bluuebunny/crossref_metadata_2025 huggingface dataset:
AFLP analysis reveals high genetic diversity but low population structure in Coccidioides posadasiiisolates from Mexico and Argentina
Authors: Duarte-Escalante Esperanza , Zúñiga Gerardo , Frías-De-León María Guadalupe , Canteros Cristina , Castañón-Olivares Laura Rosio , Reyes-Montes María Rocío del
Published: September 2013

Background

Coccidioides immitisandC. posadasiicause coccidioidomycosis, a disease that is endemic to North and South America, but for Central America, the incidence of coccidioidomycosis has not been clearly established. Several studies suggest genetic variability in these fungi; however, little definitive information has been discovered about the variability ofCoccidioidesfungi in Mexico (MX) and Argentina (AR). Thus, the goals for this work were to study 32Coccidioidesspp. isolates from MX and AR, identify the species of theseCoccidioidesspp. isolates, analyse their phenotypic variability, examine their genetic variability and investigate theCoccidioidesreproductive system and its level of genetic differentiation.

Methods

Coccidioidesspp. isolates from MX and AR were taxonomically identified by phylogenetic inference analysis using partial sequences of theAg2/PRAgene and their phenotypic characteristics analysed. The genetic variability, reproductive system and level of differentiation were estimated using AFLP markers. The level of genetic variability was assessed measuring the percentage of polymorphic loci, number of effective allele, expected heterocygosity and Index of Association (IA). The degree of genetic differentiation was determined by AMOVA. Genetic similarities among isolates were estimated using Jaccard index. The UPGMA was used to contsruct the corresponding dendrogram. Finally, a network of haplotypes was built to evaluate the genealogical relationships among AFLP haplotypes.

Results

All isolates ofCoccidioidesspp. from MX and AR were identified asC. posadasii. No phenotypic variability was observed among theC. posadasiiisolates from MX and AR. Analyses of genetic diversity and population structure were conducted using AFLP markers. Different estimators of genetic variability indicated that theC. posadasiiisolates from MX and AR had high genetic variability. Furthermore, AMOVA, dendrogram and haplotype network showed a small genetic differentiation among theC. posadasiipopulations analysed from MX and AR. Additionally, theIAcalculated for the isolates suggested that the species has a recombinant reproductive system.

Conclusions

No phenotypic variability was observed among theC. posadasiiisolates from MX and AR. The high genetic variability observed in the isolates from MX and AR and the small genetic differentiation observed among theC. posadasiiisolates analysed, suggest that this species could be distributed as a single genetic population in Latin America.
Clinical variables serve as prognostic factors in a model for survival from glioblastoma multiforme: an observational study of a cohort of consecutive non-selected patients from a single institution
Authors: Michaelsen Signe Regner , Christensen Ib Jarle , Grunnet Kirsten , Stockhausen Marie-Thérése , Broholm Helle , Kosteljanetz Michael , Poulsen Hans Skovgaard
Published: September 2013

Background

Although implementation of temozolomide (TMZ) as a part of primary therapy for glioblastoma multiforme (GBM) has resulted in improved patient survival, the disease is still incurable. Previous studies have correlated various parameters to survival, although no single parameter has yet been identified. More studies and new approaches to identify the best and worst performing patients are therefore in great demand.

Methods

This study examined 225 consecutive, non-selected GBM patients with performance status (PS) 0–2 receiving postoperative radiotherapy with concomitant and adjuvant TMZ as primary therapy. At relapse, patients with PS 0–2 were mostly treated by reoperation and/or combination with bevacizumab/irinotecan (BEV/IRI), while a few received TMZ therapy if the recurrence-free period was >6 months.

Results

Median overall survival and time to progression were 14.3 and 8.0 months, respectively. Second-line therapy indicated that reoperation and/or BEV/IRI increased patient survival compared with untreated patients and that BEV/IRI was more effective than reoperation alone. Patient age, ECOG PS, and use of corticosteroid therapy were significantly correlated with patient survival and disease progression on univariate analysis, whereas p53, epidermal growth factor receptor, and O6-methylguanine-DNA methyltransferase expression (all detected by immunohistochemistry), tumor size or multifocality, and extent of primary operation were not. A model based on age, ECOG PS, and corticosteroids use was able to predict survival probability for an individual patient.

Conclusion

The survival of RT/TMZ-treated GBM patients can be predicted based on patient age, ECOG PS, and corticosteroid therapy status.
Feline mammary basal-like adenocarcinomas: a potential model for human triple-negative breast cancer (TNBC) with basal-like subtype
Authors: Wiese David A , Thaiwong Tuddow , Yuzbasiyan-Gurkan Vilma , Kiupel Matti
Published: September 2013

Background

Breast cancer is one of the leading causes of cancer deaths. Triple-negative breast cancer (TNBC), an immunophenotype defined by the absence of immunolabeling for estrogen receptor (ER), progesterone receptor (PR) and HER2 protein, has a highly aggressive behavior. A subpopulation of TNBCs exhibit a basal-like morphology with immunohistochemical positivity for cytokeratins 5/6 (CK5/6) and/or epidermal growth factor receptor (EGFR), and have a high incidence of BRCA (breast cancer susceptibility) mutations. Feline mammary adenocarcinomas (FMAs) are highly malignant and share a similar basal-like subtype. The purpose of this study was to classify FMAs according to the current human classification of breast cancer that includes evaluation of ER, PR and HER2 status and expression of basal CK 5/6 and EGFR. Furthermore, we selected triple negative, basal-like FMAs to screen for BRCA mutations similar to those described in human TNBC.

