The role of the human papillomavirus (HPV) in cervical cancer : a review about HPV-induced carcinogenesis and its epidemiology, diagnosis, management and prevention

The human papillomavirus (HPV) was the first virus known to induce carcinogenesis and is associated with cancers of the uterine cervix, anogenital tumors and malignancies of the head and neck. This paper reviews the structure and basic genomic characteristics of the virus and outlines the clinical involvement of the main HPV serotypes, focusing on the carcinogenic role of HPV-16 and 18. The mecha¬nisms that occur in the development of cervical neoplasia due to the oncogenic proteins E6 and E7 which interfere with the regulation of the cell cycle through their interaction with p53 and retinoblastoma protein are described. Epidemiological factors, diagnostic tools and the management of the disease are also reviewed, along with the available vaccines to prevent the viral infection. Insights on current research on involvement of oxidative stress and micro-RNAs in cervical carcinogenesis are also explored as they may unlock new means of diagnosis and treatment in the future.peer-reviewe

Structure–Activity Relationships and Kinetic Studies of Peptidic Antagonists of CBX Chromodomains

To better understand the contribution of methyl-lysine (Kme) binding proteins to various disease states, we recently developed and reported the discovery of <b>1</b> (UNC3866), a chemical probe that targets two families of Kme binding proteins, CBX and CDY chromodomains, with selectivity for CBX4 and -7. The discovery of <b>1</b> was enabled in part by the use of molecular dynamics simulations performed with CBX7 and its endogenous substrate. Herein, we describe the design, synthesis, and structure–activity relationship studies that led to the development of <b>1</b> and provide support for our model of CBX7–ligand recognition by examining the binding kinetics of our antagonists with CBX7 as determined by surface-plasmon resonance

Soft sets and soft modules

Bu tezde, öncelikle soft kümelerin yapısı ve özellikleri incelenmiş ve bunlarla ilgili sonuçlar özetlenerek verilmiştir. Bu kapsamda ilk olarak soft kümeler üzerinde tanımlanmış olan soft gruplar, soft halkalar ve soft modüllerden oluşan cebirsel yapılar ayrıntılı olarak ele alınmış daha sonrada soft alt modül ailesinin toplamı ve direkt toplamı detaylı olarak araştırılmıştır.In this thesis, the structure and properties of soft sets are investigated and the results related to these sets are summarized. In this context, we first discuss in detail algebraic structures consisting of soft groups, soft rings and soft modules which are defined on soft sets. Then the sum and direct sum of the collection of soft submodules are investigated in detail

Additional file 2: of Uva-ursi extract and ibuprofen as alternative treatments of adult female urinary tract infection (ATAFUTI): study protocol for a randomised controlled trial

Participant Information Sheet Main Trial. (PDF 218 kb

Identification of Small Molecule Inhibitors That Block the <i>Toxoplasma gondii</i> Rhoptry Kinase ROP18

The protozoan parasite <i>Toxoplasma gondii</i> secretes a family of serine-threonine protein kinases into its host cell in order to disrupt signaling and alter immune responses. One prominent secretory effector is the rhoptry protein 18 (ROP18), a serine-threonine kinase that phosphorylates immunity related GTPases (IRGs) and hence blocks interferon gamma-mediated responses in rodent cells. Previous genetic studies show that ROP18 is a major virulence component of <i>T. gondii</i> strains from North and South America. Here, we implemented a high throughput screen to identify small molecule inhibitors of ROP18 <i>in vitro</i> and subsequently validated their specificity within infected cells. Although ROP18 was not susceptible to many kinase-directed inhibitors that affect mammalian kinases, the screen identified several sub-micromolar inhibitors that belong to three chemical scaffolds: oxindoles, 6-azaquinazolines, and pyrazolopyridines. Treatment of interferon γ-activated cells with one of these inhibitors enhanced immunity related GTPase recruitment to wild type parasites, recapitulating the defect of Δ<i>rop18</i> mutant parasites, consistent with targeting ROP18 within infected cells. These compounds provide useful starting points for chemical biology experiments or as leads for therapeutic interventions designed to reduce parasite virulence

Ror2 expression regulates cell invasion in RCC cells.

