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1.
L M Lindqvist I Vikstr?m J M Chambers K McArthur M Ann Anderson K J Henley L Happo L Cluse R W Johnstone A W Roberts B T Kile B A Croker C J Burns M A Rizzacasa A Strasser DC S Huang 《Cell death & disease》2012,3(10):e409
There is significant interest in treating cancers by blocking protein synthesis, to which hematological malignancies seem particularly sensitive. The translation elongation inhibitor homoharringtonine (Omacetaxine mepesuccinate) is undergoing clinical trials for chronic myeloid leukemia, whereas the translation initiation inhibitor silvestrol has shown promise in mouse models of cancer. Precisely how these compounds induce cell death is unclear, but reduction in Mcl-1, a labile pro-survival Bcl-2 family member, has been proposed to constitute the critical event. Moreover, the contribution of translation inhibitors to neutropenia and lymphopenia has not been precisely defined. Herein, we demonstrate that primary B cells and neutrophils are highly sensitive to translation inhibitors, which trigger the Bax/Bak-mediated apoptotic pathway. However, contrary to expectations, reduction of Mcl-1 did not significantly enhance cytotoxicity of these compounds, suggesting that it does not have a principal role and cautions that strong correlations do not always signify causality. On the other hand, the killing of T lymphocytes was less dependent on Bax and Bak, indicating that translation inhibitors can also induce cell death via alternative mechanisms. Indeed, loss of clonogenic survival proved to be independent of the Bax/Bak-mediated apoptosis altogether. Our findings warn of potential toxicity as these translation inhibitors are cytotoxic to many differentiated non-cycling cells. 相似文献
2.
R Moriggi Jr HS Di Mauro SC Dias JM Matos MB Urtado NF Camar?o IV Sousa Neto DC Nascimento RA Tibana CO Assump??o J Prestes CB Urtado 《Biology of sport / Institute of Sport》2015,32(4):289-294
Low intensity resistance exercise (RE) with blood flow restriction (BFR) has gained attention in the literature due to the beneficial effects on functional and morphological variables, similar to those observed during traditional RE without BFR, while the effects of BFR on post-exercise hypotension remain unclear. The aim of the present study was to compare the blood pressure (BP) response of trained normotensive individuals to RE with and without BFR. In this cross-over randomized trial, eight male subjects (23.8 ± 4 years, 74 ± 3 kg, 174 ± 4 cm) completed two exercise protocols: traditional RE (3 x 10 repetitions at 70% one-repetition maximum [1-RM]) and low intensity RE (3 x 15 repetitions at 20% 1-RM) with BFR. Blood pressure measurements were performed after 15 min of seated rest (0), immediately after and 10 min, 20 min, 30 min, 40 min, 50 min and 60 min after the experimental sessions. Similar hypotensive effects for systolic BP (SBP) were observed for both protocols (P < 0.05) after exercise, with no differences between groups (P > 0.05) and no statistically significant difference for diastolic BP (P > 0.05). These results suggest that in normotensive trained individuals, both traditional RE and RE with BFR induce hypotension for SBP, which is important to prevent cardiovascular disturbances. 相似文献
3.
DC Andrade C Henriquez–Olguín AR Beltrán MA Ramírez C Labarca M Cornejo C álvarez R Ramírez-Campillo 《Biology of sport / Institute of Sport》2015,32(2):123-128
The purpose of this study was to compare the acute effects of general, specific and combined warm-up (WU) on explosive performance. Healthy male (n = 10) subjects participated in six WU protocols in a crossover randomized study design. Protocols were: passive rest (PR; 15 min of passive rest), running (Run; 5 min of running at 70% of maximum heart rate), stretching (STR; 5 min of static stretching exercise), jumping [Jump; 5 min of jumping exercises – 3x8 countermovement jumps (CMJ) and 3x8 drop jumps from 60 cm (DJ60)], and combined (COM; protocols Run+STR+Jump combined). Immediately before and after each WU, subjects were assessed for explosive concentric-only (i.e. squat jump – SJ), slow stretch-shortening cycle (i.e. CMJ), fast stretch-shortening cycle (i.e. DJ60) and contact time (CT) muscle performance. PR significantly reduced SJ performance (p =0.007). Run increased SJ (p =0.0001) and CMJ (p =0.002). STR increased CMJ (p =0.048). Specific WU (i.e. Jump) increased SJ (p =0.001), CMJ (p =0.028) and DJ60 (p =0.006) performance. COM increased CMJ performance (p =0.006). Jump was superior in SJ performance vs. PR (p =0.001). Jump reduced (p =0.03) CT in DJ60. In conclusion, general, specific and combined WU increase slow stretch-shortening cycle (SSC) muscle performance, but only specific WU increases fast SSC muscle performance. Therefore, to increase fast SSC performance, specific fast SSC muscle actions must be included during the WU. 相似文献
4.
The tropane alkaloid (TA) scopolamine is suggested to protect Brugmansia suaveolens (Solanaceae) against herbivorous insects. To test this prediction in a natural environment, scopolamine was induced by methyl jasmonate (MJ) in potted plants which were left 10?days in the field. MJ-treated plants increased their scopolamine concentration in leaves and herbivory decreased. These findings suggest a cause?Ceffect relationship. However, experiments in laboratory showed that scopolamine affect differently the performance of the specialist larvae of the ithomiine butterfly Placidina euryanassa (C. Felder & R. Felder) and the generalist fall armyworm Spodoptera frugiperda (J. E. Smith): the specialist that sequester this TA from B. suaveolens leaves was not negatively affected, but the generalist was. Therefore, scopolamine probably acts only against insects that are not adapted to TAs. Other compounds that are MJ elicited may also play a role in plant resistance against herbivory by generalist and specialist insects, and deserve future investigations. 相似文献
5.