Methods

Twenty four FMAs were classified according to the current human histologic breast cancer classification including immunohistochemistry (IHC) for ER, PR HER2, CK5/6 and EGFR. Genetic alteration and loss of heterozygosity of BRCA1 and BRCA2 genes were analyzed in triple negative, basal-like FMAs.

Results

IHC for ER, PR and HER2 identified 14 of the 24 (58%) FMAs as a triple negative. Furthermore, 11of these 14 (79%) triple negative FMAs had a basal-like subtype. However, no genetic abnormalities were detected in BRCA1 and BRCA2 by direct sequencing and loss of heterozygosity analysis.

Conclusion

FMAs are highly aggressive neoplasms that are commonly triple negative and exhibit a basal-like morphology. This is similar to human TNBC that are also commonly classified as a basal-like subtype. While sequencing of a select number of triple negative, basal-like FMAs and testing for loss of heterozygosity of BRCA1 and BRCA2 did not identify mutations similar to those described in human TNBC, further in-depth evaluation is required to elucidate a potential role of BRCA in the tumorigenesis of triple negative, basal-like FMAs. The strong similarities in clinical behavior, morphology and IHC phenotype suggest that triple negative, basal-like FMAs may be a suitable spontaneous animal model for studying novel therapeutic approaches against human basal-like TNBC.
Validation of four candidate pancreatic cancer serological biomarkers that improve the performance of CA19.9
Authors: Makawita Shalini , Dimitromanolakis Apostolos , Soosaipillai Antoninus , Soleas Ireena , Chan Alison , Gallinger Steven , Haun Randy S , Blasutig Ivan M , Diamandis Eleftherios P
Published: September 2013

Background

The identification of new serum biomarkers with high sensitivity and specificity is an important priority in pancreatic cancer research. Through an extensive proteomics analysis of pancreatic cancer cell lines and pancreatic juice, we previously generated a list of candidate pancreatic cancer biomarkers. The present study details further validation of four of our previously identified candidates: regenerating islet-derived 1 beta (REG1B), syncollin (SYCN), anterior gradient homolog 2 protein (AGR2), and lysyl oxidase-like 2 (LOXL2).

Methods

The candidate biomarkers were validated using enzyme-linked immunosorbent assays in two sample sets of serum/plasma comprising a total of 432 samples (Sample Set A: pancreatic ductal adenocarcinoma (PDAC, n = 100), healthy (n = 92); Sample Set B: PDAC (n = 82), benign (n = 41), disease-free (n = 47), other cancers (n = 70)). Biomarker performance in distinguishing PDAC from each control group was assessed individually in the two sample sets. Subsequently, multiparametric modeling was applied to assess the ability of all possible two and three marker panels in distinguishing PDAC from disease-free controls. The models were generated using sample set B, and then validated in Sample Set A.

Results

Individually, all markers were significantly elevated in PDAC compared to healthy controls in at least one sample set (p ≤ 0.01). SYCN, REG1B and AGR2 were also significantly elevated in PDAC compared to benign controls (p ≤ 0.01), and AGR2 was significantly elevated in PDAC compared to other cancers (p < 0.01). CA19.9 was also assessed. Individually, CA19.9 showed the greatest area under the curve (AUC) in receiver operating characteristic (ROC) analysis when compared to the tested candidates; however when analyzed in combination, three panels (CA19.9 + REG1B (AUC of 0.88), CA19.9 + SYCN + REG1B (AUC of 0.87) and CA19.9 + AGR2 + REG1B (AUC of 0.87)) showed an AUC that was significantly greater (p < 0.05) than that of CA19.9 alone (AUC of 0.82). In a comparison of early-stage (Stage I-II) PDAC to disease free controls, the combination of SYCN + REG1B + CA19.9 showed the greatest AUC in both sample sets, (AUC of 0.87 and 0.92 in Sets A and B, respectively).

Conclusions

Additional serum biomarkers, particularly SYCN and REG1B, when combined with CA19.9, show promise as improved diagnostic indicators of pancreatic cancer, which therefore warrants further validation.
Simultaneous identification of 36 mutations in KRAS codons 61and 146, BRAF, NRAS, and PIK3CAin a single reaction by multiplex assay kit
Authors: Bando Hideaki , Yoshino Takayuki , Shinozaki Eiji , Nishina Tomohiro , Yamazaki Kentaro , Yamaguchi Kensei , Yuki Satoshi , Kajiura Shinya , Fujii Satoshi , Yamanaka Takeharu , Tsuchihara Katsuya , Ohtsu Atsushi
Published: September 2013

Background

Retrospective analyses in the West suggest that mutations in KRAS codons 61 and 146, BRAF, NRAS, and PIK3CA are negative predictive factors for cetuximab treatment in colorectal cancer patients. We developed a novel multiplex kit detecting 36 mutations in KRAS codons 61 and 146, BRAF, NRAS, and PIK3CA using Luminex (xMAP) assay in a single reaction.

Methods

Tumor samples and clinical data from Asian colorectal cancer patients treated with cetuximab were collected. We investigated KRAS, BRAF, NRAS, and PIK3CA mutations using both the multiplex kit and direct sequencing methods, and evaluated the concordance between the 2 methods. Objective response, progression-free survival (PFS), and overall survival (OS) were also evaluated according to mutational status.

