virus entry after HCV binding with or without co-receptor CD81. The claudin-1 assembly with tight junctions is regulated by post translational modifications. During claudins assembly and disassembly with tight junctions, phosphorylation is required at C-terminal tail. In cellular proteins, interplay between phosphorylation and O-β-GlcNAc modification is believed to be functional switch, but it is very difficult to monitor these functional and vibrant changes in vivo. Netphos 2.0 and Disphos 1.3 programs were used for potential phosphorylation; NetPhosK 1.0 and KinasePhos for kinase prediction; and YinOYang 1.2 and OGPET to predict possible O-glycosylation sites. We also identified Yin Yang sites that may have potential for O-β-GlcNAc and phosphorylation interplay at same Ser/Thr residues. We for the first time proposed that alternate phosphorylation and O-β-GlcNAc modification on Ser 192, Ser 205, Ser 206; and Thr 191 may provide an on/off switch to regulate assembly of claudin-1 at tight junctions. In addition these phosphorylation sites may be targeted by novel chemotherapeutic agents to prevent phosphorylation lead by HCV viral entry complex.
Hepatitis B virus induces G1 phase arrest by regulating cell cycle genes in HepG2.2.15 cells
Authors: Wang Tianzhen , Zhao Ran , Wu Yiqi , Kong Dan , Zhang Lei , Wu Di , Li Chao , Zhang Chong , Yu Zuxi , Jin Xiaoming
Published: May 2011

Background

To investigate the effect of HBV on the proliferative ability of host cells and explore the potential mechanism.

Methods

MTT, colony formation assay and tumourigenicity in nude mice were performed to investigate the effect of HBV on the proliferative capability of host cells. In order to explore the potential mechanism, cell cycle and apoptosis were analysed. The cell cycle genes controlling the G1/S phase transition were detected by immunohistochemistry, westernblot and RT-PCR.

Results

HepG2.2.15 cells showed decreased proliferation ability compared to HepG2 cells. G1 phase arrest was the main cause but was not associated with apoptosis. p53, p21 and total retinoblastoma (Rb) were determined to be up-regulated, whereas cyclinE was down-regulated at both the protein and mRNA levels in HepG2.2.15 cells. The phosphorylated Rb in HepG2.2.15 cells was decreased.

Conclusions

Our results suggested that HBV inhibited the capability of proliferation of HepG2.2.15 cells by regulating cell cycle genes expression and inducing G1 arrest.
Subchronic inhalation toxicity of gold nanoparticles
Authors: Sung Jae Hyuck , Ji Jun Ho , Park Jung Duck , Song Moon Yong , Song Kyung Seuk , Ryu Hyeon Ryol , Yoon Jin Uk , Jeon Ki Soo , Jeong Jayoung , Han Beom Seok , Chung Yong Hyun , Chang Hee Kyung , Lee Ji Hyun , Kim Dong Won , Kelman Bruce J , Yu Il Je
Published: May 2011

Background

Gold nanoparticles are widely used in consumer products, including cosmetics, food packaging, beverages, toothpaste, automobiles, and lubricants. With this increase in consumer products containing gold nanoparticles, the potential for worker exposure to gold nanoparticles will also increase. Only a few studies have produced data on the in vivo toxicology of gold nanoparticles, meaning that the absorption, distribution, metabolism, and excretion (ADME) of gold nanoparticles remain unclear.

Results

The toxicity of gold nanoparticles was studied in Sprague Dawley rats by inhalation. Seven-week-old rats, weighing approximately 200 g (males) and 145 g (females), were divided into 4 groups (10 rats in each group): fresh-air control, low-dose (2.36 × 104 particle/cm3, 0.04 μg/m3), middle-dose (2.36 × 105 particle/cm3, 0.38 μg/m3), and high-dose (1.85 × 106 particle/cm3, 20.02 μg/m3). The animals were exposed to gold nanoparticles (average diameter 4-5 nm) for 6 hours/day, 5 days/week, for 90-days in a whole-body inhalation chamber. In addition to mortality and clinical observations, body weight, food consumption, and lung function were recorded weekly. At the end of the study, the rats were subjected to a full necropsy, blood samples were collected for hematology and clinical chemistry tests, and organ weights were measured. Cellular differential counts and cytotoxicity measurements, such as albumin, lactate dehydrogenase (LDH), and total protein were also monitored in a cellular bronchoalveolar lavage (BAL) fluid. Among lung function test measurements, tidal volume and minute volume showed a tendency to decrease comparing control and dose groups during the 90-days of exposure. Although no statistically significant differences were found in cellular differential counts, histopathologic examination showed minimal alveoli, an inflammatory infiltrate with a mixed cell type, and increased macrophages in the high-dose rats. Tissue distribution of gold nanoparticles showed a dose-dependent accumulation of gold in only lungs and kidneys with a gender-related difference in gold nanoparticles content in kidneys.

