Chondroitin Sulfate Proteoglycan 4 as a Marker for Aggressive Squamous Cell Carcinoma

Chondroitin sulfate (CS) proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is currently under investigation as a marker of cancer malignancy, and as a potential target of anticancer drug treatment. CSPG4 acts as a driver of tumourigenesis by regulating turnover of the extracellular matrix (ECM) to promote tumour cell invasion, migration as well as inflammation and angiogenesis. While CSPG4 has been widely studied in certain malignancies, such as melanoma, evidence is emerging from global gene expression studies, which suggests a role for CSPG4 in squamous cell carcinoma (SCC). While relatively treatable, lack of widely agreed upon diagnostic markers for SCCs is problematic, especially for clinicians managing certain patients, including those who are aged or infirm, as well as those with underlying conditions such as epidermolysis bullosa (EB), for which a delayed diagnosis is likely lethal. In this review, we have discussed the structure of CSPG4, and quantitatively analysed CSPG4 expression in the tissues and pathologies where it has been identified to determine the usefulness of CSPG4 expression as a diagnostic marker and therapeutic target in management of malignant SCC

Anti-cancer potential of synergistic phytochemical combinations is influenced by the genetic profile of prostate cancer cell lines

Introduction: Despite strong epidemiological evidence that dietary factors modulate cancer risk, cancer control through dietary intervention has been a largely intractable goal for over sixty years. The effect of tumour genotype on synergy is largely unexplored. Methods: The effect of seven dietary phytochemicals, quercetin (0–100 μM), curcumin (0–80 μM), genistein, indole-3-carbinol (I3C), equol, resveratrol and epigallocatechin gallate (EGCG) (each 0–200 μM), alone and in all paired combinations om cell viability of the androgen-responsive, pTEN-null (LNCaP), androgen-independent, pTEN-null (PC-3) or androgen-independent, pTEN-positive (DU145) prostate cancer (PCa) cell lines was determined using a high throughput alamarBlue® assay. Synergy, additivity and antagonism were modelled using Bliss additivism and highest single agent equations. Patterns of maximum synergy were identified by polygonogram analysis. Network pharmacology approaches were used to identify interactions with known PCa protein targets. Results: Synergy was observed with all combinations. In LNCaP and PC-3 cells, I3C mediated maximum synergy with five phytochemicals, while genistein was maximally synergistic with EGCG. In contrast, DU145 cells showed resveratrol-mediated maximum synergy with equol, EGCG and genistein, with I3C mediating maximum synergy with only quercetin and curcumin. Knockdown of pTEN expression in DU145 cells abrogated the synergistic effect of resveratrol without affecting the synergy profile of I3C and quercetin. Discussion: Our study identifies patterns of synergy that are dependent on tumour cell genotype and are independent of androgen signaling but are dependent on pTEN. Despite evident cell-type specificity in both maximally-synergistic combinations and the pathways that phytochemicals modulate, these combinations interact with similar prostate cancer protein targets. Here, we identify an approach that, when coupled with advanced data analysis methods, may suggest optimal dietary phytochemical combinations for individual consumption based on tumour molecular profile

A cancer stem cell-like phenotype is associated with miR-10b expression in aggressive squamous cell carcinomas

Background Cutaneous squamous cell carcinomas (cSCC) are the primary cause of premature deaths in patients suffering from the rare skin-fragility disorder recessive dystrophic epidermolysis bullosa (RDEB), which is in marked contrast to the rarely metastasizing nature of these carcinomas in the general population. This remarkable difference is attributed to the frequent development of chronic wounds caused by impaired skin integrity. However, the specific molecular and cellular changes to malignancy, and whether there are common players in different types of aggressive cSCCs, remain relatively undefined. Methods MiRNA expression profiling was performed across various cell types isolated from skin and cSCCs. Microarray results were confirmed by qPCR and by an optimized in situ hybridization protocol. Functional impact of overexpression or knock-out of a dysregulated miRNA was assessed in migration and 3D-spheroid assays. Sample-matched transcriptome data was generated to support the identification of disease relevant miRNA targets. Results Several miRNAs were identified as dysregulated in cSCCs compared to control skin. These included the metastasis-linked miR-10b, which was significantly upregulated in primary cell cultures and in archival biopsies. At the functional level, overexpression of miR-10b conferred the stem cell-characteristic of 3D-spheroid formation capacity to keratinocytes. Analysis of miR-10b downstream effects identified a novel putative target of miR-10b, the actin- and tubulin cytoskeleton-associated protein DIAPH2. Conclusion The discovery that miR-10b mediates an aspect of cancer stemness – that of enhanced tumor cell adhesion, known to facilitate metastatic colonization – provides an important avenue for future development of novel therapies targeting this metastasis-linked miRNA

Human Group IIA Phospholipase A2 : three decades on from its discovery

Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function

Hur låter det efter mastering?