Results

In total, 82 of 83 samples (78 surgically resected specimens and 5 biopsy specimens) were analyzed using both methods. All multiplex assays were performed using 50 ng of template DNA. The concordance rate between the methods was 100%. Overall, 49 (59.8%) patients had all wild-type tumors, 21 (25.6%) had tumors harboring KRAS codon 12 or 13 mutations, and 12 (14.6%) had tumors harboring KRAS codon 61, KRAS codon 146, BRAF, NRAS, or PIK3CA mutations. The response rates in these patient groups were 38.8%, 4.8%, and 0%, respectively. Median PFS in these groups was 6.1 months (95% confidence interval (CI): 3.1–9.2), 2.7 months (1.2–4.2), and 1.6 months (1.5–1.7); median OS was 13.8 months (9.2–18.4), 8.2 months (5.7–10.7), and 6.3 months (1.3–11.3), respectively. Statistically significant differences in both PFS and OS were found between patients with all wild-type tumors and those with KRAS codon 61, KRAS codon 146, BRAF, NRAS, or PIK3CA mutations (PFS: 95% CI, 0.11–0.44; P < 0.0001; OS: 95% CI, 0.15–0.61; P < 0.0001).

Conclusions

Our newly developed multiplex kit is practical and feasible for investigation of a range of sample types. Moreover, mutations in KRAS codon 61, KRAS codon 146, BRAF, NRAS, or PIK3CA detected in Asian patients were not predictive of clinical benefits from cetuximab treatment, similar to the result obtained in European studies.
An observational study of response heterogeneity in children with attention deficit hyperactivity disorder following treatment switch to modified-release methylphenidate
Authors: Hautmann Christopher , Rothenberger Aribert , Döpfner Manfred
Published: September 2013

Background

Methylphenidate (MPH) has been shown to be effective in the treatment of attention deficit hyperactivity disorder (ADHD) in children. The overall population of children and adolescents with ADHD may comprise distinct clusters of patients that differ in response to MPH. The aim of this analysis was to look for subgroups with different treatment trajectories and to identify their distinctive features.

Methods

OBSEER was a prospective, observational study examining the effectiveness and safety of once-daily modified-release MPH over 3 months in patients (aged 6–17 years) with ADHD under routine care. Assessments were carried out at baseline (Visit 1), after 1–3 weeks (Visit 2) and 6–12 weeks (Visit 3) after first use of once-daily modified-release MPH. Change in ADHD symptoms, as rated by parents and teachers, was examined post hoc in patients of the intent-to-treat-population (N = 822), using growth-mixture modelling to detect response trajectory groups after switching medication. Age, MPH dose at Visit 1 before medication switch, prescribed once-daily modified-release MPH dose at Visits 1 and 2, conduct problems and emotional symptoms were considered predictors of response subgroups.

Results

Assessing formal statistical criteria and usefulness of the models, a 4-class solution best fitted the data: after switching medication two response groups with severe symptoms at study start and subsequent substantial treatment effects, and two showing no or comparatively little treatment effect, one of which had severe and the other less severe symptoms at study start. Patient age, conduct problems and MPH dose at Visit 1 were predictors of inclusion in subgroups.

Conclusions

Older children and children with few conduct problems were more likely to be members of a patient cluster with fewer symptoms at study start. Children with a low MPH dose before medication switch had a higher chance of being in the patient cluster with a strong treatment response after switching medication. The current analyses should assist in identifying children likely to achieve a favourable treatment course with MPH and, additionally, those who are in need of alternative treatment options.
Forkhead box transcription factor 1 expression in gastric cancer: FOXM1 is a poor prognostic factor and mediates resistance to docetaxel
Authors: Li Xiaoxiao , Qiu Wensheng , Liu Bin , Yao Ruyong , Liu Shihai , Yao Yasai , Liang Jun
Published: September 2013

Background

Forkhead box transcription factor 1 (FOXM1) has been reported to overexpress and correlate with pathogenesis in a variety of human malignancies. However, little research has been done to investigate its clinical significance in gastric cancer.

Methods

We examined the expression of FOXM1 in 103 postoperational gastric cancer tissues and 5 gastric cell lines by immunohistochemistry and western blot analysis respectively. Data on clinic-pathological features and relevant prognostic factors in these patients were then analyzed. Moreover, the association of FOXM1 expression and chemosensitivity to docetaxel in gastric cancer cells was further explored.

Results

Our study demonstrated that the level of FOXM1 expression was significantly higher in gastric cancer than in para-cancer tissues (P < 0.001) and normal gastric cell lines (P = 0.026). No significant association was found between FOXM1 expression and any clinical pathological features (P > 0.1). FOXM1 amplification was identified as an independent prognostic factor in gastric cancer (P = 0.001), and its affection is more significant in patients with tumor size larger than 5 cm (P = 0.004), pT3-4 (P = 0.003) or pIII-IV (P = 0.001). Additionally, shown to mediate docetaxel resistance in gastric cancers by our research, FOXM1 was revealed to alter microtubule dynamics in response to the treatment of docetaxel, and the drug resistance could be reversed with FOXM1 inhibitor thiostrepton treatment.