Conclusions

Lungs were the only organ in which there were dose-related changes in both male and female rats. Changes observed in lung histopathology and function in high-dose animals indicate that the highest concentration (20 μg/m3) is a LOAEL and the middle concentration (0.38 μg/m3) is a NOAEL for this study.
Galanin-Immunoreactivity Identifies a Distinct Population of Inhibitory Interneurons in Laminae I-III of the Rat Spinal Cord
Authors: Tiong Sheena YX , Polgár Erika , van Kralingen Josie C , Watanabe Masahiko , Todd Andrew J
Published: May 2011

Background:

Inhibitory interneurons constitute 30-40% of neurons in laminae I-III and have an important antinociceptive role. However, because of the difficulty in classifying them we know little about their organisation. Previous studies have identified 3 non-overlapping groups of inhibitory interneuron, which contain neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS) or parvalbumin, and have shown that these differ in postsynaptic targets. Some inhibitory interneurons contain galanin and the first aim of this study was to determine whether these form a different population from those containing NPY, nNOS or parvalbumin. We also estimated the proportion of neurons and GABAergic axons that contain galanin in laminae I-III.

Results:

Galanin cells were concentrated in laminae I-IIo, with few in laminae IIi-III. Galanin showed minimal co-localisation with NPY, nNOS or parvalbumin in laminae I-II, but most galanin-containing cells in lamina III were nNOS-positive. Galanin cells constituted ∼7%, 3% and 2% of all neurons in laminae I, II and III, and we estimate that this corresponds to 26%, 10% and 5% of the GABAergic neurons in these laminae. However, galanin was only found in ∼6% of GABAergic boutons in laminae I-IIo, and ∼1% of those in laminae IIi-III.

Conclusions:

These results show that galanin, NPY, nNOS and parvalbumin can be used to define four distinct neurochemical populations of inhibitory interneurons. Together with results of a recent study, they suggest that the galanin and NPY populations account for around half of the inhibitory interneurons in lamina I and a quarter of those in lamina II.
Density of CD4(+) and CD8(+) T lymphocytes in biopsy samples can be a predictor of pathological response to chemoradiotherapy (CRT) for rectal cancer
Authors: Yasuda Koji , Nirei Takako , Sunami Eiji , Nagawa Hirokazu , Kitayama Joji
Published: May 2011

Background

Although preoperative radiotherapy (RT) is widely used as the initial treatment for locally advanced rectal cancer (RC) in the neoadjuvant setting, factors determining clinical response have not been adequately defined. Radiosensitivity has recently been shown to be greatly affected by immune function of the host.

Methods

In 48 cases of advanced RC, we retrospectively examined the density of tumor infiltrating CD4(+) and CD8(+) T cells using immunohistochemical staining of biopsy samples before CRT, and examined the correlation with tumor response.

Results

The numbers of both CD4(+) and CD8(+) tumor-infiltrating lymphocytes (TIL) in pre-CRT biopsy samples were strongly correlated with tumor reduction ratio evaluated by barium enema. Moreover, the densities of CD4(+) and CD8(+) TIL were significantly associated with histological grade after CRT. The density of CD8(+) TIL was an independent prognostic factor for achieving complete response after CRT.

Conclusions

In RC patients, T lymphocyte-mediated immune reactions play an important role in tumor response to CRT, and the quantitative measurement of TIL in biopsy samples before CRT can be used as a predictor of the clinical effectiveness of CRT for advanced RC.
Intramuscular myxoma associated with an increased carbohydrate antigen 19.9 level in a woman: a case report
Authors: Theodorou Dimitrios , Kleidi Eleftheria S , Doulami Georgia I , Drimousis Panagiotis G , Larentzakis Andreas , Toutouzas Kostas , Katsaragakis Stylianos
Published: May 2011

Introduction

Intramuscular myxoma is a rare benign soft tissue tumor. The lack of specific symptoms and widely used laboratory tests makes the diagnosis quite difficult. We present a case of an Intramuscular myxoma associated with an increased carbohydrate antigen 19.9 level. To the best of our knowledge, there have not been any reported cases of an association of Intramuscular myxoma with tumor markers in the literature.

