bluuebunny/crossref_metadata_2025 huggingface dataset:
The mitogen-activated protein kinome from Anopheles gambiae: identification, phylogeny and functional characterization of the ERK, JNK and p38 MAP kinases
Authors: Horton Ashley A , Wang Bo , Camp Lauren , Price Mark S , Arshi Arora , Nagy Mate , Nadler Steven A , Faeder James R , Luckhart Shirley
Published: November 2011

Background

Anopheles gambiae is the primary mosquito vector of human malaria parasites in sub-Saharan Africa. To date, three innate immune signaling pathways, including the nuclear factor (NF)-kappaB-dependent Toll and immune deficient (IMD) pathways and the Janus kinase/signal transducers and activators of transcription (Jak-STAT) pathway, have been extensively characterized in An. gambiae. However, in addition to NF-kappaB-dependent signaling, three mitogen-activated protein kinase (MAPK) pathways regulated by JNK, ERK and p38 MAPK are critical mediators of innate immunity in other invertebrates and in mammals. Our understanding of the roles of the MAPK signaling cascades in anopheline innate immunity is limited, so identification of the encoded complement of these proteins, their upstream activators, and phosphorylation profiles in response to relevant immune signals was warranted.

Results

In this study, we present the orthologs and phylogeny of 17 An. gambiae MAPKs, two of which were previously unknown and two others that were incompletely annotated. We also provide detailed temporal activation profiles for ERK, JNK, and p38 MAPK in An. gambiae cells in vitro to immune signals that are relevant to malaria parasite infection (human insulin, human transforming growth factor-beta1, hydrogen peroxide) and to bacterial lipopolysaccharide. These activation profiles and possible upstream regulatory pathways are interpreted in light of known MAPK signaling cascades.

Conclusions

The establishment of a MAPK "road map" based on the most advanced mosquito genome annotation can accelerate our understanding of host-pathogen interactions and broader physiology of An. gambiae and other mosquito species. Further, future efforts to develop predictive models of anopheline cell signaling responses, based on iterative construction and refinement of data-based and literature-based knowledge of the MAP kinase cascades and other networked pathways will facilitate identification of the "master signaling regulators" in biomedically important mosquito species.
Francisella RNA polymerase contains a heterodimer of non-identical α subunits
Authors: Mukhamedyarov Damir , Makarova Kira S , Severinov Konstantin , Kuznedelov Konstantin
Published: November 2011

Background

All sequenced genomes of representatives of the Francisella genus contain two rpoA genes, which encode non-identical RNA polymerase (RNAP) subunits, α1 and α2. In all other bacteria studied to date, a dimer of identical α subunits initiates the assembly of the catalytically proficient RNAP core (subunit composition α2ββ'). Based on an observation that both α1 and α2 are incorporated into Francisella RNAP, Charity et al. (2007) previously suggested that up to four different species of RNAP core enzyme might form in the same Francisella cell.

Results

By in vitro assembly from fully denatured state, we determined that both Francisella α subunits are required for efficient dimerization; no homodimer formation was detected. Bacterial two-hybrid system analysis likewise indicated strong interactions between the α1 and α2 N-terminal domains (NTDs, responsible for dimerization). NTDs of α2 did not interact detectably, while weak interaction between α1 NTDs was observed. This weak homotypic interaction may explain low-level transcription activity observed in in vitro RNAP reconstitution reactions containing Francisella large subunits (β', β) and α1. No activity was observed with RNAP reconstitution reactions containing α2, while robust transcription activity was detected in reactions containing α1 and α2. Phylogenetic analysis based on RpoA resulted in a tree compatible with standard bacterial taxonomy with both Francisella RpoA branches positioned within γ-proteobacteria. The observed phylogeny and analysis of constrained trees are compatible with Francisella lineage-specific rpoA duplication followed by acceleration of evolutionary rate and subfunctionalization.

Conclusions

The results strongly suggest that most Francisella RNAP contains α heterodimer with a minor subfraction possibly containing α1 homodimer. Comparative sequence analysis suggests that this heterodimer is oriented, in a sense that only one monomer, α1, interacts with the β subunit during the α2β RNAP subassembly formation. Most likely the two rpoA copies in Francisella have emerged through a lineage-specific duplication followed by subfunctionalization of interacting paralogs.
Clinical characteristics and outcomes of Mycobacterium tuberculosis disease in adult patients with hematological malignancies
Authors: Chen Chien-Yuan , Sheng Wang-Huei , Cheng Aristine , Tsay Woei , Huang Shang-Yi , Tang Jih-Luh , Chen Yee-Chun , Wang Jaun-Yuan , Tien Hwei-Fang , Chang Shan-Chwen
Published: November 2011

Background

Diseases caused by Mycobacterium tuberculosis (TB) among adult patients with hematological malignancies have rarely been investigated.

Methods

Adult patients with hematological malignancies at National Taiwan University Hospital between 1996 and 2009 were retrospectively reviewed. Patients with positive serology for HIV were excluded. TB disease is diagnosed by positive culture(s) in the presence of compatible symptoms and signs. The demographics, laboratory and, microbiological features, were analyzed in the context of clinical outcomes.