Conclusions

FOXM1 can be a useful marker for predicting patients’ prognosis and monitoring docetaxel response, and might be a new therapeutic target in docetaxel resistant gastric cancer.
Femtosecond laser modification of an array of vertically aligned carbon nanotubes intercalated with Fe phase nanoparticles
Authors: Labunov Vladimir , Prudnikava Alena , Bushuk Serguei , Filatov Serguei , Shulitski Boris , Tay Beng Kang , Shaman Yury , Basaev Alexander
Published: September 2013

Femtosecond lasers (FSL) are playing an increasingly important role in materials research, characterization, and modification. Due to an extremely short pulse width, interactions of FSL irradiation with solid surfaces attract special interest, and a number of unusual phenomena resulted in the formation of new materials are expected. Here, we report on a new nanostructure observed after the interaction of FSL irradiation with arrays of vertically aligned carbon nanotubes (CNTs) intercalated with iron phase catalyst nanoparticles. It was revealed that the FSL laser ablation transforms the topmost layer of CNT array into iron phase nanospheres (40 to 680 nm in diameter) located at the tip of the CNT bundles of conical shape. Besides, the smaller nanospheres (10 to 30 nm in diameter) are found to be beaded at the sides of these bundles. Some of the larger nanospheres are encapsulated into carbon shells, which sometime are found to contain CNTs. The mechanism of creation of such nanostructures is proposed.
Effects of a Metabotropic Glutamate Receptor Subtype 7 Negative Allosteric Modulator in the Periaqueductal Grey on Pain Responses and Rostral Ventromedial Medulla Cell Activity in Rat
Authors: Palazzo Enza , Marabese Ida , Luongo Livio , Boccella Serena , Bellini Giulia , Giordano Maria Elvira , Rossi Francesca , Scafuro Mariantonietta , de Novellis Vito , Maione Sabatino
Published: September 2013

The metabotropic glutamate receptor 7 (mGluR7) negative allosteric modulator, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), was locally microinjected into the ventrolateral periaqueductal gray (VL PAG) and the effect on pain responses in formalin and spare nerve injury (SNI) - induced neuropathic pain models was monitored in the rat. The activity of rostral ventromedial medulla (RVM) “pronociceptive” ON and “antinociceptive” OFF cells was also evaluated. Intra-VL PAG MMPIP blocked the first and second phase of nocifensive behaviour in the formalin pain model. MMPIP increased the tail flick latency and simultaneously increased the activity of the OFF cells while inhibiting that of ON cells in rats with SNI of the sciatic nerve. MMPIP failed to modify nociceptive responses and associated RVM ON and OFF cell activity in sham rats. An increase in mGluR7 gene, protein and staining, the latter being associated with vesicular glutamate transporter-positive profiles, has been found in the VL PAG in SNI rats. Blockade of mGluR7 within the VL PAG has an antinociceptive effect in formalin and neuropathic pain models. VL PAG mGluR7 blockade offers a target for dis-inhibiting the VL PAG-RVM pathway and silencing pain in inflammatory and neuropathic pain models.
Yukmijihwang-tang for the treatment of xerostomia in the elderly: study protocol for a randomized, double-blind, placebo-controlled, two-center trial
Authors: Han Gajin , Park Jae-Woo , Ko Seok-Jae , Son Jihee , Seon Jongki , Kim Juyeon , Kim Seulki , Yeo Inkwon , Ryu Bongha , Kim Jinsung
Published: September 2013

Background

Xerostomia, a subjective sense of dry mouth, is not generally regarded a disease despite its high prevalence among the elderly, and therefore continues to impair affected patients’ quality of life. In traditional Korean medicine, ‘Yin-Deficiency’ has been implicated in the pathogenesis of xerostomia among the elderly. Yukmijihwang-tang is a famous herbal prescription used to relieve ‘Yin-Deficiency’, and reportedly has antioxidant effects; therefore, it is postulated that Yukmijihwang-tang can be used to treat xerostomia in the elderly. However, to our knowledge, no clinical trial has been conducted on the effects of Yukmijihwang-tang on xerostomia. Thus, we designed a randomized clinical trial to investigate the effects and safety of Yukmijihwang-tang on xerostomia in the elderly. In addition, we will clarify the aforementioned assumption that ‘Yin-Deficiency’ is the major cause of xerostomia in the elderly by identifying a correlation between xerostomia and ‘Yin-Deficiency’.

Methods/Design

This randomized, double-blind, placebo-controlled trial will be carried out at two centers: Kyung Hee University Korean Medicine Hospital and Kyung Hee University Hospital at Gangdong. We will recruit 96 subjects aged 60-80 years who have experienced xerostomia for 3 months prior to participation. Subjects who present with score >40 on the visual analogue scale for xerostomia and unstimulated salivary flow rate under 0.3mL/min will be included and the randomization will be carried out by an independent statistician by using a random number creation program. The subjects and all researchers except the statistician will be blinded to the group assignment. Yukmijihwang-tang or placebo will be administered to each group for 8 weeks. The primary outcome is change in the scores for the visual analogue scale for xerostomia and the dry mouth symptom questionnaire from 0 to 8 weeks.

Discussion

It will be assessed whether Yukmijihwang-tang can be used as a new herbal treatment for xerostomia in the elderly by demonstrating its therapeutic effects in a well-designed clinical trial.

Trial registration

ClinicalTrials.gov Identifier:NCT01579877
FGF10 Signaling differences between type I pleuropulmonary blastoma and congenital cystic adenomatoid malformation
Authors: Lezmi Guillaume , Verkarre Virginie , Khen-Dunlop Naziha , Vibhushan Shamila , Hadchouel Alice , Rambaud Caroline , Copin Marie-Christine , Rittie Jean-Luc , Benachi Alexandra , Fournet Jean-Christophe , Delacourt Christophe
Published: September 2013

Background

Type I pleuropulmonary blastoma (PPB) and congenital cystic adenomatoid malformation of the lung (CCAM) are cystic lung diseases of childhood. Their clinical and radiological presentations are often similar, and pathologic discrimination remains difficult in many cases. As a consequence, type I PPB and CCAM are frequently confused, leading to delayed adequate management for type I PPB. Recent studies have suggested a role for fibroblast growth factor (FGF) 10 signal pathway in CCAM pathogenesis. The objective of our study was to determine whether FGF10 signaling differs between CCAM and type I PPB.