Case presentation

A 45-year-old Caucasian woman presented to our department for resection of a mass in her left groin area, discovered incidentally on a triplex ultrasonography of her lower extremities. The diagnosis of Intramuscular myxoma was confirmed on histopathology after the complete surgical excision of the tumor. On laboratory examination, the serum level of carbohydrate antigen 19.9 was found to be elevated, but it returned to normal six months after resection of the mass.

Conclusion

Carbohydrate antigen 19.9 is a tumor marker that increases in a variety of malignant and benign conditions. After the exclusion of all other possible reasons for carbohydrate antigen 19.9 elevation, we assumed a possible connection of carbohydrate antigen 19.9 elevation and Intramuscular myxoma, an issue that requires needs further investigation.
Exon array analysis reveals neuroblastoma tumors have distinct alternative splicing patterns according to stage and MYCN amplification status
Authors: Guo Xiang , Chen Qing-Rong , Song Young K , Wei Jun S , Khan Javed
Published: May 2011

Background

Neuroblastoma (NB) tumors are well known for their pronounced clinical and molecular heterogeneity. The global gene expression and DNA copy number alterations have been shown to have profound differences in tumors of low or high stage and those with or without MYCN amplification. RNA splicing is an important regulatory mechanism of gene expression, and differential RNA splicing may be associated with the clinical behavior of a tumor.

Methods

In this study, we used exon array profiling to investigate global alternative splicing pattern of 47 neuroblastoma samples in stage 1 and stage 4 with normal or amplified MYCN copy number (stage 1-, 4- and 4+). The ratio of exon-level expression to gene-level expression was used to detect alternative splicing events, while the gene-level expression was applied to characterize whole gene expression change.

Results

Principal component analysis (PCA) demonstrated distinct splicing pattern in three groups of samples. Pairwise comparison identified genes with splicing changes and/or whole gene expression changes in high stage tumors. In stage 4- compared with stage 1- tumors, alternatively spliced candidate genes had little overlap with genes showing whole gene expression changes, and most of them were involved in different biological processes. In contrast, a larger number of genes exhibited either exon-level splicing, gene-level expression or both changes in stage 4+ versus stage 1- tumors. Those biological processes involved in stage 4- tumors were disrupted to a greater extent by both splicing and transcription regulations in stage 4+ tumors.

Conclusions

Our results demonstrated a significant role of alternative splicing in high stage neuroblastoma, and suggested a MYCN-associated splicing regulation pathway in stage 4+ tumors. The identification of differentially spliced genes and pathways in neuroblastoma tumors of different stages and molecular subtypes may be important to the understanding of cancer biology and the discovery of diagnostic markers or therapeutic targets in neuroblastoma.
Insecticide susceptibility of Aedes aegypti and Aedes albopictus in Central Africa
Authors: Kamgang Basile , Marcombe Sébastien , Chandre Fabrice , Nchoutpouen Elysée , Nwane Philippe , Etang Josiane , Corbel Vincent , Paupy Christophe
Published: May 2011

Background

Aedes aegypti(Linnaeus, 1762) andAedes albopictus(Skuse, 1894) are the main vectors of dengue (DENV) and chikungunya (CHIKV) viruses worldwide. As there is still no vaccine or specific treatment for DENV and CHIKV, vector control remains the cornerstone of prevention and outbreak control. Unfortunately, vector control programs are facing operational challenges with mosquitoes becoming resistant to commonly used insecticides in several areas through the world. Throughout Central Africa no recent data are available susceptible/resistant status of either vector species since the introduction/arrival ofAe. albopictusin this area. We therefore studied the level of resistance of these two major vectors to insecticides commonly used in Africa for mosquito control.