Results

Fifty-three of 2984 patients (1.78%) were diagnosed with TB disease. The estimated incidence was 120 per 100,000 adult patients with hematological malignancies. Patients with acute myeloid leukemia had a significantly higher incidence of TB disease than other subtypes of hematological malignancies (2.87% vs. 1.21%, p = 0.002, odds ratio, 2.40; 95% confidence interval, 1.39-4.41). Thirty-eight patients (72%) with non-disseminated pulmonary TB disease presented typically with mediastinal lymphadenopathy (53%), pleural effusion (47%) and fibrocalcific lesions (43%) on chest imaging. The 15 (28%) patients with extra-pulmonary disease had lower rates of defervescence within 72 h of empirical antimicrobial therapy (13% vs 45%, p = 0.03) and a higher 30-day in-hospital mortality (20% vs. 0%, p = 0.004) compared to those with disease confined to the lungs.

Conclusions

TB disease is not uncommon among patients with hematological malignancies in Taiwan. Patients who received a diagnosis of extra-pulmonary TB suffered higher mortality than those with pulmonary TB alone. Clinicians should consider TB in the differential diagnoses of prolonged fever in patients with hematological malignancies, particularly in regions of high endemicity.
Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells
Authors: Taylor David J , Parsons Christine E , Han Haiyong , Jayaraman Arul , Rege Kaushal
Published: November 2011

Background

Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis.

Methods

FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis.

Results

Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward malignant cells over normal pancreatic epithelial cells.

Conclusions

The identification of a number of FDA-approved drugs as TRAIL sensitizers can expand chemotherapeutic options for combination treatments in prostate and pancreatic cancer diseases.
Isolation of a nanomolar scFv inhibiting the endopeptidase activity of botulinum toxin A, by single-round panning of an immune phage-displayed library of macaque origin
Authors: Chahboun Siham , Hust Michael , Liu Yvonne , Pelat Thibaut , Miethe Sebastian , Helmsing Saskia , Jones Russell GA , Sesardic Dorothea , Thullier Philippe
Published: November 2011

Background

Botulinum neurotoxin A (BoNT/A), mainly represented by subtype A1, is the most toxic substance known. It causes naturally-occurring food poisoning, and is among the biological agents at the highest risk of being weaponized. Several antibodies neutralizing BoNT/A by targeting its heavy chain (BoNT/A-H) have been isolated in the past. For the first time however, an IgG (4LCA) recently isolated by hybridoma technology and targeting the BoNT/A light chain (BoNT/A-L), was shown to inhibit BoNT/A endopeptidase activity and protect in vivo against BoNT/A. In the present study, a phage-displayed library was constructed from a macaque (Macaca fascicularis) hyper-immunized with BoNTA/L in order to isolate scFvs inhibiting BoNT/A endopeptidase activity for clinical use.

Results

Diversity of the scFvs constituting the library was limited due to the frequent presence, within the genes intended to be part of the library, of restriction sites utilized for its construction. After screening with several rounds of increasing stringency, as is usual with phage technology, the library got overwhelmed by phagemids encoding incomplete scFvs. The screening was successfully re-performed with a single round of high stringency. In particular, one of the isolated scFvs, 2H8, bound BoNT/A1 with a 3.3 nM affinity and effectively inhibited BoNT/A1 endopeptidase activity. The sequence encoding 2H8 was 88% identical to human germline genes and its average G-score was -0.72, quantifying the high human-like quality of 2H8.

Conclusions

The presence of restrictions sites within many of the sequences that were to be part of the library did not prevent the isolation of an scFv, 2H8, by an adapted panning strategy. ScFv 2H8 inhibited toxin endopeptidase activity in vitro and possessed human-like quality required for clinical development. More generally, the construction and screening of phage-displayed libraries built from hyper-immunized non-human primates is an efficient solution to isolate antibody fragments with therapeutic potential.
Anti-tumor effects of fibroblast growth factor-binding protein (FGF-BP) knockdown in colon carcinoma
Authors: Schulze Daniel , Plohmann Philipp , Höbel Sabrina , Aigner Achim
Published: November 2011

Background

Fibroblast growth factors FGF-1 and FGF-2 are often upregulated in tumors, but tightly bound to heparan sulphate proteoglycans of the extracellular matrix (ECM). One mechanism of their bioactivation relies on the FGF-binding protein (FGF-BP) which, upon reversible binding to FGF-1 or -2, leads to their release from the ECM. FGF-BP increases tumorigenicity and is highly expressed in tumors like colon carcinoma. In this paper, we analyse cellular and molecular consequences of RNAi-mediated FGF-BP knockdown in colon carcinoma, and explore the therapeutic effects of the nanoparticle-mediated delivery of small interfering RNAs (siRNAs) for FGF-BP targeting.

Results

Employing stable RNAi cells, we establish a dose-dependence of cell proliferation on FGF-BP expression levels. Decreased proliferation is mirrored by alterations in cell cycle distribution and upregulation of p21, which is relevant for mediating FGF-BP effects. While inhibition of proliferation is mainly associated with reduced Akt and increased GSK3β activation, antibody array-based analyses also reveal other alterations in MAPK signalling. Additionally, we demonstrate induction of apoptosis, mediated through caspase-3/7 activation, and alterations in redox status upon FGF-BP knockdown. These effects are based on the upregulation of Bad, Bax and HIF-1α, and the downregulation of catalase. In a therapeutic FGF-BP knockdown approach based on RNAi, we employ polymer-based nanoparticles for the in vivo delivery of siRNAs into established wildtype colon carcinoma xenografts. We show that the systemic treatment of mice leads to the inhibition of tumor growth based on FGF-BP knockdown.

