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51.
Tomas Buchler Zbynek Bortlicek Alexandr Poprach Katerina Kubackova Igor Kiss Milada Zemanova Ondrej Fiala Ladislav Dusek Rostislav Vyzula Bohuslav Melichar 《Urologic oncology》2014,32(5):569-575
ObjectivesThe aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs).Patients and methodsA national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs.ResultsMedian progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013.ConclusionPFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy. 相似文献
52.
Natural feed additive of Macleaya cordata: Safety assessment in rats a 90-day feeding experiment 总被引:1,自引:0,他引:1
Adela Zdarilova Eva Vrublova Jitka Vostalova Borivoj Klejdus David Stejskal Jitka Proskova Pavel Kosina Alena Svobodova Rostislav Vecera Jan Hrbac Drahomira Cernochova Jaroslav Vicar Jitka Ulrichova Vilim Simanek 《Food and chemical toxicology》2008,46(12):3721-3726
Macleaya cordata (Willd.) (Papaveraceae) is used as an active component in the natural feed additive Sangrovit®. Sangrovit® contains mixture of the intact aerial parts and the fraction of quaternary benzo[c]phenanthridine alkaloids from M. cordata (FQBA). In a 90-day pilot toxicity trial, Sangrovit® and the FQBA were tested for safety. Male Wistar rats were fed for 90 days with 100, 7000 or 14000 mg of Sangrovit® or 600 mg of FQBA in 1 kg of feed. Body and organ weights, clinical chemistry and hematology markers, oxidative stress parameters, morphological structure of tongue, liver, ileum, kidney and heart samples, and total cytochrome P450 in liver were monitored. The results showed no statistically significant alterations in any parameter between control and treated animals, except for the group treated with 14000 ppm Sangrovit® that resulted in elevation of reduced glutathione level and superoxide dismutase activity in liver. 相似文献
53.
David Kubicek Miroslav Hornak Jakub Horak Rostislav Navratil Gabriela Tauwinklova Jiri Rubes Katerina Vesela 《Reproductive biomedicine online》2019,38(3):330-339
Research question
What is the incidence and origin of meiotic whole and segmental aneuploidies detected by karyomapping at a blastocyst stage in human-derived IVF embryos? What is the distribution of various types of errors, including rare chromosomal abnormalities?Design
The incidence of chromosomal aneuploidies was assessed in 967 trophectoderm biopsies from 180 couples who underwent 215 cycles of IVF with preimplantation genetic testing for monogenetic disease with a known causal mutation with a mean maternal age of 32.7 years. DNA from both parents and a reference sample was genotyped together with the analysed trophectoderm samples by karyomapping (single-nucleotide-polymorphism-based array).Results
Chromosomal abnormalities were detected in 31% of the analysed samples. At least one whole chromosomal aneuploidy was detected in 27.1% of the trophectoderm biopsies, whereas a segmental aneuploidy was detected in 5.1% of the trophectoderm biopsies. Our results reveal that segmental aneuploidies predominantly affect paternally derived chromosomes (70.4%; P < 0.01) compared with whole chromosomal aneuploidies that more frequently affect maternally derived chromosomes (90.1%; P < 0.0001). Also, the frequency of meiosis I (MI) and meiosis II (MII) errors was established in meiotic trisomies; MI errors were observed to be more frequent (n?=?102/147 [69.4%]) than MII errors (n?=?45/147 [30.6%]).Conclusions
Karyomapping is a robust method that is suitable for preimplantation genetic testing for monogenetic disease and for detecting meiotic aneuploidies, including meiotic segmental aneuploidies, and provides complex information about their parental origin. Our results revealed that segmental aneuploidy more frequently affects paternal chromosomes compared with whole chromosomal aneuploidy in human IVF embryos at the blastocyst stage. 相似文献54.
Kelika A. Konda Rostislav Castillo Segundo R. Leon Alfonso Silva-Santisteban Ximena Salazar Jeffrey D. Klausner Thomas J. Coates Carlos F. Cáceres 《AIDS and behavior》2017,21(1):152-162
Men who have sex with men (MSM) and transgender women (TW) are key populations in the HIV epidemic. HIV status communication between sex partners can inform decisions regarding sexual behavior. MSM and TW were asked about HIV status communication with sex partners at baseline, 9- and 18-months. GEE models assessed associations with HIV status communication at baseline using prevalence ratios (PRs) and longitudinally using odds ratios (ORs). At baseline, those who had previously had an HIV test, disclosed their HIV status to 42 % of their sex partners. HIV status communication was associated with knowing their sex partner’s HIV status at baseline (aPR 5.20) and longitudinally (aOR 1.86). HIV positivity at baseline was negatively associated with HIV status communication during follow-up (aOR 0.55). All reported aPRs and aORs have p < 0.05. Interventions promoting HIV status communication and more frequent HIV testing should be explored as current efforts are insufficient. 相似文献
55.
56.