Results

Aedes aegyptiandAe. albopictuswere sampled in six urban localities of Cameroon (Garoua, Bertoua, Yaoundé, Bafia, Buea) and Gabon (Libreville). Larval bioassays, carried out to determine the lethal concentrations (LC50and LC95) and resistance ratios (RR50and RR95) suggested that both vector species were susceptible toBti(Bacillus thuringiensis var israeliensis) and temephos. Bioassays were also performed on adults using WHO diagnostic test kits to assess phenotypic resistance to deltamethrin, DDT, fenitrothion and propoxur. These experiments showed that one population ofAe. aegypti(Libreville) and two populations ofAe. albopictus(Buea and Yaoundé) were resistant to DDT (mortality 36% to 71%). Resistance to deltamethrin was also suspected inAe. albopictusfrom Yaoundé (83% mortality). All other field mosquito populations were susceptible to deltamethrin, DDT, fenitrothion and propoxur. No increase in the knockdown times (Kdt50and Kdt95) was noted in the Yaoundé resistant population compared to otherAe. albopictuspopulations, suggesting the possible involvement of metabolic resistance to deltamethrin and DDT.

Conclusion

In view of the recent increase in dengue and chikungunya outbreaks in Central Africa, these unique comparative data on the insecticide susceptibility ofAe. aegyptiandAe. albopictuscould help public health services to design more effective vector control measures.
Gene expression profiles in BCL11B-siRNA treated malignant T cells
Authors: Huang Xin , Shen Qi , Chen Si , Chen Shaohua , Yang Lijian , Weng Jianyu , Du Xin , Grabarczyk Piotr , Przybylski Grzegorz K , Schmidt Christian A , Li Yangqiu
Published: May 2011

Background

Downregulation of the B-cell chronic lymphocytic leukemia (CLL)/lymphoma11B (BCL11B) gene by small interfering RNA (siRNA) leads to growth inhibition and apoptosis of the human T-cell acute lymphoblastic leukemia (T-ALL) cell line Molt-4. To further characterize the molecular mechanism, a global gene expression profile of BCL11B-siRNA -treated Molt-4 cells was established. The expression profiles of several genes were further validated in the BCL11B-siRNA -treated Molt-4 cells and primary T-ALL cells.

Results

142 genes were found to be upregulated and 109 genes downregulated in the BCL11B-siRNA -treated Molt-4 cells by microarray analysis. Among apoptosis-related genes, three pro-apoptotic genes, TNFSF 10, BIK, BNIP 3, were upregulated and one anti-apoptotic gene, BCL2L 1 was downregulated. Moreover, the expression of SPP 1 and CREBBP genes involved in the transforming growth factor (TGF-β) pathway was down 16-fold. Expression levels of TNFSF 10, BCL2L 1, SPP 1, and CREBBP were also examined by real-time PCR. A similar expression pattern of TNFSF 10, BCL2L 1, and SPP 1 was identified. However, CREBBP was not downregulated in the BLC11B-siRNA -treated Molt-4 cells.

Conclusion

BCL11B-siRNA treatment altered expression profiles of TNFSF 10, BCL2L 1, and SPP 1 in both Molt-4 T cell line and primary T-ALL cells.
Antisense oligodeoxynucleotides targeting ATM strengthen apoptosis of laryngeal squamous cell carcinoma grown in nude mice
Authors: Feng Jun , Zou Jian , Li Li , Zhao Yongsheng , Liu Shixi
Published: May 2011

Background

To conserve laryngeal function and elevate living quality of laryngeal squamous cell carcinoma (LSCC) patients, we designed antisense oligodeoxynucleotides (AS-ODNs) to reduce expression of ATM and to enhance the apoptosis of hep-2 (Human epidermoid laryngeal carcinoma) cells to radiation in vitro and in vivo.

Methods

The expression of ATM mRNA and protein in hep-2 cells were examined by real-time quantitative PCR and western blotting respectively. Clonogenic survival assay was carried out to detect the survival ability of hep-2 cells after irradiation, and analyzed the cell apoptosis by flow cytometry. The volume of solid tumors was measured, while TUNEL assay and western blotting used to analyze cell apoptosis and protein expression after irradiation.

Results

The relative ATM mRNA and protein expression in hep-2 cells treated with ATM AS-ODNs were decreased to 11.03 ± 2.51% and 48.14 ± 5.53% of that in untreated cells respectively (P <0.05). After irradiation, the survival fraction (SF) of cells treated with ATM AS-ODNs was lower than that of other groups at the same dose of radiation (P < 0.05). The inhibition rate in hep-2 cells solid tumor exposed to X-ray alone was 5.95 ± 4.52%, while it was 34.28 ± 2.43% in the group which irradiated in combination with the treatment of ATM AS-ODNs (P < 0.05). The apoptotic index for the group irradiated in combination with ATM AS-ODNs injection was 17.12 ± 4.2%, which was significantly higher than that of others (P < 0.05).