<p>Analysis of invasive potential using Boyden matrigel coated chamber assays under normal culture conditions with <b>A</b>) 786-0 cells show a significant reduction in invasion in both independent shRNA Ror2 knockdowns in comparison with parental 786-0 and vector control cells (representative images shown below). Additionally, <b>B</b>) 786-0 & <b>C</b>) HEK293T cells under normal culture conditions show a significant increase in cell invasion with overexpression of wild-type Ror2 that is reduced with expression of Ror2-DM (representative images shown below). The percentage of area covered was quantitated from random fields using ImageJ. <i>P</i>-values were calculated using an Anova one-way analysis with error bars representing stdev shown (*<.05, **<.001).</p

Ror2 regulation of MMP2 expression in RCC cells is dependent upon an intact kinase domain.

<p>Quantitative RT-PCR for 786-0 cells shows a significant correlated decrease in <b>A</b>) Ror2 and <b>B</b>) MMP2 mRNA levels in both shRNA knockdown cell lines relative to control. <b>C</b>) Additionally, induction of wildtype Ror2 and Ror2-DM is evident following treatment with doxycycline (500 ng/ml). <b>D</b>) But a matching increase in MMP2 is only seen with overexpression of wildtype Ror2. For all quantitative RT-PCR assays, transcript values were normalized to β-actin RNA internal standard with fold change calculated in reference to either 786-0 control or unstimulated GFP expressing cells. Error bars represent SEM across triplicates of a representative duplicated experiment. Gelatin Zymography shows increased levels of both the precursor pro-MMP2 and its cleaved active form with overexpression of wildtype Ror2 relative to GFP vector control in both <b>E</b>) 786-0 and <b>F</b>) HEK293T cells. Quantification of the levels of active MMP2 normalized to the media only control (Con) is shown below each gel. <b>G</b>) Invasion of 786-0 cells seeded in Boyden matrigel coated chambers under normal culture conditions show a significant decrease upon treatment with MMP2 inhibitor (OA-Hy - 60 uM) in both independent shRNA knockdowns and Ror2 overexpression in comparison with vehicle control. The percentage of area covered was quantitated from random fields using ImageJ. Error bars represent stdev across duplicates of a representative duplicated experiment. <i>P</i>-values were calculated using an Anova one-way analysis (*<.05, **<.001).</p

Expression of Ror2 promotes <i>in vivo</i> tumor growth and invasion.

<p><b>A&C</b>) Tabulated rates of successful injection and growth of all 786-0 xenograft tumors are shown. <b>B</b>) Average tumor size (cm) with error bars showing stdev for resulting xenograft tumors following paired orthotropic injections of 786-0 cells containing either the control empty vector, pcDNA6 or hRor2 exhibited a trend to increased <i>in vivo</i> tumor growth with Ror2 overexpression. <b>D</b>) Average tumor size (mm) with error bars showing stdev for resulting xenograft tumors following subcutaneous injection of 786-0 cells containing either the control empty vector, GFP, wild-type Ror2, or Ror2-DM showed a significant increase in <i>in vivo</i> tumor growth with wild-type Ror2 overexpression. <i>P</i>-values were calculated using an Anova one-way analysis (*<.05 **<.01). <b>E</b>) Representative image of an orthotopic xenograft consisting of 786-0 vector control cells. <b>F</b>) Increased invasion of local tissues was evident with Ror2 expression, with arrows highlighting areas of continued invasion into the spleen.</p

High Ror2 expression correlates with increased tumor growth and stage in primary human RCC tumors.

<p>Tumor percentage breakdowns of TCGA ccRCC cases (468) stratified by Ror2-High and Ror2-Low expression show Ror2-High tumors exhibiting significant increases in <b>A</b>) tumor size, <b>B</b>) higher nuclear grade, <b>C</b>) clinical stage, and <b>D</b>) tumor stage. <i>P</i>-values were calculated using either an Anova one-way analysis or Fisher's exact test (*<.05, **<.001).</p

Summary of clinical characteristics of patients in the TCGA ccRCC dataset.

<p>Summary of clinical characteristics of patients in the TCGA ccRCC dataset.</p