The Interaction of peptides with functionalized carbon nanotubes

A literature study was conducted to review peptide adhesion to carbon nanotubes and they were found to be important in the drug designing industries. To attain target specificity CNTs (functionalized with DNA, peptides etc.) have been used as potential vector system. Prior studies show that single walled nanotubes (SWNTs) when functionalized with peptides have been proven to be better delivery systems than the previous vector delivery systems. Functionalized SWNTs can deliver the peptides to the specific target organs in the right concentration without having prominent toxic effect. Toxicity studies show that since the SWNTs have shorter half life periods most of them get washed away after they deliver the ligands to the target organs. It has been shown that SWNTs that are toxic to the body are so solely due to manufacturing defects. Pure SWNTs are not toxic to the body. Recently functionalized CNTs are also used for cancer therapy. A docking study was carried out on interaction of hydrogen and nitrogen functionalized SWNTs with peptides where vasopressin is the model peptide. In order to study the effect of dimensions of SWNTs and functionalized group attached to the SWNTs on the strength of a bond, binding free energies were calculated from the docking models. Hydrogen functionalized, nitrogen functionalized and non-functionalized SWNTs binding energies were compared with each other. Results show that functionalized SWNTs tend to bind with more peptide molecules than nonfunctionalized SWNTs. The interactions on the inner walls of SWNTs are more unstable than the outer wall interactions

Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole

PURPOSE: We determined hormone concentrations (estradiol [E2], estrone [E1], estrone conjugates [E1-C], androstenedione [A], testosterone [T]) before and on anastrozole therapy where we also determined plasma concentrations of anastrozole and its metabolites. EXPERIMENTAL: Postmenopausal women who were to receive adjuvant anastrozole for resected early breast cancer were studied. Pretreatment, blood samples were obtained for the acquisition of DNA and for plasma hormone measurements (E2, E1, E1-C, A, and T). A second blood draw was obtained at least 4 weeks after starting anastrozole for hormone, anastrozole and metabolite measurements. For hormone assays, a validated bioanalytical method using gas chromatography negative ionization tandem mass spectrometry was used. Anastrozole and metabolite assays involved extraction of plasma followed by LC/MS/MS assays. RESULTS: 649 patients were evaluable. Pretreatment and during anastrozole, there was large inter-individual variability in E2, E1, and E1-C as well as anastrozole and anastrozole metabolite concentrations. E2 and E1 concentrations were below the lower limits of quantitation in 79% and 70%, respectively, of patients on anastrozole therapy, but those with reliable concentrations had a broad range (0.627-234.0 pg/mL, 1.562-183.2 pg/mL, respectively). Considering E2, 8.9% had the same or higher concentration relative to baseline while on anastrozole, documented by the presence of drug. CONCLUSIONS: We demonstrated large inter-individual variability in anastrozole and anastrozole metabolite concentrations as well as E1, E2, E1-C, A, and T concentrations before and while on anastrozole. These findings suggest that the standard 1mg daily dose of anastrozole is not optimal for a substantial proportion of women with breast cancer

Anastrozole has an association between degree of estrogen suppression and outcomes in early breast cancer and is a ligand for estrogen receptor α

Purpose: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. Experimental design: Matched case-control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. Results: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1-/- T47D breast cancer cell line. Conclusions: This matched case-control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk

An integrated model of the transcriptome of HER2-positive breast cancer

Our goal in these analyses was to use genomic features from a test set of primary breast tumors to build an integrated transcriptome landscape model that makes relevant hypothetical predictions about the biological and/or clinical behavior of HER2-positive breast cancer. We interrogated RNA-Seq data from benign breast lesions, ER+, triple negative, and HER2-positive tumors to identify 685 differentially expressed genes, 102 alternatively spliced genes, and 303 genes that expressed single nucleotide sequence variants (eSNVs) that were associated with the HER2-positive tumors in our survey panel. These features were integrated into a transcriptome landscape model that identified 12 highly interconnected genomic modules, each of which represents a cellular processes pathway that appears to define the genomic architecture of the HER2-positive tumors in our test set. The generality of the model was confirmed by the observation that several key pathways were enriched in HER2-positive TCGA breast tumors. The ability of this model to make relevant predictions about the biology of breast cancer cells was established by the observation that integrin signaling was linked to lapatinib sensitivity in vitro and strongly associated with risk of relapse in the NCCTG N9831 adjuvant trastuzumab clinical trial dataset. Additional modules from the HER2 transcriptome model, including ubiquitin-mediated proteolysis, TGF-beta signaling, RHO-family GTPase signaling, and M-phase progression, were linked to response to lapatinib and paclitaxel in vitro and/or risk of relapse in the N9831 dataset. These data indicate that an integrated transcriptome landscape model derived from a test set of HER2-positive breast tumors has potential for predicting outcome and for identifying novel potential therapeutic strategies for this breast cancer subtype