Conclusions

FGF-BP is integrated in a complex network of cytoprotective effects, and represents a promising therapeutic target for RNAi-based knockdown approaches.
Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review
Authors: Watkins Casey E , Litchfield John , Song Eunkyung , Jaishankar Gayatri B , Misra Niva , Holla Nikhil , Duffourc Michelle , Krishnaswamy Guha
Published: November 2011

Chronic Granulomatous Disease (CGD), a disorder of the NADPH oxidase system, results in phagocyte functional defects and subsequent infections with bacterial and fungal pathogens (such as Aspergillus species and Candida albicans). Deletions and missense, frameshift, or nonsense mutations in the gp91phox gene (also termed CYBB), located in the Xp21.1 region of the X chromosome, are associated with the most common form of CGD. When larger X-chromosomal deletions occur, including the XK gene deletion, a so-called "Contiguous Gene Deletion Syndrome" may result. The contiguous gene deletion syndrome is known to associate the Kell phenotype/McLeod syndrome with diseases such as X-linked chronic granulomatous disease, Duchenne muscular dystrophy, and X-linked retinitis pigmentosa. These patients are often complicated and management requires special attention to the various facets of the syndrome.
A one-dimensional extremely covalent material: monatomic carbon linear chain
Authors: Zhang Yaozhong , Su Yanjie , Wang Liang , Kong Eric Siu-Wai , Chen XiaoShuang , Zhang Yafei
Published: November 2011

Polyyne and cumulene of infinite length as the typical covalent one-dimensional (1D) monatomic linear chains of carbon have been demonstrated to be metallic and semiconductor (Eg = 1.859 eV), respectively, by first-principles calculations. Comparing with single-walled carbon nanotubes, the densities are evidently low and the thermodynamic properties are similar below room temperature but much different at the high temperature range. Polyyne possesses a Young's modulus as high as 1.304 TPa, which means it is even much stiffer than carbon nanotubes and to be the superlative strong 1D material along the axial direction. The Young's modulus of cumulene is estimated to be 760.78 GPa. In addition, polyyne is predicted to be as a one-dimensional electronic material with very high mobility.
Characterization of ultrathin InSb nanocrystals film deposited on SiO2/Si substrate
Authors: Li Dengyue , Li Hongtao , Sun Hehui , Zhao Liancheng
Published: November 2011

Recently, solid-phase recrystallization of ultrathin indium antimonide nanocrystals (InSb NCs (films grown on SiO2/Si substrate is very attractive, because of the rapid development of thermal annealing technique. In this study, the recrystallization behavior of 35 nm indium antimonide film was studied. Through X-ray diffraction (XRD) analysis, it is demonstrated that the InSb film is composed of nanocrystals after high temperature rapid thermal annealing. Scanning electron microscopy shows that the film has a smooth surface and is composed of tightly packed spherical grains, the average grain size is about 12.3 nm according to XRD results. The optical bandgap of the InSb NCs film analyzed by Fourier Transform infrared spectroscopy measurement is around 0.26 eV. According to the current-voltage characteristics of the InSb NCs/SiO2/p-Si heterojunction, the film has the rectifying behavior and the turn-on voltage value is near 1 V.
The existence of fixed points for new nonlinear multivalued maps and their applications
Authors: He Zhenhua , Du Wei-Shih , Lin Ing-Jer
Published: November 2011

In this paper, we first establish some new fixed point theorems for
M
T
-functions. By using these results, we can obtain some generalizations of Kannan's fixed point theorem and Chatterjea's fixed point theorem for nonlinear multivalued contractive maps in complete metric spaces. Our results generalize and improve some main results in the literature and references therein.

Mathematics Subject Classifications

47H10; 54H25
A generalised fixed point theorem of presic type in cone metric spaces and application to markov process
Authors: George Reny , Reshma KP , Rajagopalan R
Published: November 2011

A generalised common fixed point theorem of Presic type for two mappings f: X → X and T: X
k
→ X in a cone metric space is proved. Our result generalises many well-known results.

2000 Mathematics Subject Classification

47H10
Children with disorders of sex development: A qualitative study of early parental experience
Authors: Crissman Halley P , Warner Lauren , Gardner Melissa , Carr Meagan , Schast Aileen , Quittner Alexandra L , Kogan Barry , Sandberg David E
Published: November 2011

Background

Clinical research on psychological aspects of disorders of sex development (DSD) has focused on psychosexual differentiation with relatively little attention directed toward parents' experiences of early clinical management and their influence on patient and family psychosocial adaptation.

Objectives

To characterize parental experiences in the early clinical care of children born with DSD.

Study Design

Content analysis of interviews with parents (n = 41) of 28 children, newborn to 6 years, with DSD.

Results

Four major domains emerged as salient to parents: (1) the gender assignment process, (2) decisions regarding genital surgery, (3) disclosing information about their child's DSD, and (4) interacting with healthcare providers. Findings suggested discordance between scientific and parental understandings of the determinants of "sex" and "gender." Parents' expectations regarding the benefits of genital surgery appear largely met; however, parents still had concerns about their child's future physical, social and sexual development. Two areas experienced by many parents as particularly stressful were: (1) uncertainties regarding diagnosis and optimal management, and (2) conflicts between maintaining privacy versus disclosing the condition to access social support.

