452 research outputs found
„O strojach dawnych i o teraźniejszej tego wieku modzie” w ujęciu Jakuba Kazimierza Haura (1632–1709)
No full textThe article describes the work of Jakub Kazimierz Haur, entitled The Store or Treasury of Excellent Secrets of Land Economy, first published in 1693. It is a voluminous book of more than five hundred pages, in which the author presented a lot of information from various disciplines – agriculture, meteorology, astrology, medicine, hygiene, veterinary medicine, plastic arts, geography and law, as well as some practical instructions on educating children, reading, hunting or protection against witchcraft. The book also touches on issues relating to costumes, and the parts of the text devoted to these issues were divided by the author into three categories. The first part is devoted to the history of costumes, both in Poland and in other countries, the second part provides information on 17th century fashion in the territory of Poland, and the third part gives practical tips on the cleaning and care of clothes. The book explicitly shows the author’s passion for didacticism, reflected especially in the fragments in which he criticizes women for being excessively influenced by fashion and for blindly copying foreign culture. Nevertheless, the 17th-century author considers clothing to be an important part of everyday life and recommends proper care of it. It should be noted that some of the in the book on how to take care of clothes is still valid today.Artykuł przybliża dzieło Jakuba Kazimierza Haura zatytułowane Skład albo skarbiec znakomitych sekretów ekonomiej ziemiańskiej wydane po raz pierwszy w roku 1693. Jest to bardzo obszerna, licząca ponad pięćset stron, księga, w której autor zawarł szereg informacji z najróżniejszych dziedzin – rolnictwa, meteorologii, astrologii, medycyny, higieny, weterynarii, sztuk plastycznych, geografii i prawa, a także garść porad dotyczących kulinariów, wychowywania dzieci, czytelnictwa, łowiectwa czy zabezpieczania się przed czarami. Na kartach tego dzieła znalazła swoje miejsce także tematyka związana ze strojami. Te fragmenty tekstu podzielił autor na trzy kategorie. Pierwszą stanowią rozważania o historii ubioru zarówno w Polsce, jak i w innych krajach, drugą – informacje o XVII-wiecznej modzie na terenie Rzeczypospolitej, trzeci obszar rozważań Haura obejmuje natomiast praktyczne porady dotyczące czyszczenia odzieży i dbania o nią. W utworze wyraźnie daje o sobie znać skłonność autora do dydaktyzmu, szczególnie w tych fragmentach, w których krytykuje on Polki za nadmierne uleganie dyktatowi mody i ślepe naśladownictwo obcej kultury. Niezależnie jednak od tego XVII-wieczny autor postrzega strój jako ważny element codzienności i zaleca o niego dbać, przy czym niektóre zamieszczone w dziele porady dotyczące konserwacji odzieży nie straciły do dziś aktualności
Src inhibitors in lung cancer: current status and future directions
No full textSrc tyrosine kinases regulate multiple genetic and signaling pathways involved in the proliferation, survival, angiogenesis, invasion, and migration of various types of cancer cells They are frequently expressed and activated in many cancer types, including lung cancer. Several Src inhibitors, including dasatinib, saracatinib, bosutinib, and KX2-391, are currently being investigated in clinical trials. Preliminary results of the use of single-agent Src inhibitors in unselected patients with lung cancer show that these inhibitors have a favorable safety profile and anticancer activity. Their combination with cytotoxic chemotherapy, other targeted therapy, and radiation therapy is currently being explored. In this review, we summarize the rationale for and the current status of Src inhibitor development and discuss future directions based on emerging preclinical data
MET–GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors
No full textAbstract
Purpose: Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized that assays reflecting MET signaling associated protein complexes could redefine tumors dependent on MET and could add additional precision beyond genomic assessments.
Experimental Design: We used biochemical approaches, cellular viability studies, and proximity ligation assays to assess MET dependence. We examined MET signaling complexes in lung cancer patient specimens (N = 406) and patient-derived xenograft (PDX) models of solid tumors (N = 308). We evaluated response to crizotinib in a MET-amplified cohort of PDX models of lung cancer (N = 6) and provide a case report of a lung cancer patient harboring a Δexon14 MET splice variant.
Results: We found the interaction of MET with the adaptor protein GRB2 is necessary for oncogenic survival signaling by MET. MET-GRB2 complexes were identified only within MET-amplified PDX models and patient specimens but exhibit substantial variability. Lack of MET-GRB2 complexes was associated with lack of response to MET TKI in cell lines and PDX models. Presence of MET-GRB2 complexes can further subtype tumors with Δexon14 MET splice variants. Presence of these complexes correlated with response to crizotinib in one patient with Δexon14 MET lacking MET gene amplification.