Conclusion

AS-ODNs of ATM reduce ATM expression and enhance hep-2 cells apoptosis to radiation in vitro and in vivo.
Targeted Therapy With the T-Cell–Engaging Antibody Blinatumomab of Chemotherapy-Refractory Minimal Residual Disease in B-Lineage Acute Lymphoblastic Leukemia Patients Results in High Response Rate and Prolonged Leukemia-Free Survival
Authors: Topp Max S. , Kufer Peter , Gökbuget Nicola , Goebeler Mariele , Klinger Matthias , Neumann Svenja , Horst Heinz-A. , Raff Thorsten , Viardot Andreas , Schmid Mathias , Stelljes Matthias , Schaich Markus , Degenhard Evelyn , Köhne-Volland Rudolf , Brüggemann Monika , Ottmann Oliver , Pfeifer Heike , Burmeister Thomas , Nagorsen Dirk , Schmidt Margit , Lutterbuese Ralf , Reinhardt Carsten , Baeuerle Patrick A. , Kneba Michael , Einsele Hermann , Riethmüller Gert , Hoelzer Dieter , Zugmaier Gerhard , Bargou Ralf C.
Published: May 2011

Purpose

Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL.

Patients and Methods

Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours.

Results

Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events.

Conclusion

Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.
Pazopanib Efficacy in Renal Cell Carcinoma: Evidence for Predictive Genetic Markers in Angiogenesis-Related and Exposure-Related Genes
Authors: Xu Chun-Fang , Bing Nan X. , Ball Howard A. , Rajagopalan Dilip , Sternberg Cora N. , Hutson Thomas E. , de Souza Paul , Xue Zhengyu G. , McCann Lauren , King Karen S. , Ragone Leigh J. , Whittaker John C. , Spraggs Colin F. , Cardon Lon R. , Mooser Vincent E. , Pandite Lini N.
Published: May 2011

Purpose

Pazopanib, an oral angiogenesis inhibitor, is approved for the treatment of advanced renal cell carcinoma (RCC). Response to pazopanib monotherapy varies between patients, and no validated biomarkers predictive of treatment outcome have been identified. We tested the hypothesis that this variability is partially dependent on germline genetic variants that may affect pazopanib exposure or angiogenesis pathways.

Patients and Methods

Twenty-seven functional polymorphisms within 13 genes were evaluated in 397 patients with RCC. Genetic association with progression-free survival (PFS) and objective response rate (RR) was analyzed using the Cox proportional hazards model and proportional odds model, respectively.

Results

Three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2, and VEGFA showed nominally significant association (P ≤ .05) with PFS and RR, respectively. Compared with the wild-type AA genotype (median PFS, 48 weeks), the IL8 2767TT variant genotype showed inferior PFS (27 weeks, P = .009). The HIF1A 1790AG genotype was associated with inferior PFS and reduced RR, compared with the wild-type GG genotype (median PFS, 20 v 44 weeks; P = .03; RR, 30% v 43%, P = .02). Reductions in RR were detected for the NR1I2 −25385TT genotype, compared with the wild-type CC genotype (37% v 50%, P = .03), and for the VEGFA −1498CC genotype compared with the TT genotypes (33% v 51%).

Conclusion

Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue.
Actual Status of Distribution and Prognostic Impact of Extramural Discontinuous Cancer Spread in Colorectal Cancer
Authors: Ueno Hideki , Mochizuki Hidetaka , Shirouzu Kazuo , Kusumi Takaya , Yamada Kazutaka , Ikegami Masahiro , Kawachi Hiroshi , Kameoka Shingo , Ohkura Yasuo , Masaki Tadahiko , Kushima Ryoji , Takahashi Keiichi , Ajioka Yoichi , Hase Kazuo , Ochiai Atsushi , Wada Ryo , Iwaya Keiichi , Nakamura Takahiro , Sugihara Kenichi
Published: May 2011

Purpose

To clarify the prognostic impact of tumor nodules without residual lymph node (LN) structure (ND) in colorectal cancer and to determine optimal categorization of ND in tumor staging.

Patients and Methods

A multicenter, retrospective pathologic review was performed for 1,716 patients with stages I to III curatively resected colorectal cancer treated at 11 institutions between 1994 and 1998. An additional 2,242 patients from nine institutions were enrolled between 1999 and 2003 as a second cohort to validate the results.