Conclusions

Parents' experiences and gaps in understanding can be used to inform the clinical care of patients with DSD and their families. Improving communication between parents and providers (and between parents and their support providers) throughout the early clinical management process may be important in decreasing stress and improving outcomes for families of children with DSD.
Gliovascular and cytokine interactions modulate brain endothelial barrier in vitro
Authors: Chaitanya Ganta V , Cromer Walter E , Wells Shannon R , Jennings Merilyn H , Couraud P Olivier , Romero Ignacio A , Weksler Babette , Erdreich-Epstein Anat , Mathis J Michael , Minagar Alireza , Alexander J Steven
Published: November 2011

The glio-vascular unit (G-unit) plays a prominent role in maintaining homeostasis of the blood-brain barrier (BBB) and disturbances in cells forming this unit may seriously dysregulate BBB. The direct and indirect effects of cytokines on cellular components of the BBB are not yet unclear. The present study compares the effects of cytokines and cytokine-treated astrocytes on brain endothelial barrier. 3-dimensional transwell co-cultures of brain endothelium and related-barrier forming cells with astrocytes were used to investigate gliovascular barrier responses to cytokines during pathological stresses. Gliovascular barrier was measured using trans-endothelial electrical resistance (TEER), a sensitive index of in vitro barrier integrity. We found that neither TNF-α, IL-1β or IFN-γ directly reduced barrier in human or mouse brain endothelial cells or ECV-304 barrier (independent of cell viability/metabolism), but found that astrocyte exposure to cytokines in co-culture significantly reduced endothelial (and ECV-304) barrier. These results indicate that the barrier established by human and mouse brain endothelial cells (and other cells) may respond positively to cytokines alone, but that during pathological conditions, cytokines dysregulate the barrier forming cells indirectly through astrocyte activation involving reorganization of junctions, matrix, focal adhesion or release of barrier modulating factors (e.g. oxidants, MMPs).
The effects of notch filtering on electrically evoked myoelectric signals and associated motor unit index estimates
Authors: Li Xiaoyan , Rymer William Z , Li Guanglin , Zhou Ping
Published: November 2011

Background

Notch filtering is the most commonly used technique for suppression of power line and harmonic interference that often contaminate surface electromyogram (EMG) signals. Notch filters are routinely included in EMG recording instrumentation, and are used very often during clinical recording sessions. The objective of this study was to quantitatively assess the effects of notch filtering on electrically evoked myoelectric signals and on the related motor unit index measurements.

Methods

The study was primarily based on an experimental comparison of M wave recordings and index estimates of motor unit number and size, with the notch filter function of the EMG machine (Sierra Wave EMG system, Cadwell Lab Inc, Kennewick, WA, USA) turned on and off, respectively. The comparison was implemented in the first dorsal interosseous (FDI) muscle from the dominant hand of 15 neurologically intact subjects and bilaterally in 15 hemiparetic stroke subjects.

Results

On average, for intact subjects, the maximum M wave amplitude and the motor unit number index (MUNIX) estimate were reduced by approximately 22% and 18%, respectively, with application of the built-in notch filter function in the EMG machine. This trend held true when examining the paretic and contralateral muscles of the stroke subjects. With the notch filter on vs. off, across stroke subjects, we observed a significant decrease in both maximum M wave amplitude and MUNIX values in the paretic muscles, as compared with the contralateral muscles. However, similar reduction ratios were obtained for both maximum M wave amplitude and MUNIX estimate. Across muscles of both intact and stroke subjects, it was observed that notch filtering does not have significant effects on motor unit size index (MUSIX) estimate. No significant difference was found in MUSIX values between the paretic and contralateral muscles of the stroke subjects.

Conclusions

The notch filter function built in the EMG machine may significantly reduce the M wave amplitude and the MUNIX measurement. However, the notch filtering does not jeopardize the evaluation of the reduction ratio in maximum M wave amplitude and MUNIX estimate of the paretic muscles of stroke subjects when compared with the contralateral muscles.
Local Knowledge and Conservation of Seagrasses in the Tamil Nadu State of India
Authors: Newmaster AF , Berg KJ , Ragupathy S , Palanisamy M , Sambandan K , Newmaster SG
Published: November 2011

Local knowledge systems are not considered in the conservation of fragile seagrass marine ecosystems. In fact, little is known about the utility of seagrasses in local coastal communities. This is intriguing given that some local communities rely on seagrasses to sustain their livelihoods and have relocated their villages to areas with a rich diversity and abundance of seagrasses. The purpose of this study is to assist in conservation efforts regarding seagrasses through identifying Traditional Ecological Knowledge (TEK) from local knowledge systems of seagrasses from 40 coastal communities along the eastern coast of India. We explore the assemblage of scientific and local traditional knowledge concerning the 1. classification of seagrasses (comparing scientific and traditional classification systems), 2. utility of seagrasses, 3. Traditional Ecological Knowledge (TEK) of seagrasses, and 4. current conservation efforts for seagrass ecosystems. Our results indicate that local knowledge systems consist of a complex classification of seagrass diversity that considers the role of seagrasses in the marine ecosystem. This fine-scaled ethno-classification gives rise to five times the number of taxa (10 species = 50 local ethnotaxa), each with a unique role in the ecosystem and utility within coastal communities, including the use of seagrasses for medicine (e.g., treatment of heart conditions, seasickness, etc.), food (nutritious seeds), fertilizer (nutrient rich biomass) and livestock feed (goats and sheep). Local communities are concerned about the loss of seagrass diversity and have considerable local knowledge that is valuable for conservation and restoration plans. This study serves as a case study example of the depth and breadth of local knowledge systems for a particular ecosystem that is in peril.