Conclusions: Proximity assays measuring MET-GRB2 signaling complexes provide novel insights into MET-mediated signaling and could complement current clinical genomics-based assay platforms. Clin Cancer Res; 23(22); 7084–96. ©2017 AACR.</jats:p
Abstract 5222: A landscape of deubiquinating enzymes (DUB) in lung cancer using activity based protein profiling (ABPP)
No full textAbstract
Dysregulation of ubiquitin signaling has been linked to many diseases, including cancer. Numerous DUBs are implicated in key pro-cancer pathways, including regulation of HIF1α, control of RAS signaling, signaling through both canonical and non-canonical NFκB pathways, and regulation of p53 activity. Overexpression of USP14, USP17 and USP28 is linked to promoting non-small cell lung cancer (NSCLC). OTUB1 has shown to trigger lung cancer progress by inhibiting RAS monoubiquitination in KRAS mutant NSCLC. Notably, BAP1 (tumor suppressor) expression decreases in lung cancer tissues although its mRNA levels did not reflect it. Based on these findings, we hypothesized that profiling DUB proteins and their activity in lung cancer cells and tissues could uncover new therapeutic targets. Since proteogenomics studies have revealed that mRNA expression is not a reliable predictor of the protein expression, we have used ABPP assays to profile DUB. ABPP, which uses chemical probes directed against the active sites of enzymes to interrogate the functional state of enzymes in biological samples, can serve as an important tool to nominate DUB targets. HA-tagged active site-directed ubiquitin probe, HA-Ub-VME was used to evaluate the DUBs profile of KRAS and EGFR mutant cell lines. Cell lysate was labeled in presence or absence of DUB inhibitors (DUBi) and the modified enzymes were visualized by anti-HA immunoblotting. Labeled proteome was enriched and analyzed using mass spectrometry and data was analyzed using APOSTL. In addition to DUB profiling, we screened lung cancer cell lines to DUBi, including small cell lung cancer, KRAS mutant, EGFR mutant, and models of EGFR TKI resistance. Immunoblotting in various KRAS and EGFR mutant cell lines displayed diverse profiles of DUBs. Enrichment of DUBs in A549 cells showed 23 DUBs and competition with bAP15, a well-known DUBi for USP14 resulted in reduced probe binding to USP14. We optimized the approach to capture maximum DUBs by examining parameters such as protein/probe ratio, probe incubation time and probing different lung cancer cells that may harvest a larger or complementary repertoire of DUBs. A preliminary screen of DUBi across 20 SCLC and NSCLC cell lines lead to a panel of DUBi (IC50=100nM-5µM), with broad or selective activity in particular cell lines. These results are being used for competitive DUB profiling using ABPP to comprehend target engagement and resulting changes in cell viability induced by DUBi. These results enable future studies to profile the DUB landscape in lung cancer cell lines, PDX tumor cohorts, and tumor tissues from patients. DUB ABPP can identify important DUBs in lung cancer cells to both identify new drug targets, as well as discern mechanism of action of drugs identified from compound screening campaigns.
Citation Format: Shikha Mahajan, Bin Fang, Fumi Kinose, Eric B. Haura. A landscape of deubiquinating enzymes (DUB) in lung cancer using activity based protein profiling (ABPP) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5222. doi:10.1158/1538-7445.AM2017-5222</jats:p
From modules to medicine: How modular domains and their associated networks can enable personalized medicine
No full textAbstractUnveiling of cancer genomes is unleashing new therapeutic strategies for cancer. With cancer parts lists in hand, new approaches to personalized medicine can be developed by understanding the assembly of cancer machines using modular domains in proteins and their associated networks. Using the Src-homology-2 (SH2) domain as an example, new profiling approaches can discern global patterns of tyrosine phosphorylation in cancer cells that can enable molecular cancer medicine. Identifying and quantifying protein–protein interactions also has the potential to subtype tumors and guide clinical decision making. These approaches should extend the impact of genomics through viewing the architecture of cancer systems and improve predictions of patient outcome and therapeutic response, as well as guide combination therapy approaches that attack cancer systems
Abstract 4853: NRP2b, a unique isoform of NRP2, promotes aggressive lung cancer phenotypes
No full textAbstract
Neuropilins (NRPs) 1 and 2 are highly-related receptors for class 3 semaphorins, and interact with heparin-binding growth factors and their receptors (e.g. HGF-MET, VEGF-VEGFR2 etc.). We previously reported that NRP2 is upregulated by TGFβ and is required for its pro-tumorigenic activity. Here, we show that this upregulation preferentially involves NRP2b, a largely uninvestigated isoform encoding a divergent, yet highly-conserved C-terminus. Importantly, using a panel of lung cancer cell lines and orthotopic metastasis model, NRP2b promoted migration, invasion, metastasis and tumorsphere formation, whereas the prototype receptor, NRP2a had opposite effects. TGFβ-mediated resistance to gefitinib in EGFR mutated tumors also was dependent on NRP2b expression. In addition, NRP2b, but not NRP2a, linked MET activation by HGF to AKT phosphorylation. Mechanistically, in co-immunoprecipitation assays, we found that NRP2a robustly interacted with PTEN, while the interaction with NRP2b was weak. At the clinical level, NRP2b expression was commonly upregulated in patient lung cancer samples and this upregulation was a significant poor-prognostic factor. Collectively, these data indicate that NRP2b plays an important role in lung cancer invasion, metastasis and EGFR inhibitor resistance. Furthermore, isoform-specific interactions between NRP2 and PTEN may be responsible for the observed differences in MET signaling in response to HGF.
Citation Format: Anastasios Dimou, Patrick Nasarre, Joyce Nair-Menon, Federico Cappuzzo, Lorenza Landi, Armida D'Incecco, Hidetaka Uramato, Takeshi Yoshida, Eric Haura, Monica Gooz, Kent Armeson, Robert Gemmill, Harry Drabkin. NRP2b, a unique isoform of NRP2, promotes aggressive lung cancer phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4853. doi:10.1158/1538-7445.AM2017-4853</jats:p
Treatment of Advanced Non-Small-Cell Lung Cancer: A Review of Current Randomized Clinical Trials and an Examination of Emerging Therapies
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Cek Plagiasi LINGUISTICS: An Overview of the Study of Language. Research Report
No full textLinguistics and its branches play important role for language users to understand and examine the study of language. As the basis knowledge of language, it is very essential for them to learn and acquire more and deeper especially in comprehending the theoretical and also the practice. It is why the author tries to introduce this book as a handbook for the beginner to initiate and establish all the linguistics material related English language related to the history English development, morphology, syntax, discourse analysis, pragmatics, semantics, structure of English text, and etc. Decisively, it is counted on that it could enhance the language users 'familiarity, awareness, expertise, insight and know-how to determine linguistics
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