Methods

Immunohistochemical studies were performed for expression of FGF10, its receptor FGFR2b, and its inhibitor sonic hedgehog (SHH) in focal type I PPB (n=6), CCAM type I (n=7), CCAM type II (n=7), and control lungs (n=5).

Results

FGF10, FGFR2b, and SHH expressions differed markedly between type I PPB and both types of CCAM. Type I and type II CCAM cystic walls expressed FGF10, FGFR2b, and SHH, whereas staining was absent or poor in type I PBB cystic walls. Expression of FGF10, FGFR2b, and SHH did not differ between CCAM cystic walls and control airway walls.

Conclusions

These findings show that immunohistochemistry with FGF10, FGFR2b, or SHH could be useful in differentiating CCAM from type I PPB, when a child presents with a focal cystic lung lesion. The absence of strong expression of FGF10, FGFR2b, and/or SHH makes the diagnosis of CCAM very doubtful.
Glanders: an overview of infection in humans
Authors: Van Zandt Kristopher E , Greer Marek T , Gelhaus H Carl
Published: September 2013

Glanders is a highly contagious and often fatal zoonotic disease, primarily of solipds. In the developed world, glanders has been eradicated. However, prior use of B. mallei as a biological weapon and its high mortality in inhalation animal studies has affirmed B. mallei as a biodefense concern. This threat requires the development of new glanders medical countermeasures (MCMs), as there is a lack of an effective vaccine and lengthy courses of multiple antibiotics needed to eradicate B. mallei. Here, we present a literature review of human glanders in which we discuss the clinical epidemiology and risk factors, potential routes of exposure, symptoms, the incubation period, and specific diagnostics. This review focuses on pulmonary glanders, as this is the most likely outcome of a biological weapons attack. Additionally, we outline current treatment regimens and propose a clinical definition of human pulmonary glanders infection.
Small nucleolar RNAs as new biomarkers in chronic lymphocytic leukemia
Authors: Ronchetti Domenica , Mosca Laura , Cutrona Giovanna , Tuana Giacomo , Gentile Massimo , Fabris Sonia , Agnelli Luca , Ciceri Gabriella , Matis Serena , Massucco Carlotta , Colombo Monica , Reverberi Daniele , Recchia Anna Grazia , Bossio Sabrina , Negrini Massimo , Tassone Pierfrancesco , Morabito Fortunato , Ferrarini Manlio , Neri Antonino
Published: September 2013

Background

Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs are non-coding RNAs involved in the maturation of other RNA molecules. Alterations of sno/scaRNA expression may play a role in cancerogenesis. This study elucidates the patterns of sno/scaRNA expression in 211 chronic lymphocytic leukemia (CLL) patients (Binet stage A) also in comparison with those of different normal B-cell subsets.

Methods

The patterns of sno/scaRNA expression in highly purified CD19+ B-cells of 211 CLL patients and in 18 normal B-cell samples - 6 from peripheral blood, and 12 from tonsils (4 germinal center, 2 marginal zone, 3 switched memory and 3 naïve B-cells) - were analyzed on the Affymetrix GeneChip® Human Gene 1.0 ST array.

Results

CLLs display a sno/scaRNAs expression profile similar to normal memory, naïve and marginal-zone B-cells, with the exception of a few down-regulated transcripts (SNORA31, -6, -62, and -71C). Our analyses also suggest some heterogeneity in the pattern of sno/scaRNAs expression which is apparently unrelated to the major biological (ZAP-70 and CD38), molecular (IGHV mutation) and cytogenetic markers. Moreover, we found that SNORA70F was significantly down-regulated in poor prognostic subgroups and this phenomenon was associated with the down-regulation of its host gene COBLL1. Finally, we generated an independent model based on SNORA74A and SNORD116-18 expression, which appears to distinguish two different prognostic CLL groups.

Conclusions

These data extend the view of sno/scaRNAs deregulation in cancer and may contribute to discover novel biomarkers associated with the disease and potentially useful to predict the clinical outcome of early stage CLL patients.
Erythropoietin is a JAK2 and ERK1/2 effector that can promote renal tumor cell proliferation under hypoxic conditions
Authors: Miyake Makito , Goodison Steve , Lawton Adrienne , Zhang Ge , Gomes-Giacoia Evan , Rosser Charles J
Published: September 2013

Background

Erythropoietin (EPO) provides an alternative to transfusion for increasing red blood cell mass and treating anemia in cancer patients. However, recent studies have reported increased adverse events and/or reduced survival in patients receiving both EPO and chemotherapy, potentially related to EPO-induced cancer progression. Additional preclinical studies that elucidate the possible mechanism underlying EPO cellular growth stimulation are needed.

Methods

Using commercial tissue microarray (TMA) of a variety of cancers and benign tissues, EPO and EPO receptor immunohistochemical staining was performed. Furthermore using a panel of human renal cells (Caki-1, 786-O, 769-P, RPTEC), in vitro and in vivo experiments were performed with the addition of EPO in normoxic and hypoxic states to note phenotypic and genotypic changes.

