Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures

The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by 'RTK swapping' by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation.

Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures

The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by 'RTK swapping' by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation.

Mantle- and crust-derived magmatism in the southern Fennoscandian Shield at c. 1.8 Ga; evidence from geochemistry, isotopes and geochronology

Geokemi och isotopsammansättningarna hos ca 1,8 Ga (miljarder år) gamla mafiska bergartsintrusioner studerades i två huvudområden: i) Transskandinaviska magmatiska bältet (TMB) i Bergslagen, Småland och Blekinge, södra Sverige, inklusive några prov från det ca 1,87 Ga gamla Hedesunda-komplexet i östra Bergslagen, samt ii) mindre, postkollisionala komplex i södra Finland och ryska Karelen. I det senare fallet var även tillhörande granitoider inkluderade i studierna. TMB-bergarterna skiljer sig avsevärt i utvecklingsgrad och omfattar sammansättningsmässigt bergarter från ultramafiter till kvartsdioriter. Dessa bergarters geokemi är kännetecknande för kontinentala öbågar. För sydligaste TMB och Hedesunda antyder geokemin en något mera oceanisk öbågekaraktär. Tillsammans med tidigare data antyder de av Rutanen analyserade Nd- och Sr-isotopförhållanden för TMB en ’milt utarmad’ mantelsammansättning. De mafiska bergarterna i södra Finland och ryska Karelen varierar från ultramafiska till monzodioritiska, men med avsevärt högre alkalihalter jämfört med TMB. Källan för all den studerade mafiska magmatismen kan beskrivas som en utarmad mantel som i varierande grad påverkats av fluider och smältor ur subducerande litosfärplattor. Geokemin antyder infiltrering och påverkning av H2O-dominerande fluider i övre manteln för TMB. Den mafiska ca 1,8 Ga gamla magmatismen österut avspeglar en ökande påverkan av sedimentderiverade karbonatfluider och smältor inom allt djupare mantelområden. Denna subduktionsrelaterade mantelanrikning skedde under den föregående öbågeutvecklingen i södra delarna av Finland och Sverige, samt ryska Karelen. Geokemin för en grupp granitoider, associerade med de ca 1,8 Ga gamla intrusionerna i södra Finland visar både vulkanisk öbåge och synkollisional granitoidkaraktär. Denna grupp har ett blandat magmatiskt och sedimentärt Svekofenniskt ursprung, vilket kan antas p.g.a. deras Nd- och Sr-isotopförhållanden. En annan grupp av granitoider ligger geokemiskt mellan vulkanisk öbåge- och intraplatt-granitoider, och har magmatiskt ursprung. Geokemin och isotoperna hos dessa intrusioner kan förklaras med hybridisering mellan de kraftigt anrikade, mantelderiverade magmorna, och granitmagmor från den äldre skorpan. Den ca 1,8 Ga gamla TMB-magmatismen i Sverige skedde vid sammanslutning av kontinentalrandbågar, med kontinuerlig subduktion mot öster i Bergslagen, och mot norr i de sydligare delarna. Samtidigt i öster intruderade de postkollisionala intrusionerna i skorpan omedelbart efter kollisionen med den Volgo-Sarmatiska kontinenten från sydost. Denna invecklade paleotektoniska konfiguration orsakade en tektonisk regim där litosfäriska mantelkällor levererade de starkt anrikade magmorna, vilkas uppstigning troligen möjliggjordes av djupgående postkollisionala skjuvzoner. Intrusionerna orsakade uppsmältning av den omgivande skorpan, vilket framkallade den associerade granitoidmagmatismen.

SVUL:n Kymenlaakson piirin mestaruusajot Kotkassa 31.7.-1.8.1943

13 x 21 cm

Luettelo 1/8 1947 voimassa olleista, kansanhuoltoa koskevista säännöksistä, jotka on julkaistu asetuskokoelmassa

20 x 29 cm

Förteckning över den 1/8 1947 ikraftvarande och i författningssamlingen publicerade stadganden rörande folkförsörjningen

20 x 29 cm

Tutustukaa Helsinkiin kiertokäyntipäivillä 1-8.III. 1936

kuv., 14 x 21 cm

Tutustukaa Helsinkiin kiertokäyntipäivillä 1-8.III. 1936

kuv., 14 x 21 cm

No evidence for mutations in exons 1, 8 and 18 of the patched gene in sporadic skin lesions of Brazilian patients

There is strong evidence that the patched (PTCH) gene is a gene for susceptibility to the nevoid basal cell carcinoma syndrome. PTCH has also been shown to mutate in both familial and sporadic basal cell carcinomas. However, mutations of the gene seem to be rare in squamous cell carcinomas. In order to characterize the role of the gene in the broader spectrum of sporadic skin malignant and pre-malignant lesions, we performed a polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis of genomic DNA extracted from 105 adult patients (46 females and 59 males). There were 66 patients with basal cell carcinomas, 30 with squamous cell carcinomas, 2 with malignant melanomas and 7 patients with precancerous lesions. Two tissue samples were collected from each patient, one from the central portion of the tumor and another from normal skin. Using primers that encompass the entire exon 1, exon 8 and exon 18, where most of the mutations have been detected, we were unable to demonstrate any band shift. Three samples suspected to present aberrant migrating bands were excised from the gel and sequenced directly. In addition, we sequenced 12 other cases, including tumors and corresponding normal samples. A wild-type sequence was found in all 15 cases. Although our results do not exclude the presence of clonal alterations of the PTCH gene in skin cancers or mutations in other exons that were not screened, the present data do not support the presence of frequent mutations reported for non-melanoma skin cancer of other populations.

Insecta Fennica enumerans 1:8

Painovuosi nimekkeestä.

Plan för staden Nikolaistad fastställd 1/8 1855

Mittakaava laskettu janamittakaavasta

Suomen taloudellinen kartta 1:100000: (kihlakunnankartta) = Finlands ekonomiska karta 1:100000 : (häradskarta) - Lehti = Blad 1:8, 2:8, Kotka

0-meridiaani : Helsinki.

La Varenne, 1/8/20, chaise à porteurs [défilé] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 60329

Colombes, 1/8/20, départ du 800 m [sélection olympique] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 60341