Key words: local health and nutrition, traditional ecological knowledge (TEK), conservation and natural resources management, consensus, ethnomedicine, ethnotaxa, cultural heritage
Perceptions of the value of traditional ecological knowledge to formal school curricula: opportunities and challenges from Malekula Island, Vanuatu
Authors: McCarter Joe , Gavin Michael C
Published: November 2011

Background

The integration of traditional ecological knowledge (TEK) into formal school curricula may be a key tool for the revitalisation of biocultural diversity, and has the potential to improve the delivery of educational objectives. This paper explores perceptions of the value of TEK to formal education curricula on Malekula Island, Vanuatu. We conducted 49 interviews with key stakeholders (local TEK experts, educators, and officials) regarding the use of the formal school system to transmit, maintain, and revitalise TEK. Interviews also gathered information on the areas where TEK might add value to school curricula and on the perceived barriers to maintaining and revitalising TEK via formal education programs.

Results

Participants reported that TEK had eroded on Malekula, and identified the formal school system as a principal driver. Most interviewees believed that if an appropriate format could be developed, TEK could be included in the formal education system. Such an approach has potential to maintain customary knowledge and practice in the focus communities. Participants identified several specific domains of TEK for inclusion in school curricula, including ethnomedical knowledge, agricultural knowledge and practice, and the reinforcement of respect for traditional authority and values. However, interviewees also noted a number of practical and epistemological barriers to teaching TEK in school. These included the cultural diversity of Malekula, tensions between public and private forms of knowledge, and multiple values of TEK within the community.

Conclusions

TEK has potential to add value to formal education systems in Vanuatu by contextualising the content and process of curricular delivery, and by facilitating character development and self-awareness in students. These benefits are congruent with UNESCO-mandated goals for curricular reform and provide a strong argument for the inclusion of TEK in formal school systems. Such approaches may also assist in the maintenance and revitalisation of at-risk systems of ethnobiological knowledge. However, we urge further research attention to the significant epistemological challenges inherent in including TEK in formal school, particularly as participants noted the potential for such approaches to have negative consequences.
Induction chemotherapy with paclitaxel and cisplatin to concurrent radiotherapy and weekly paclitaxel in the treatment of loco-regionally advanced, stage IV (M0), head and neck squamous cell carcinoma. Mature results of a prospective study
Authors: Pergolizzi Stefano , Santacaterina Anna , Adamo Barbara , Franchina Tindara , Denaro Nerina , Ferraro Pina , Ricciardi Giusy RR , Settineri Nicola , Adamo Vincenzo
Published: November 2011

Background

to evaluate activity and toxicity of a sequential treatment in advanced, non metastatic, mostly unresectable, head and neck squamous cell carcinoma.

Methods

Patients with loco-regionally advanced or unresectable, head and neck cancer, were prospectively treated with 3 courses of induction chemotherapy followed by concurrent chemoradiation. Induction chemotherapy consisted of paclitaxel 175 mg/m2 day 1 and cisplatin 75 mg/m2 day 2, given every 3 weeks, to a total of three courses. Curative radiotherapy started 4 weeks after the last cycle of chemotherapy with the goal of delivering a total dose ≥ 66 Gy. During RT weekly paclitaxel (40 mg/m2) was administered.

Results

The trial accrued 43 patients from January 1999 to December 2002. All patients received 3 courses of induction chemotherapy and the planned dose of radiotherapy. Thirty-eight patients were able to tolerate weekly paclitaxel during irradiation at least for 4 courses. After induction therapy there were 32 overall responses, 74.4% (23 partial and 9 complete); at completion of concomitant treatment overall responses were 42, 97.7% (20 partial and 22 complete). Median time to treatment failure was 20 months and the disease progression rate at 3 and 5 years was 33% and 23%, respectively. The median overall survival time was 24 months and 3 and 5 years overall survival rates were 37% and 26%, respectively. The major toxicity was mucositis.

Conclusions

This combined treatment was found to be feasible and active in advanced or unresectable, head and neck squamous cell carcinoma patients. Long-term results observed in this trial encourage to consider this approach in further investigation using newer radiation delivering technique and new molecularly agents.
Psychometric assessment of the Wagnild and Young's resilience scale in Kano, Nigeria
Authors: Abiola Tajudeen , Udofia Owoidoho
Published: November 2011

Background

Resilience seemed to lie at the core of the recent promotion of positive mental health and wellbeing. This concept has been well studied in western countries and less in developing countries, particularly Nigeria. The aim of the study is therefore, to demonstrate the internal consistency and concurrent validity of the Resilience Scale (RS) and its 14-item short version (RS-14) in a Nigerian sample.