Results

LN metastasis (LNM) and ND were observed in 33.7% and 16.0% (smooth-contour nodule [S-ND], 8.2%; irregular-contour nodule [I-ND], 10.7%) of patients in the first cohort. S-ND and I-ND were similarly distributed in the regional area. There was no considerable difference in the impact on survival between S-ND (hazard ratio [HR], 2.7; 95% CI, 1.9 to 3.8) and I-ND (HR, 4.3; 95% CI, 3.3 to 5.8) or between LNM (HR, 4.5; 95% CI, 3.4 to 6.0) and ND (HR, 4.0; 95% CI, 3.1 to 5.3). LNM and ND were similarly associated with the mode of recurrence. Tumor nodules ≥ 5 mm growing with venous/perineural invasion (ND [v/pni+]), judged with 0.61 κ value among 11 observers, had an independent prognostic value for 5-year survival of 42%; similar results were observed in the second cohort.

Conclusion

These results do not support the TNM system in which S-ND is treated differently from I-ND in tumor staging; LNM and ND should be considered together in the same category. The presence of ND (v/pni+) has a considerable adverse prognostic effect.
Success Story of Targeted Therapy in Chronic Myeloid Leukemia: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2008
Authors: Björkholm Magnus , Ohm Lotta , Eloranta Sandra , Derolf Åsa , Hultcrantz Malin , Sjöberg Jan , Andersson Therese , Höglund Martin , Richter Johan , Landgren Ola , Kristinsson Sigurdur Y. , Dickman Paul W.
Published: May 2011

Purpose

Chronic myeloid leukemia (CML) management changed dramatically with the development of imatinib mesylate (IM), the first tyrosine kinase inhibitor targeting the BCR-ABL1 oncoprotein. In Sweden, the drug was approved in November 2001. We report relative survival (RS) of patients with CML diagnosed during a 36-year period.

Patients and Methods

Using data from the population-based Swedish Cancer Registry and population life tables, we estimated RS for all patients diagnosed with CML from 1973 to 2008 (n = 3,173; 1,796 males and 1,377 females; median age, 62 years). Patients were categorized into five age groups and five calendar periods, the last being 2001 to 2008. Information on use of upfront IM was collected from the Swedish CML registry.

Results

Relative survival improved with each calendar period, with the greatest improvement between 1994-2000 and 2001-2008. Five-year cumulative relative survival ratios (95% Cls) were 0.21 (0.17 to 0.24) for patients diagnosed 1973-1979, 0.54 (0.50 to 0.58) for 1994-2000, and 0.80 (0.75 to 0.83) for 2001-2008. This improvement was confined to patients younger than 79 years of age. Five-year RSRs for patients diagnosed from 2001 to 2008 were 0.91 (95% CI, 0.85 to 0.94) and 0.25 (95% CI, 0.10 to 0.47) for patients younger than 50 and older than 79 years, respectively. Men had inferior outcome. Upfront overall use of IM increased from 40% (2002) to 84% (2006). Only 18% of patients older than 80 years of age received IM as first-line therapy.

Conclusion

This large population-based study shows a major improvement in outcome of patients with CML up to 79 years of age diagnosed from 2001 to 2008, mainly caused by an increasing use of IM. The elderly still have poorer outcome, partly because of a limited use of IM.
Finding Freedom in Hamlet
Authors: Scodel Joshua
Published: May 2011

Hamlet and its protagonist place liberty at their center of vision by exploring its diverse senses. Freedom in Hamlet is of different kinds, always limited and hard to obtain or keep. The play's other characters serve as clarifying foils to Hamlet himself, who as the closely watched son of the murdered king is limited in his freedom to maneuver and whose quest for freedom is both fueled and stymied by the Ghost's command that he kill his uncle. Hamlet dramatizes the felt connections between external constraints on freedom of action and internal states that inhibit or foster such freedom. To assert some degree of social and political freedom depends on attaining freedom from thoughts and feelings that block free action. Hamlet probes the early modern semantic range of free and its cognates, which could denote sociopolitical status, on the one hand, and aspects of moral character and behavior, on the other. Influenced but not bound by Stoic and Christian conceptions of freedom, Hamlet can act most freely, and ultimately kill Claudius, after achieving a sense of inner moral freedom based on trust in a “divinity” that oversees the world.