Results

EPO expression score was significantly elevated in lung cancer and lymphoma (compared to benign tissues), while EPOR expression score was significantly elevated in lymphoma, thyroid, uterine, lung and prostate cancers (compared to benign tissues). EPO and EPOR expression scores in RCC and benign renal tissue were not significantly different. Experimentally, we show that exposure of human renal cells to recombinant EPO (rhEPO) induces cellular proliferation, which we report for the first time, is further enhanced in a hypoxic state. Mechanistic investigations revealed that EPO stimulates the expression of cyclin D1 while inhibiting the expression of p21cip1 and p27kip1 through the phosphorylation of JAK2 and ERK1/2, leading to a more rapid progression through the cell cycle. We also demonstrate an increase in the growth of renal cell carcinoma xenograft tumors when systemic rhEPO is administered.

Conclusions

In summary, we elucidated a previously unidentified mechanism by which EPO administration regulates progression through the cell cycle, and show that EPO effects are significantly enhanced under hypoxic conditions.
Enhanced tolerance of transgenic potato plants expressing choline oxidase in chloroplasts against water stress
Authors: Cheng Yu-Jie , Deng Xi-Ping , Kwak Sang-Soo , Chen Wei , Eneji Anthony E
Published: September 2013

Background

Glycinebetaine, whose biosynthesis could be catalyzed by choline oxidase (COD), is an extremely efficient compatible solute for scavenging oxidative stress-inducing molecules and protecting the photosynthetic system in plants. To study the effects of the codA transgene for choline oxidase on the drought resistance and recovery, a transgenic potato cultivar (SC) bearing codA gene and a non-transgenic (NT) control cultivar were raised in pots under moderate and severe drought stress. The experiment was constituted by a two-day-pretreatment with 20% PEG and a four-day-water stress combined with two-day-recovery treatment.

Results

Under the four-day-water stress, plants were provided with normal water condition, 10% or 20% polyethylene glycol. The results of pretreatment showed an expression of codA gene in transgenic potato and an accumulation of glycine betaine (GB); leaf water potential was higher in SC than in NT. In the stress-recovery-treatment, SC showed stronger antioxidant ability, more efficient photosynthetic system, higher chlorophyll content, lower malondialdehyde content and better recovery from water deficit stress than NT.

Conclusion

Although this work concentrated on the short-term water stress and recover treatments on transgenic potato plants with the over-expression of CodA gene and its control line. The datas shows that the exogenous codA gene provided potato a stronger drought resistance and recovery ability.
Comparative testicular transcriptome of wild type and globozoospermic Dpy19l2knock out mice
Authors: Karaouzène Thomas , El Atifi Michèle , Issartel Jean-Paul , Grepillat Marianne , Coutton Charles , Martinez Delphine , Arnoult Christophe , Ray Pierre F
Published: September 2013

Background

Globozoospermia is a male infertility phenotype characterized by the presence in the ejaculate of near 100% acrosomeless round-headed spermatozoa with normal chromosomal content. Following intracytoplasmic sperm injection (ICSI) these spermatozoa give a poor fertilization rate and embryonic development. We showed previously that most patients have a 200 kb homozygous deletion, which includes DPY19L2 whole coding sequence. Furthermore we showed that the DPY19L2 protein is located in the inner nuclear membrane of spermatids during spermiogenesis and that it is necessary to anchor the acrosome to the nucleus thus performing a function similar to that realized by Sun proteins within the LINC-complex (Linker of Nucleoskeleton and Cytoskeleton). SUN1 was described to be necessary for gametogenesis and was shown to interact with the telomeres. It is therefore possible that Dpy19l2 could also interact, directly or indirectly, with the DNA and modulate gene expression during spermatogenesis.

In this study, we compared the transcriptome of testes from Dpy19l2 knock out and wild type mice in order to identify a potential deregulation of transcripts that could explain the poor fertilization potential of Dpy19l2 mutated spermatozoa.

Methods

RNA was extracted from testes from DPY19L2 knock out and wild type mice. The transcriptome was carried out using GeneChip® Mouse Exon 1.0 ST Arrays. The biological processes and molecular functions of the differentially regulated genes were analyzed with the PANTHER software.

Results

A total of 76 genes were deregulated, 70 were up-regulated and 6 (including Dpy19l2) were down-regulated. These genes were found to be involved in DNA/RNA binding, structural organization, transport and catalytic activity.

Conclusions

We describe that an important number of genes are differentially expressed in Dpy19l2 mice. This work could help improving our understanding of Dpy19l2 functions and lead to a better comprehension of the molecular mechanism involved in spermatogenesis.
The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease
Authors: Raha Animesh Alexander , Vaishnav Radhika Anand , Friedland Robert Paul , Bomford Adrian , Raha-Chowdhury Ruma
Published: September 2013

Background

The pathological features of the common neurodegenerative conditions, Alzheimer’s disease (AD), Parkinson’s disease and multiple sclerosis are all known to be associated with iron dysregulation in regions of the brain where the specific pathology is most highly expressed. Iron accumulates in cortical plaques and neurofibrillary tangles in AD where it participates in redox cycling and causes oxidative damage to neurons. To understand these abnormalities in the distribution of iron the expression of proteins that maintain systemic iron balance was investigated in human AD brains and in the APP-transgenic (APP-tg) mouse.

Results

Protein levels of hepcidin, the iron-homeostatic peptide, and ferroportin, the iron exporter, were significantly reduced in hippocampal lysates from AD brains. By histochemistry, hepcidin and ferroportin were widely distributed in the normal human brain and co-localised in neurons and astrocytes suggesting a role in regulating iron release. In AD brains, hepcidin expression was reduced and restricted to the neuropil, blood vessels and damaged neurons. In the APP-tg mouse immunoreactivity for ferritin light-chain, the iron storage isoform, was initially distributed throughout the brain and as the disease progressed accumulated in the core of amyloid plaques. In human and mouse tissues, extensive AD pathology with amyloid plaques and severe vascular damage with loss of pericytes and endothelial disruption was seen. In AD brains, hepcidin and ferroportin were associated with haem-positive granular deposits in the region of damaged blood vessels.