Results

The RS, RS-14, the Hospital Anxiety Depression Scale (HADS) and two screening questions on experience of recent and upcoming distress were administered to 70 clinical students who consented to participate after a major professional examination. Internal consistency and convergent validity were assessed. The participants mean age was 22.50 years (SD = 0.60). The mean score of RS and RS-14 were 130.23 (SD = 17.08) and 74.17 (SD = 10.14) respectively. Cronbach's alpha coefficient for the RS was 0.87 and that of the RS-14 was 0.81. The mean RS score by gender was 132.04 (SD = 19.08) and 126.52 (SD = 11.50) for males and females respectively and the difference was significant (t = 2.50; p = 0.012). The correlation of RS with RS-14 (r = 0.97; p = 0.000), the HADS depression (r = -0.28; p = 0.017) and anxiety (r = -0.26; p = 0.028) subscales, were significant. The corresponding t-test values for the means of RS and RS-14 scores for both cases and non-cases as determined by HADS, were significant at p < 0.05 and p < 0.01 for the depression and anxiety subscales respectively. The difference between RS means of those who experienced distress (38/125.69) to those that did not (32/134.05) from the recent clinical examination was also significant (t = 2.01; p = 0.045).

Conclusions

The study confirms that the RS and RS-14 may be potentially useful instruments to measure resilience in Nigerians.
T cell receptor transgenic lymphocytes infiltrating murine tumors are not induced to express foxp3
Authors: Quatromoni Jon G , Morris Lilah F , Donahue Timothy R , Wang Yue , McBride William , Chatila Talal , Economou James S
Published: November 2011

Regulatory T cells (Treg) that express the transcription factor Foxp3 are enriched within a broad range of murine and human solid tumors. The ontogeny of these Foxp3 Tregs - selective accumulation or proliferation of natural thymus-derived Treg (nTreg) or induced Treg (iTreg) converted in the periphery from naïve T cells - is not known. We used several strains of mice in which Foxp3 and EGFP are coordinately expressed to address this issue. We confirmed that Foxp3-positive CD4 T cells are enriched among tumor-infiltrating lymphocytes (TIL) and splenocytes (SPL) in B16 murine melanoma-bearing C57BL/6 Foxp3EGFPmice. OT-II Foxp3EGFPmice are essentially devoid of nTreg, having transgenic CD4 T cells that recognize a class II-restricted epitope derived from ovalbumin; Foxp3 expression could not be detected in TIL or SPL in these mice when implanted with ovalbumin-transfected B16 tumor (B16-OVA). Likewise, TIL isolated from B16 tumors implanted in Pmel-1 Foxp3EGFPmice, whose CD8 T cells recognize a class I-restricted gp100 epitope, were not induced to express Foxp3. All of these T cell populations - wild-type CD4, pmel CD8 and OTII CD4 - could be induced in vitro to express Foxp3 by engagement of their T cell receptor (TCR) and exposure to transforming growth factor β (TGFβ). B16 melanoma produces TGFβ and both pmel CD8 and OTII CD4 express TCR that should be engaged within B16 and B16-OVA respectively. Thus, CD8 and CD4 transgenic T cells in these animal models failed to undergo peripheral induction of Foxp3 in a tumor microenvironment.
An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males
Authors: Chung Ren-Hua , Ma Deqiong , Wang Kai , Hedges Dale J , Jaworski James M , Gilbert John R , Cuccaro Michael L , Wright Harry H , Abramson Ruth K , Konidari Ioanna , Whitehead Patrice L , Schellenberg Gerard D , Hakonarson Hakon , Haines Jonathan L , Pericak-Vance Margaret A , Martin Eden R
Published: November 2011

Background

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. The skewed prevalence toward males and evidence suggestive of linkage to the X chromosome in some studies suggest the presence of X-linked susceptibility genes in people with ASD.

Methods

We analyzed genome-wide association study (GWAS) data on the X chromosome in three independent autism GWAS data sets: two family data sets and one case-control data set. We performed meta- and joint analyses on the combined family and case-control data sets. In addition to the meta- and joint analyses, we performed replication analysis by using the two family data sets as a discovery data set and the case-control data set as a validation data set.

Results

One SNP, rs17321050, in the transducin β-like 1X-linked (TBL1X) gene [OMIM:300196] showed chromosome-wide significance in the meta-analysis (P value = 4.86 × 10-6) and joint analysis (P value = 4.53 × 10-6) in males. The SNP was also close to the replication threshold of 0.0025 in the discovery data set (P = 5.89 × 10-3) and passed the replication threshold in the validation data set (P = 2.56 × 10-4). Two other SNPs in the same gene in linkage disequilibrium with rs17321050 also showed significance close to the chromosome-wide threshold in the meta-analysis.

Conclusions

TBL1X is in the Wnt signaling pathway, which has previously been implicated as having a role in autism. Deletions in the Xp22.2 to Xp22.3 region containing TBL1X and surrounding genes are associated with several genetic syndromes that include intellectual disability and autistic features. Our results, based on meta-analysis, joint analysis and replication analysis, suggest that TBL1X may play a role in ASD risk.
Replication competent HIV-1 viruses that express intragenomic microRNA reveal discrete RNA-interference mechanisms that affect viral replication
Authors: Klase Zachary , Houzet Laurent , Jeang Kuan-Teh
Published: November 2011

Background

It remains unclear whether retroviruses can encode and express an intragenomic microRNA (miRNA). Some have suggested that processing by the Drosha and Dicer enzymes might preclude the viability of a replicating retroviral RNA genome that contains a cis-embedded miRNA. To date, while many studies have shown that lentiviral vectors containing miRNAs can transduce mammalian cells and express the inserted miRNA efficiently, no study has examined the impact on the replication of a lentivirus such as HIV-1 after the deliberate intragenomic insertion of a bona fide miRNA.

