Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitro as well as new vessel growth ex vivo (p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction ( p ! 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis ( annexin V staining, p ! 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n=3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth. Copyright (C) 2007 S. Karger AG, Basel

In vivo and in vitro studies of Th17 response to specific immunotherapy in house dust mite-induced allergic rhinitis patients

10.1371/journal.pone.0091950PLoS ONE93-POLN

Adrenal adenomatoid tumor in a patient with human immunodeficiency virus

We present the clinical course of a patient with human immunodeficiency virus and an adrenal adenomatoid tumor (AAT). We describe the clinical course and laboratory, radiographic, and microscopic findings of a patient with human immunodeficiency virus (HIV) and an adenomatoid tumor of the right adrenal gland. A review of the literature was also done via electronic searches through PubMed for articles from 1965 to 2008 that contained the following search terms, adenomatoid tumor limited to the English language only. A 22 year-old African-American male with HIV was incidentally found to have a hypermetabolic right adrenal mass. The patient underwent laparoscopic adrenalectomy and the mass had morphological and immunohistochemical features that were consistent with an AAT. A review of the medical literature reveals that almost all cases of AAT were in male patients (96%) with a mean age of 41±11 years (range=22–64) with no significant difference in laterality (right side=46%, left side=50%, unknown=4%). AAT have an average size of 4.2±3.5 cm (range=0.5–14.3 cm). Pre-operative imaging studies do not appear to be able to reliably distinguish AAT from other types of adrenocortical tumors. For reasons that require further research, AAT typically occur in male patients and may be associated with immunosuppression. AAT can be safely removed laparoscopically with no evidence of long-term recurrence even with tumor extension beyond the adrenal capsule

Can LANA CITS Support Learning in Autistic Children? A case study evaluation

LANA CITS is a Conversational Intelligent Tutoring System that uses the Visual, Auditory, and Kinaesthetic learning style (VAK). It supports learning in autistic pupils, who are studying in mainstream primary schools. Facilitating the learning of these pupils using traditional teaching within mainstream schools is complex and poorly understood. This paper present investigation into how LANA CITS using VAK learning style model can adapt to autistic pupils learning style and improve their learning in mainstream schools. This paper provides a case study evaluation of three children with high-functioning autism examining the effectiveness of learning with LANA CITS. The case study took place in primary school in Saudi Arabia. The results were positive with the students engaged in the tutorial and the teacher noticed some improvement over classroom activities. This results support for the continuing development, evaluation, and use of CITS for pupils with autism in mainstream schools

What is the potential for bisexual men in China to act as a bridge of HIV transmission to the female population? Behavioural evidence from a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>HIV prevalence among men who have sex with men (MSM) in China has rapidly increased in recent years. It is suggested that MSM could be a potential bridge of HIV transmission to the general female population. We investigated the bisexual behaviour of MSM in China through systematic review and meta-analysis.</p> <p>Methods</p> <p>We conducted a systematic review and meta-analyses on published peer-reviewed Chinese and English literature during 2001-2010 according to the PRISMA guidelines. Marital status and sexual behavioural indicators of MSM were presented graphically using forest plots. The pooled effect rates with 95% confidence intervals were also calculated. Meta-regression analyses were performed to examine the factors associated with high heterogeneities across the studies.</p> <p>Results</p> <p>Forty-three eligible articles (11 in English and 32 in Chinese) were identified. Our results showed that 17.0% (95% CI: 15.1-19.1%) of MSM in China are currently married to a woman and 26.3% (95% CI: 23.6-29.1%) of MSM had female sexual partners in the last six months. The pooled estimates for condom use rate between MSM and female sex partners was 41.4% (95% CI: 35.5-47.5%) at the last sex act; and 25.6% (95% CI: 23.0-28.4%) in the last six months. The consistent condom use rates with regular, non-commercial, casual and commercial female sex partners in the last six months were 23.3% (95% CI: 11.25-42.1%), 39.0% (95% CI: 28.8-50.3%) and 55.8% (95% CI: 41.4-69.4%), respectively.</p> <p>Conclusions</p> <p>A substantial proportion of Chinese MSM is currently married or had sexual relations with a female in the past six months. In addition, low condom usage was common between married MSM and their wives, hence posing a higher risk of transmitting HIV. Harm-reduction programs targeting married MSM and their female partners are necessary to curb the further spread of HIV infection to the general female population.</p

Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts

BACKGROUND:Recent studies have demonstrated that activation of autophagy increases the lifespan of organisms from yeast to flies. In contrast to the lifespan extension effect in lower organisms, it has been reported that overexpression of unc-51-like kinase 3 (ULK3), the mammalian homolog of autophagy-specific gene 1 (ATG1), induces premature senescence in human fibroblasts. Therefore, we assessed whether the activation of autophagy would genuinely induce premature senescence in human cells. METHODOLOGY/PRINCIPAL FINDINGS:Depletion of ATG7, ATG12, or lysosomal-associated membrane protein 2 (Lamp2) by transfecting siRNA or infecting cells with a virus containing gene-specific shRNA resulted in a senescence-like state in two strains of primary human fibroblasts. Prematurely senescent cells induced by autophagy impairment exhibited the senescent phenotypes, similar to the replicatively senescent cells, such as increased senescence associated β-galactosidase (SA-β-gal) activity, reactive oxygen species (ROS) generation, and accumulation of lipofuscin. In addition, expression levels of ribosomal protein S6 kinase1 (S6K1), p-S6K1, p-S6, and eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) in the mammalian target of rapamycin (mTOR) pathway and beclin-1, ATG7, ATG12-ATG5 conjugate, and the sequestosome 1 (SQSTM1/p62) monomer in the autophagy pathway were decreased in both the replicatively and the autophagy impairment-induced prematurely senescent cells. Furthermore, it was found that ROS scavenging by N-acetylcysteine (NAC) and inhibition of p53 activation by pifithrin-α or knockdown of p53 using siRNA, respectively, delayed autophagy impairment-induced premature senescence and restored the expression levels of components in the mTOR and autophagy pathways. CONCLUSION:Taken together, we concluded that autophagy impairment induces premature senescence through a ROS- and p53-dependent manner in primary human fibroblasts

SHINE Transcription Factors Act Redundantly to Pattern the Archetypal Surface of Arabidopsis Flower Organs

Floral organs display tremendous variation in their exterior that is essential for organogenesis and the interaction with the environment. This diversity in surface characteristics is largely dependent on the composition and structure of their coating cuticular layer. To date, mechanisms of flower organ initiation and identity have been studied extensively, while little is known regarding the regulation of flower organs surface formation, cuticle composition, and its developmental significance. Using a synthetic microRNA approach to simultaneously silence the three SHINE (SHN) clade members, we revealed that these transcription factors act redundantly to shape the surface and morphology of Arabidopsis flowers. It appears that SHNs regulate floral organs' epidermal cell elongation and decoration with nanoridges, particularly in petals. Reduced activity of SHN transcription factors results in floral organs' fusion and earlier abscission that is accompanied by a decrease in cutin load and modified cell wall properties. SHN transcription factors possess target genes within four cutin- and suberin-associated protein families including, CYP86A cytochrome P450s, fatty acyl-CoA reductases, GSDL-motif lipases, and BODYGUARD1-like proteins. The results suggest that alongside controlling cuticular lipids metabolism, SHNs act to modify the epidermis cell wall through altering pectin metabolism and structural proteins. We also provide evidence that surface formation in petals and other floral organs during their growth and elongation or in abscission and dehiscence through SHNs is partially mediated by gibberellin and the DELLA signaling cascade. This study therefore demonstrates the need for a defined composition and structure of the cuticle and cell wall in order to form the archetypal features of floral organs surfaces and control their cell-to-cell separation processes. Furthermore, it will promote future investigation into the relation between the regulation of organ surface patterning and the broader control of flower development and biological functions

Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release

Micelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a ‘magic bullet’ a major step forward

Cross-oncopanel study reveals high sensitivity and accuracy with overall analytical performance depending on genomic regions

BackgroundTargeted sequencing using oncopanels requires comprehensive assessments of accuracy and detection sensitivity to ensure analytical validity. By employing reference materials characterized by the U.S. Food and Drug Administration-led SEquence Quality Control project phase2 (SEQC2) effort, we perform a cross-platform multi-lab evaluation of eight Pan-Cancer panels to assess best practices for oncopanel sequencing.ResultsAll panels demonstrate high sensitivity across targeted high-confidence coding regions and variant types for the variants previously verified to have variant allele frequency (VAF) in the 5-20% range. Sensitivity is reduced by utilizing VAF thresholds due to inherent variability in VAF measurements. Enforcing a VAF threshold for reporting has a positive impact on reducing false positive calls. Importantly, the false positive rate is found to be significantly higher outside the high-confidence coding regions, resulting in lower reproducibility. Thus, region restriction and VAF thresholds lead to low relative technical variability in estimating promising biomarkers and tumor mutational burden.ConclusionThis comprehensive study provides actionable guidelines for oncopanel sequencing and clear evidence that supports a simplified approach to assess the analytical performance of oncopanels. It will facilitate the rapid implementation, validation, and quality control of oncopanels in clinical use.Peer reviewe