Syftet med detta examensarbete är att undersöka i vilken grad en given publik påverkas av och uppfattar förändringar i två versioner av en och samma låt – före och efter att de båda versionerna utsatts för en teknisk process som kallas mastering. Vår problemformulering är följande: Är det möjligt att genom mastering åstadkomma två kommersiellt gångbara produkter av en och samma låt – en mixad av en amatör och en av en professionell mixtekniker? Metoden har varit att utforma en låt som två personer låtits mixa: en amatör, som aldrig genomfört en mix tidigare och en professionell mixare, som alltså aktivt verkar i branschen och tar betalt för utfört mixarbete. Dessa två färdiga mixar (lyssningsomgång 1) samt två mastrade versioner av samma mixar (lyssningsomgång 2) har spelats upp för en publik, som utifrån ett antal förutsättningar och frågor fått bedöma materialet. En musikalisk produktion innehåller flera olika element, även kallade spår, som tillsammans bildar det man kallar ”en låt”. Dessa element kan exempelvis vara slagverk, instrument, effekter och vokaler, som alla förutom dess musikaliska kvalitéer också har en teknisk funktion i det frekvensregister som det mänskliga örat kan uppfatta. En mixteknikers uppgift är att skapa balans och harmoni mellan dessa spår, så de tillsammans blir en välljudande helhet. Efter utförd mix följer ett avslutande steg som kallas mastering. I denna process jobbar man endast med ett spår, som alltså är den färdiga mixen. En ändring i detta spår kommer alltså påverka alla de spår som man behandlade separat under mixarbetet. Resultatet visar att vår publik har svårt att skilja mellan amatörens och den professionelles mix – efter att låtarna genomgått mastering. I masteringen har man alltså lyckats kompensera för de brister vissa lyssnare uppfattade i amatörens mix och många gånger även göra den intressantare än proffsets mastrade version. Vi har varit noggranna med att utesluta tillfälligheter som en inverkande faktor på slutresultatet. Detta för att experimentet skall gå att återupprepa i denna form. Det kan diskuteras huruvida sättet vi utformat låten på gjort arbetet ”lätt” för amatörm ixaren; de 91 ljudspåren vi har levererat innehåller inga ”fel” så som störande övertoner eller okontrollerat spel. Den aspekten hade varit relevant om syftet med studien hade varit att upptäcka skillnader mellan en amatör och en proffs-mixtekniker. Eftersom vår problemformulering är av ett annat slag tror vi att den aktuella utformningen av låten hjälper vår studie. Det vore som förslag på framtida forskning intressant att utöka antalet undersökningsdeltagare, från nuvarande 10 till exempelvis 40, för att få ett ännu tydligare underlag. Vidare vore det intressant att göra en detaljerad analys av undersökningsdeltagarnas bakgrunder, för att kunna göra kopplingar mellan deras svar och personligheter

Synthesis and characterization of CdS quantum dots-polystyrene composite

Methodology for incorporation of 50 A CdS quantum dots (QD) in a polystyrene matrix, based on phase transfer of CdS quantum dots from an aqueous to organic phase, was developed. The obtained composite was characterized using optical, structural and thermal techniques. Infra red measurements revealed formation of chemical bonds between the surface of the CdS QDs and the polystyrene matrix. The polystyrene matrix blocked the surface states that promote radiationless recombination, resulting in enhanced band-to-band luminescence of CdS QDs. On the other hand, in the presence of CdS QDs the thermal decomposition of polystyrene was shifted towards higher temperature for about 100 degreesC. (C) 2000 Elsevier Science B.V. All rights reserved

Emerging roles for phospholipase A2 enzymes in cancer

Phospholipase A (PLA) enzymes (EC3.1.4.4) regulate the release of biologically active fatty acids and lysophospholipids from membrane phospholipid pools. These lipids are also substrates for intracellular biochemical pathways that generate potent autocrine and paracrine lipid mediators such as the eicosanoids and platelet activating factor. These factors, in turn, regulate cell proliferation, survival, differentiation, motility, tissue vascularisation, and immune surveillance in virtually all tissues, functions that are subverted by cancer cells for tumour growth and metastasis. Thus the relevance of PLA-dependent pathways to the genesis and progression of cancer has been of interest since their discovery and with recent technological advances, their role in tumourigenesis has become more tractable experimentally. Limited human genetic studies have not yet identified PLA enzymes as classical mutated oncogenes or tumour suppressor genes. However, there is strong evidence that of the 22 identified human PLA enzymes, ten of which have been studied in cancer to date, most are aberrantly expressed in a proportion of tumours derived from diverse organs. Correlative and functional studies implicate the expression of some secreted enzymes (sPLAs), particularly the best studied enzyme Group IIA sPLA in either tumour promotion or inhibition, depending on the organ involved and the biochemical microenvironment of tumours. As in immune-mediated inflammatory pathologies, genetic deletion studies in mice, supported by limited studies with human cells and tissues, have identified an important role for Group IVA PLA in regulating certain cancers. Pharmacological intervention studies in prostate cancer suggest that hGIIA-dependent tumour growth is dependent on indirect regulation of Group IVA PLA. Group VI calcium-independent PLA enzymes have also been recently implicated in tumourigenesis with in vitro studies suggesting multiple possible roles for these enzymes. Though apparently complex, further characterization of the regulatory relationships amongst PLA enzymes, lipid mediator biosynthetic enzymes and the lipid mediators they produce during tumour progression is required to define the biochemical context in which the enzymes modulate cancer growth and development

Chondroitin Sulfate Proteoglycan 4 as a Marker for Aggressive Squamous Cell Carcinoma

Chondroitin sulfate (CS) proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is currently under investigation as a marker of cancer malignancy, and as a potential target of anticancer drug treatment. CSPG4 acts as a driver of tumourigenesis by regulating turnover of the extracellular matrix (ECM) to promote tumour cell invasion, migration as well as inflammation and angiogenesis. While CSPG4 has been widely studied in certain malignancies, such as melanoma, evidence is emerging from global gene expression studies, which suggests a role for CSPG4 in squamous cell carcinoma (SCC). While relatively treatable, lack of widely agreed upon diagnostic markers for SCCs is problematic, especially for clinicians managing certain patients, including those who are aged or infirm, as well as those with underlying conditions such as epidermolysis bullosa (EB), for which a delayed diagnosis is likely lethal. In this review, we have discussed the structure of CSPG4, and quantitatively analysed CSPG4 expression in the tissues and pathologies where it has been identified to determine the usefulness of CSPG4 expression as a diagnostic marker and therapeutic target in management of malignant SCC