Results

We have constructed several HIV-1 molecular clones, each containing a discrete cellular miRNA positioned in Nef. These retroviral genomes express the inserted miRNA and are generally replication competent in T-cells. The inserted intragenomic miRNA was observed to elicit two different consequences for HIV-1 replication. First, the expression of miRNAs with predicted target sequences in the HIV-1 genome was found to reduce viral replication. Second, in one case, where an inserted miRNA was unusually well-processed by Drosha, this processing event inhibited viral replication.

Conclusion

This is the first study to examine in detail the replication competence of HIV-1 genomes that express cis-embedded miRNAs. The results indicate that a replication competent retroviral genome is not precluded from encoding and expressing a viral miRNA.
Prevalence study of Bovine viral diarrhea virus by evaluation of antigen capture ELISA and RT-PCR assay in Bovine, Ovine, Caprine, Buffalo and Camel aborted fetuses in Iran
Authors: Safarpoor Dehkordi Farhad
Published: November 2011

Bovine viral diarrhea virus is a pestivirus in the family Flaviviridae that cause abortions and stillbirths in livestock and its traditional diagnosis is based on cell culture and virus neutralization test. In this study, for more sensitive, specific detection and determined the prevalence of virus in aborted Bovine, Ovine, Caprine, Buffalo and Camel fetuses the antigen capture ELISA and RT-PCR were recommended. From the total of 2173 aborted fetuses, 347 (15.96%) and 402 (18.49%) were positive for presence of Bovine viral diarrhea virus by antigen capture ELISA and RT-PCR respectively. Statistical analysis of data showed significant differences between ELISA and RT-PCR for detection of virus in aborted fetuses.

These results indicate a high presence of this pathogen in Iran and that RT- PCR is considerably faster and more accurate than ELISA for identification of Bovine viral diarrhea virus.

To our knowledge the Camels and Bovine are the most resistant and sensitive to Bovine viral diarrhea's abortions respectively and the prevalence of virus in Caprine is more than Ovine aborted fetuses. This study is the first prevalence report of Bovine viral diarrhea virus in aborted Bovine, Ovine, Caprine, Buffalo and Camel fetuses by evaluation of ELISA and RT-PCR in Iran.
miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells
Authors: Lee Yee-Ming , Lee Jen-Yi , Ho Chao-Chi , Hong Qi-Sheng , Yu Sung-Liang , Tzeng Chii-Ruey , Yang Pan-Chyr , Chen Huei-Wen
Published: November 2011

Introduction

Estrogen is involved in several physiological and pathological processes through estrogen receptor (ER)-mediated transcriptional gene regulation. miRNAs (miRs), which are noncoding RNA genes, may respond to estrogen and serve as posttranscriptional regulators in tumorigenic progression, especially in breast cancer; however, only limited information about this possibility is available. In the present study, we identified the estrogen-regulated miR-34b and investigated its functional role in breast cancer progression.

Methods

Estrogen-regulated miRNAs were identified by using a TaqMan low density array. Our in vivo Tet-On system orthotopic model revealed the tumor-suppressive ability of miR-34b. Luciferase reporter assays and chromatin immunoprecipitation assay demonstrated miR-34b were regulated by p53-ER interaction.

Results

In this study, we identified one such estrogen downregulated miRNA, miR-34b, as an oncosuppressor that targets cyclin D1 and Jagged-1 (JAG1) in an ER+/wild-type p53 breast cancer cell line (MCF-7), as well as in ovarian and endometrial cells, but not in ER-negative or mutant p53 breast cancer cell lines (T47D, MBA-MB-361 and MDA-MB-435). There is a negative association between ERα and miR-34b expression levels in ER+ breast cancer patients. Tet-On induction of miR-34b can cause inhibition of tumor growth and cell proliferation. Also, the overexpression of miR-34b inhibited ER+ breast tumor growth in an orthotopic mammary fat pad xenograft mouse model. Further validation indicated that estrogen's inhibition of miR-34b expression was mediated by interactions between ERα and p53, not by DNA methylation regulation. The xenoestrogens diethylstilbestrol and zeranol also showed similar estrogenic effects by inhibiting miR-34b expression and by restoring the protein levels of the miR-34b targets cyclin D1 and JAG1 in MCF-7 cells.

Conclusions

These findings reveal that miR-34b is an oncosuppressor miRNA requiring both ER+ and wild-type p53 phenotypes in breast cancer cells. These results improve our ability to develop new therapeutic strategies to target the complex estrogenic pathway in human breast cancer progression through miRNA regulation.
Cancer stem cell markers in breast cancer: pathological, clinical and prognostic significance
Authors: Ali H Raza , Dawson Sarah-Jane , Blows Fiona M , Provenzano Elena , Pharoah Paul D , Caldas Carlos
Published: November 2011

Introduction

The cancer stem cell (CSC) hypothesis states that tumours consist of a cellular hierarchy with CSCs at the apex driving tumour recurrence and metastasis. Hence, CSCs are potentially of profound clinical importance. We set out to establish the clinical relevance of breast CSC markers by profiling a large cohort of breast tumours in tissue microarrays (TMAs) using immunohistochemistry (IHC).