Rose JL Reeves KC Likhotvorik RI Hoyt DG 《The Journal of pharmacology and experimental therapeutics》2007,321(1):318-326
Engagement of integrin cell adhesion receptors suppresses bleomycin (BLM)-induced DNA strand breakage in endothelial cells. Previous investigation of cells from poly(ADP-ribose) polymerase (PARP)-1 knockout mice and with an inhibitor of the enzyme indicated that this facilitator of base excision repair (BER) is required for integrin-mediated suppression of DNA strand breakage. Here, small inhibitory RNA (siRNA) was used to assess the requirement for the BER proteins, DNA ligase III (Lig3) alpha, PARP-1, and X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), and for the long-patch BER ligase, DNA ligase I (Lig1), in integrin-mediated protection from BLM-induced DNA breakage. Murine lung endothelial cells (MLECs) were transfected with siRNA, treated with anti-beta1 integrin antibody, and then BLM. 3'-OH in DNA and accumulation of phosphorylated histone H2AX (gammaH2AX), which reflects double-strand breakage, were measured. Integrin antibody inhibited the increases in 3'-OH caused by BLM in MLECs transfected with either control or Lig1 siRNA. However, after knockdown of Lig3alpha, PARP-1, or XRCC1, suppression of DNA breakage by integrin antibody was limited. BLM increased gammaH2AX levels, and integrin treatment inhibited this by 57 to 73% in MLECs transfected with control siRNA. Integrin engagement also inhibited increases in gammaH2AX in BLM-treated cells transfected with Lig1 siRNA. In contrast, Lig3alpha, PARP-1, and XRCC1 siRNAs prevented integrin-mediated inhibition of BLM-induced gammaH2AX levels. The results suggest that the BER proteins, Lig3alpha, PARP-1, and XRCC1, are required for integrin-mediated suppression of BLM-induced DNA breakage. 相似文献
57.
Milenković I Witte M Turecek R Heinrich M Reinert T Rübsamen R 《Journal of neurophysiology》2007,98(3):1634-1644
At the initial stages in neuronal development, GABAergic and glycinergic neurotransmission exert depolarizing responses, assumed to be of importance for maturation, which in turn shift to hyperpolarizing in early postnatal life due to development of the chloride homeostasis system. Spherical bushy cells (SBC) of the mammalian cochlear nucleus integrate excitatory glutamatergic inputs with inhibitory (GABAergic and glycinergic) inputs to compute signals that contribute to sound localization based on interaural time differences. To provide a fundamental understanding of the properties of GABAergic neurotransmission in mammalian cochlear nucleus, we investigated the reversal potential of the GABA-evoked currents (E GABA) by means of gramicidin-perforated-patch recordings in developing SBC. The action of GABA switches from depolarizing to hyperpolarizing by the postnatal day 7 due to the negative shift in E GABA. Furthermore, we studied the expression pattern of the K+-Cl(-)-extruding cotransporter KCC2, previously shown to induce a switch from neonatal Cl(-) efflux to the mature Cl(-) influx in various neuron types, thereby causing a shift from depolarizing to hyperpolarizing GABA action. The KCC2 protein is expressed in SBC already at birth, yet its activity is attained toward the end of the first postnatal week as indicated by pharmacological inhibition. Interruption of the Cl(-) extrusion by [(dihydroindenyl)oxy] alkanoic acid or furosemide gradually shifted E(GABA) in positive direction with increasing maturity, suggesting that KCC2 could be involved in maintaining low [Cl(-)]i after the postnatal day 7 thereby providing the hyperpolarizing Cl(-)-mediated inhibition in SBC. 相似文献
58.
Brozkova K Budinska E Bouchal P Hernychova L Knoflickova D Valik D Vyzula R Vojtesek B Nenutil R 《Breast cancer research : BCR》2008,10(3):R48-11
Introduction
Microarray-based gene expression profiling represents a major breakthrough for understanding the molecular complexity of breast cancer. cDNA expression profiles cannot detect changes in activities that arise from post-translational modifications, however, and therefore do not provide a complete picture of all biologically important changes that occur in tumors. Additional opportunities to identify and/or validate molecular signatures of breast carcinomas are provided by proteomic approaches. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) offers high-throughput protein profiling, leading to extraction of protein array data, calling for effective and appropriate use of bioinformatics and statistical tools.Methods
Whole tissue lysates of 105 breast carcinomas were analyzed on IMAC 30 ProteinChip Arrays (Bio-Rad, Hercules, CA, USA) using the ProteinChip Reader Model PBS IIc (Bio-Rad) and Ciphergen ProteinChip software (Bio-Rad, Hercules, CA, USA). Cluster analysis of protein spectra was performed to identify protein patterns potentially related to established clinicopathological variables and/or tumor markers.Results
Unsupervised hierarchical clustering of 130 peaks detected in spectra from breast cancer tissue lysates provided six clusters of peaks and five groups of patients differing significantly in tumor type, nuclear grade, presence of hormonal receptors, mucin 1 and cytokeratin 5/6 or cytokeratin 14. These tumor groups resembled closely luminal types A and B, basal and HER2-like carcinomas.Conclusion
Our results show similar clustering of tumors to those provided by cDNA expression profiles of breast carcinomas. This fact testifies the validity of the SELDI-TOF MS proteomic approach in such a type of study. As SELDI-TOF MS provides different information from cDNA expression profiles, the results suggest the technique's potential to supplement and expand our knowledge of breast cancer, to identify novel biomarkers and to produce clinically useful classifications of breast carcinomas. 相似文献59.
MicroRNAs (miRNAs) are small non-coding RNAs 18-25 nucleotides in length that downregulate gene expression during various
crucial cell processes such as apoptosis, differentiation and development. Changes in the expression profiles of miRNAs have
been observed in a variety of human tumors, including colorectal cancer (CRC). Functional studies indicate that miRNAs act
as tumor suppressors and oncogenes. These findings significantly extend Vogelstein's model of CRC pathogenesis and have shown
great potential for miRNAs as a novel class of therapeutic targets. Several investigations have also described the ability
of miRNA expression profiles to predict prognosis and response to selected treatments in CRC patients, and support diagnosis
of CRC among cancer of unknown primary site. miRNAs' occurrence has been repeatedly observed also in serum and plasma, and
miRNAs as novel minimally invasive biomarkers have indicated reasonable sensitivity for CRC detection and compare favorably
with the fecal occult blood test. In this review, we summarize the knowledge regarding miRNAs' functioning in CRC while emphasizing
their significance in pathogenetic signaling pathways and their potential to serve as disease biomarkers and novel therapeutic
targets. 相似文献
60.