Conclusion

Our results suggest that the reduction in ferroportin levels are likely associated with cerebral ischaemia, inflammation, the loss of neurons due to the well-characterised protein misfolding, senile plaque formation and possibly the ageing process itself. The reasons for the reduction in hepcidin levels are less clear but future investigation could examine circulating levels of the peptide in AD and a possible reduction in the passage of hepcidin across damaged vascular endothelium. Imbalance in the levels and distribution of ferritin light-chain further indicate a failure to utilize and release iron by damaged and degenerating neurons.
Combination of extracts from Aristolochia cymbifera with streptomycin as a potential antibacterial drug
Authors: Silva Willer F , Cecílio Samyra G , Magalhães Cintia LB , Ferreira Jaqueline MS , Tótola Antonio H , de Magalhaes Jose C
Published: September 2013

The appearance of new antibiotic-resistant bacteria is a societal problem that requires the development of new alternative treatments. Therefore, this work evaluated the antibacterial activity of ethanolic (EHI), dichloromethanic (EDI) and hexanic (EHE) extracts from Aristolochia cymbifera stems and the combination of these extracts with an antimicrobial drug to develop a new antibacterial therapy. The EDI, EHE and EHI extracts were obtained by maceration using three different solvents. The minimal inhibitory concentrations (MIC) of these extracts were determined using the microdilution test to determine the antibacterial potential of these extracts and their combination with streptomycin against Staphylococcus aureus, Bacillus cereus, Klebsiella pneumoniae and Shigella flexneri. The extract dose leading to the cytotoxicity of 50% of the cells (CC50) was evaluated using mammalian cells MA104 and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. The extracts had a MIC under 500 mg/L and a CC50 lower than 50 mg/L. The antibiotic/extract proportion influenced the antibacterial activity of the mixtures, and the proportion that optimized the antibacterial activity of streptomycin was a mixture that contained 75 percent of extract. This composition included less than 6.5 mg/L of extract and 2.5 mg/L of streptomycin and has potential as a new antibacterial therapy.
The microbiological and clinical outcome of guide wire exchanged versus newly inserted antimicrobial surface treated central venous catheters
Authors: Parbat Nisha , Sherry Norelle , Bellomo Rinaldo , Schneider Antoine G , Glassford Neil J , Johnson Paul DR , Bailey Michael
Published: September 2013

Introduction

The management of suspected central venous catheter (CVC)-related sepsis by guide wire exchange (GWX) is not recommended. However, GWX for new antimicrobial surface treated (AST) triple lumen CVCs has never been studied. We aimed to compare the microbiological outcome of triple lumen AST CVCs inserted by GWX (GWX-CVCs) with newly inserted triple lumen AST CVCs (NI-CVCs).

Methods

We studied a cohort of 145 consecutive patients with GWX-CVCs and contemporaneous site-matched control cohort of 163 patients with NI-CVCs in a tertiary intensive care unit (ICU).

Results

GWX-CVC and NI-CVC patients were similar for mean age (58.7 vs. 62.2 years), gender (88 (60.7%) vs. 98 (60.5%) male) and illness severity on admission (mean Acute Physiology and Chronic Health Evaluation (APACHE) III: 71.3 vs. 72.2). However, GWX patients had longer median ICU lengths of stay (12.2 vs. 4.4 days; P < 0.001) and median hospital lengths of stay (30.7 vs. 18.0 days; P < 0.001). There was no significant difference with regard to the number of CVC tips with bacterial or fungal pathogen colonization among GWX-CVCs vs. NI-CVCs (5 (2.5%) vs. 6 (7.4%); P = 0.90). Catheter-associated blood stream infection (CA-BSI) occurred in 2 (1.4%) GWX patients compared with 3 (1.8%) NI-CVC patients (P = 0.75). There was no significant difference in hospital mortality (35 (24.1%) vs. 48 (29.4%); P = 0.29).

Conclusions

GWX-CVCs and NI-CVCs had similar rates of tip colonization at removal, CA-BSI and mortality. If the CVC removed by GWX is colonized, a new CVC must then be inserted at another site. In selected ICU patients at higher central vein puncture risk receiving AST CVCs GWX may be an acceptable initial approach to line insertion.
Is non-operative management safe and effective for all splenic blunt trauma? A systematic review
Authors: Cirocchi Roberto , Boselli Carlo , Corsi Alessia , Farinella Eriberto , Listorti Chiara , Trastulli Stefano , Renzi Claudio , Desiderio Jacopo , Santoro Alberto , Cagini Lucio , Parisi Amilcare , Redler Adriano , Noya Giuseppe , Fingerhut Abe
Published: September 2013

Introduction

The goal of non-operative management (NOM) for blunt splenic trauma (BST) is to preserve the spleen. The advantages of NOM for minor splenic trauma have been extensively reported, whereas its value for the more severe splenic injuries is still debated. The aim of this systematic review was to evaluate the available published evidence on NOM in patients with splenic trauma and to compare it with the operative management (OM) in terms of mortality, morbidity and duration of hospital stay.