Methods

We included 4, 125 patients enrolled in the SEARCH population-based study with tumours represented in TMAs and classified into molecular subtype according to a validated IHC-based five-marker scheme. IHC was used to detect CD44/CD24, ALDH1A1, aldehyde dehydrogenase family 1 member A3 (ALDH1A3) and integrin alpha-6 (ITGA6). A 'Total CSC' score representing expression of all four CSC markers was also investigated. Association with breast cancer specific survival (BCSS) at 10 years was assessed using a Cox proportional-hazards model. This study was complied with REMARK criteria.

Results

In ER negative cases, multivariate analysis showed that ITGA6 was an independent prognostic factor with a time-dependent effect restricted to the first two years of follow-up (hazard ratio (HR) for 0 to 2 years follow-up, 2.4; 95% confidence interval (95% CI), 1.2 to 4.8; P = 0.009). The composite 'Total CSC' score carried independent prognostic significance in ER negative cases for the first four years of follow-up (HR for 0 to 4 years follow-up, 1.3; 95% CI, 1.1 to 1.6; P = 0.006).

Conclusions

Breast CSC markers do not identify identical subpopulations in primary tumours. Both ITGA6 and a composite Total CSC score show independent prognostic significance in ER negative disease. The use of multiple markers to identify tumours enriched for CSCs has the greatest prognostic value. In the absence of more specific markers, we propose that the effective translation of the CSC hypothesis into patient benefit will necessitate the use of a panel of markers to robustly identify tumours enriched for CSCs.
Arterial cerebrovascular complications in 94 adults with acute bacterial meningitis
Authors: Klein Matthias , Koedel Uwe , Pfefferkorn Thomas , Zeller Grete , Woehrl Bianca , Pfister Hans-Walter
Published: November 2011

Introduction

Intracranial vascular complications are an important complication of acute bacterial meningitis. Ischemic stroke in meningitis is reported as a result of vasculitis, vasospasm, endocarditis or intraarterial thrombosis. The aim of the study was to identify the value of measuring cerebral blood flow velocity (CBFv) on transracranial doppler (TCD) in the identification of patients at risk for meningitis-associated stroke.

Methods

We retrospectively studied patients with acute bacterial meningitis who were treated in our university hospital from 2000 to 2009. Data were analyzed with the main focus on the incidence of an increase of CBFv on TCD, defined as peak systolic values above 150 cm/s, and the development of stroke.

Results

In total, 114 patients with acute bacterial meningitis were treated, 94 of them received routine TCD studies during their hospital stay. 41/94 patients had elevated CBFv values. This increase was associated with an increased risk of stroke (odds ratio (95% confidence intervall) = 9.15 (1.96-42.67); p < 0.001) and unfavorable outcome (Glasgow Outcome Score < 4; odds ratio (95% confidence intervall) = 2.93 (1.23-6.98); p = 0.018). 11/32 (34.4%) patients with an increase of CBFv who received nimodipine and 2/9 (22.2%) patients with an increase of CBFv who did not receive nimodipine developed stroke (p = 0.69).

Conclusions

In summary, TCD was found to be a valuable bedside test to detect arterial alterations in patients with bacterial meningitis. These patients have an increased risk of stroke.
Genome sequence of the insect pathogenic fungus Cordyceps militaris, a valued traditional chinese medicine
Authors: Zheng Peng , Xia Yongliang , Xiao Guohua , Xiong Chenghui , Hu Xiao , Zhang Siwei , Zheng Huajun , Huang Yin , Zhou Yan , Wang Shengyue , Zhao Guo-Ping , Liu Xingzhong , St Leger Raymond J , Wang Chengshu
Published: November 2011

Background

Species in the ascomycete fungal genus Cordyceps have been proposed to be the teleomorphs of Metarhizium species. The latter have been widely used as insect biocontrol agents. Cordyceps species are highly prized for use in traditional Chinese medicines, but the genes responsible for biosynthesis of bioactive components, insect pathogenicity and the control of sexuality and fruiting have not been determined.

Results

Here, we report the genome sequence of the type species Cordyceps militaris. Phylogenomic analysis suggests that different species in the Cordyceps/Metarhizium genera have evolved into insect pathogens independently of each other, and that their similar large secretomes and gene family expansions are due to convergent evolution. However, relative to other fungi, including Metarhizium spp., many protein families are reduced in C. militaris, which suggests a more restricted ecology. Consistent with its long track record of safe usage as a medicine, the Cordyceps genome does not contain genes for known human mycotoxins. We establish that C. militaris is sexually heterothallic but, very unusually, fruiting can occur without an opposite mating-type partner. Transcriptional profiling indicates that fruiting involves induction of the Zn2Cys6-type transcription factors and MAPK pathway; unlike other fungi, however, the PKA pathway is not activated.

Conclusions

The data offer a better understanding of Cordyceps biology and will facilitate the exploitation of medicinal compounds produced by the fungus.