Entry record in the Land Register

The diploma thesis deals with the entry record to the Land Register of the Czech Republic. The adoption of the Act no. 89/2012 Coll., Civil Code and the Act no. 256/2013 Coll., On the Land Register, caused extended changes in the real estate register and cadastral legislation. This changes had a significant influence on some legal concepts relevant for this field of law. The diploma thesis in divided into four parts. The first part is used for the acquisition of basic knowledge on the issue of Land Register, with emphasis on principals that control the operation of the Lend Registry and making entries in it. The second part provides a thorough analysis of the current form of the institute of entry record and registration procedure with regard to previous legislation. The third section is devoted to examining of the German legislation, registration of real estate with an emphasis on the Land Registry, cadastral principles and registration of rights in the Land Register. Content of the last part of the thesis is the comparison of Czech and German legislation, focusing on selected issues and institutes. Powered by TCPDF (www.tcpdf.org

Irrationality of consumer choice and the effect of nudging decision-making: A field experiment on tipping

Ekonomy i psychology po celém světě vždy zajímala otázka procesu lidského rozhodování. Eko- nomové zd·razňují význam teorie úžitku během rozhodování, kdežto psychologové se zaměřují na r·zné vnitřní a vnější stimuly ovlivňující naše rozhodnutí. Oba tyto přístupy m·žeme najít v be- haviorální ekonomií, kde oba koncepty mezi sebou těsně spolupracují. Znalost r·zných ekonomic- kých i psychologických faktor·, které ovlivňují náš výběr m·že být mimo jiné přínosná například ve výzkumu spropitného. Abychom našli r·zné d·vody pro placení spropitného, vytvořili jsme experiment ohledně výše spropitného u českých zákazník·. Procentuální výše spropitného byla zkoumána v závislosti na pohlaví obsluhy, velikosti skupiny, která navštívila restauraci, velikosti účtu na jednu osobu a také byl zkoumán vliv tří na sobě nezávislých intervencí. Tyto intervence byly zaměřeny na altruistické chování, reciprocitu a dobrou náladu zp·sobenou personalizací. Výsledky experimentu jsou překvapující a neshodují se s výsledky z předchozích experiment·. Bylo zjištěno, že intervence spojené s altruismem a reciprocitou mají negativní vliv na výši spro- pitného, avšak intervence spojená s personalizací nemá žádný vliv na spropitné. Ve výsledku se také poukazuje na klíčový vliv země, ve které je experiment proveden.

A Prospective Correlation of Tissue Histopathology With Nucleic Acid Yield in Metastatic Castration-Resistant Prostate Cancer Biopsy Specimens

Objective: To determine histopathologic, exome, and transcriptome nucleic acid material yield from prospectively collected metastatic tissue biopsy specimens in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial metastatic site core needle biopsies after study activation on May 17, 2013. Multiple cores were obtained, and from each core, 1- to 2-mm segments were separated and formalin fixed for histopathologic examination. Tumor purity was determined for DNA and RNA from the rest of the biopsy specimen. RNA quality was assessed by calculation of an RNA integrity number and a DV200 score. Results: A total of 89 patients underwent 172 uniformly processed core needle biopsies (89 on visit 1 and 83 on visit 2) between May 30, 2013, and September 10, 2015. Metastatic sites biopsied included bone (131), lymph nodes (31), liver (5), lung (3), and pelvic soft tissues (2). Of the 172 biopsy specimens, 85 (49%) had at least one of the multiple cores positive for tumor on histopathologic examination (53 of 88 [60%] from visit 1 and 32 of 83 [39%] from visit 2; P=.006). Metastatic carcinoma was observed in 50 of 130 bone lesion specimens (38%), compared to 35 of 41 nonbone specimens (85%) (P<.001). More than 10% tumoral DNA purity was observed in 89% and 80% of visit 1 and visit 2 biopsy specimens, respectively. Similarly, more than 10% tumor RNA purity was observed in 79% of visit 1 vs 59% for visit 2 (P=.008). In all, 134 of 172 procedures (78%) yielded tumor material either by histopathologic or nucleic acid purity analysis. Conclusion: This study found that biopsy specimens from mCRPC sites yield adequate histopathologic, exome, and transcriptome material in most, but not all, cases. This finding has relevance for future genome sequencing studies on the introduction of targeted therapeutic agents. Trial Registration: clinicaltrials.gov Identifier: 01953640

Additional file 14: Table S4. of Measure transcript integrity using RNA-seq data

List of 10 low RIN/medTIN mCRPC and 10 higher RIN/medTIN mCRPC samples used for differential expression analysis. “N” = Metastatic bone site, “V1” = Visit 1. Whole datasets are available with accession # GSM1722952. (XLS 97 kb