Methods

For this systematic review we followed the "Preferred Reporting Items for Systematic Reviews and Meta-analyses" statement. A systematic search was performed on PubMed for studies published from January 2000 to December 2011, without language restrictions, which compared NOM vs. OM for splenic trauma injuries and which at least 10 patients with BST.

Results

We identified 21 non randomized studies: 1 Clinical Controlled Trial and 20 retrospective cohort studies analyzing a total of 16,940 patients with BST. NOM represents the gold standard treatment for minor splenic trauma and is associated with decreased mortality in severe splenic trauma (4.78% vs. 13.5% in NOM and OM, respectively), according to the literature. Of note, in BST treated operatively, concurrent injuries accounted for the higher mortality. In addition, it was not possible to determine post-treatment morbidity in major splenic trauma. The definition of hemodynamic stability varied greatly in the literature depending on the surgeon and the trauma team, representing a further bias. Moreover, data on the remaining analyzed outcomes (hospital stay, number of blood transfusions, abdominal abscesses, overwhelming post-splenectomy infection) were not reported in all included studies or were not comparable, precluding the possibility to perform a meaningful cumulative analysis and comparison.

Conclusions

NOM of BST, preserving the spleen, is the treatment of choice for the American Association for the Surgery of Trauma grades I and II. Conclusions are more difficult to outline for higher grades of splenic injury, because of the substantial heterogeneity of expertise among different hospitals, and potentially inappropriate comparison groups.
Effects of prehospital epinephrine during out-of-hospital cardiac arrest with initial non-shockable rhythm: an observational cohort study
Authors: Goto Yoshikazu , Maeda Tetsuo , Goto Yumiko Nakatsu
Published: September 2013

Introduction

Few clinical trials have provided evidence that epinephrine administration after out-of-hospital cardiac arrest (OHCA) improves long-term survival. Here we determined whether prehospital epinephrine administration would improve 1-month survival in OHCA patients.

Methods

We analyzed the data of 209,577 OHCA patients; the data were prospectively collected in a nationwide Utstein-style Japanese database between 2009 and 2010. Patients were divided into the initial shockable rhythm (n = 15,492) and initial non-shockable rhythm (n = 194,085) cohorts. The endpoints were prehospital return of spontaneous circulation (ROSC), 1-month survival, and 1-month favorable neurological outcomes (cerebral performance category scale, category 1 or 2) after OHCA. We defined epinephrine administration time as the time from the start of cardiopulmonary resuscitation (CPR) by emergency medical services personnel to the first epinephrine administration.

Results

In the initial shockable rhythm cohort, the ratios of prehospital ROSC, 1-month survival, and 1-month favorable neurological outcomes in the non-epinephrine group were significantly higher than those in the epinephrine group (27.7% vs. 22.8%, 27.0% vs. 15.4%, and 18.6% vs. 7.0%, respectively; all P < 0.001). However, in the initial non-shockable rhythm cohort, the ratios of prehospital ROSC and 1-month survival in the epinephrine group were significantly higher than those in the non-epinephrine group (18.7% vs. 3.0% and 3.9% vs. 2.2%, respectively; all P < 0.001) and there was no significant difference between the epinephrine and non-epinephrine groups for 1-month favorable neurological outcomes (P = 0.62). Prehospital epinephrine administration for OHCA patients with initial non-shockable rhythms was independently associated with prehospital ROSC (adjusted odds ratio [aOR], 8.83, 6.18, 4.32; 95% confidence interval [CI], 8.01-9.73, 5.82-6.56, 3.98-4.69; for epinephrine administration times ≤9 min, 10-19 min, and ≥20 min, respectively), with improved 1-month survival when epinephrine administration time was <20 min (aOR, 1.78, 1.29; 95% CI, 1.50-2.10, 1.17-1.43; for epinephrine administration times ≤9 min and 10-19 min, respectively), and with deteriorated 1-month favorable neurological outcomes (aOR, 0.63, 0.49; 95% CI, 0.48-0.80, 0.32-0.71; for epinephrine administration times 10-19 min and ≥20 min, respectively).

Conclusions

Prehospital epinephrine administration for OHCA patients with initial nonshockable rhythms was independently associated with achievement of prehospital ROSC and had association with improved 1-month survival when epinephrine administration time was <20 min.
Efficient 3D inversion of magnetic data via octree-mesh discretization, space-filling curves, and wavelets
Authors: Davis Kristofer , Li Yaoguo
Published: September 2013

Airborne magnetic survey data sets can contain from hundreds of thousands to millions of observations and typically cover large areas. The large number of measurements combined with a model mesh to accommodate the survey extent can render an inversion of these data intractable. Faced with this challenge, we have developed a three-step procedure to locally optimize the degree of model discretization and to compress the corresponding sensitivity matrix for the inversion of magnetic data. The mesh optimization is achieved through the use of adaptive octree discretization. The compression is achieved by first reordering the model cells using the Hilbert space filling curve and then applying the one-dimensional wavelet transform to the corresponding sensitivities. The fractal property of the Hilbert curve groups the spatially adjacent cells into algebraically adjacent positions in the reordered model mesh and thereby maximizes the number of zero or near-zero coefficients in the one-dimensional wavelet transform. Winnowing these insignificant coefficients finally leads to a highly sparse representation of the sensitivity matrix, which dramatically reduces the required memory and CPU time in the inversion. As a result, the proposed algorithm is capable of inverting huge data sets ([Formula: see text] measurements) with commensurate model sizes in a short time on a single desktop computer. As a test, we inverted an entire magnetic data set with 170,000 observations from a large uranium exploration program and achieved a reduction in computational cost exceeding 10,000 times.