DC Chhieng AR Frost S Niwas H Weiss WE Grizzle S Beeken 《Biotechnic & histochemistry》2013,88(1):25-36
Small biopsy samples are used increasingly to assess the biomarker expression for prognostic information and for monitoring therapeutic responses prior to and during neoadjuvant therapy. The issue of intratumor heterogeneity of expression of biomarkers, however, has raised questions about the validity of the assessment of biomarker expression based on limited tissue samples. We examined immunohistochemically the expression of HER-2neu (p185erbB-2), epidermal growth factor receptor (EGFR), Bcl-2, p53, and proliferating cell nuclear antigen (PCNA) in 30 breast carcinomas using archived, paraffin embedded tissue and determined the extent of intratumor heterogeneity. Each section was divided into four randomly oriented discrete regions, each containing a portion of the infiltrating carcinoma. For each tumor, the entire lesion and four regions were analyzed for the expression of these markers. Scores of both membrane and cytoplasmic staining of HER-2neu and EGFR, scores of cytoplasmic staining of Bcl-2, and scores of nuclear staining of both p53 and PCNA were recorded. The intensity of staining and the proportion of immunostained cells were determined. A semiquantitative immunoscore was calculated by determining the sum of the products of the intensity and corresponding proportion of stained tumor cells. We analyzed both invasive (IDC) and in situ (DCIS) carcinomas. The Wilcoxon signed-rank test was used for paired comparisons between overall and regional immunoscores and between overall and regional percentages of stained cells. Spearman's correlation coefficients were used to assess the level of agreement of overall biomarker expression with each of the regions. Generalized linear models were used to assess overall and pair-wise differences in the absolute values of percent changes between overall and regional expression of biomarkers. For IDCs, there were no statistically significant differences in the expression of the biomarkers in terms of either the percentage of cells staining or the immunoscores when comparing the entire tumor with each region except for the lower EGFR expression of arbitrarily selected region 1 and lower p53 expression of region 1 compared to that of the entire tumor section. For DCIS, there were no statistically significant differences in the expression of the biomarkers between the entire tumor and each region except in PCNA of region 2 compared to that of entire tumor section. Positive correlation of immunoscores was observed between the entire tumor and each region as well as across all four regions for IDC. Similar observations were noted with DCIS except for HER-2neu and PCNA. No statistically significant differences were observed in the absolute values of percent changes of biomarker expression between overall and the four regions for both DCIS and IDC. Therefore, no significant intratumor heterogeneity in the expression of HER-2neu, Bcl-2, and PCNA was observed in IDC. Minor regional variations were observed for EGFR and p53 in IDC. Similarly, no significant regional variation in the expression of markers was observed in DCIS except for PCNA. 相似文献
6.
Potential use of stem cells from bone marrow to repair the extracellular matrix and the central nervous system 总被引:15,自引:0,他引:15
Prockop DJ Azizi SA Colter D Digirolamo C Kopen G Phinney DG 《Biochemical Society transactions》2000,28(4):341-345
A subset of stem-like cells from bone marrow that are referred to as marrow stromal cells (MSCs) have been shown to be capable of differentiating into osteoblasts, chondrocytes, adipocytes, myocytes, astrocytes and perhaps neurons. Recently, conditions have been developed where human MSCs can be expanded almost without limit in culture without apparently losing their multipotentiality for differentiation. The cells appear to be potentially useful for the repair of extracellular matrix and the central nervous system. 相似文献
7.
In a previous report, the cDNA for human proteinase inhibitor 8 (PI8) was first identified, isolated, and subcloned into a mammalian expression vector and expressed in baby hamster kidney cells. Initial studies indicated that PI8 was able to inhibit the amidolytic activity of trypsin and form an SDS-stable approximately 67-kDa complex with human thrombin [Sprecher, C. A., et al. (1995) J. Biol Chem. 270, 29854-29861]. In the present study, we have expressed recombinant PI8 in the methylotropic yeast Pichia pastoris, purified the inhibitor to homogeneity, and investigated its ability to inhibit a variety of proteinases. PI8 inhibited the amidolytic activities of porcine trypsin, human thrombin, human coagulation factor Xa, and the Bacillus subtilis dibasic endoproteinase subtilisin A through different mechanisms but failed to inhibit the Staphylococcus aureus endoproteinase Glu-C. PI8 inhibited trypsin in a purely competitive manner, with an equilibrium inhibition constant (Ki) of less than 3.8 nM. The interaction between PI8 and thrombin occurred with a second-order association rate constant (kassoc) of 1.0 x 10(5) M-1 s-1 and a Ki of 350 pM. A slow-binding kinetics approach was used to determine the kinetic constants for the interactions of PI8 with factor Xa and subtilisin A. PI8 inhibited factor Xa via a two-step mechanism with a kassoc of 7.5 x 10(4) M-1 s-1 and an overall Ki of 272 pM. PI8 was a potent inhibitor of subtilisin A via a single-step mechanism with a kassoc of 1.16 x 10(6) M-1 s-1 and an overall Ki of 8.4 pM. The interaction between PI8 and subtilisin A may be of physiological significance, since subtilisin A is an evolutionary precursor to the intracellular mammalian dibasic processing endoproteinases. 相似文献
8.
M. Colter Chitwood Marcus A. Lashley Christopher E. Moorman Christopher S. DePerno 《Journal of Ethology》2017,35(3):251-257
An evolutionary trap occurs when an organism makes a formerly adaptive decision that now results in a maladaptive outcome. Such traps can be induced by anthropogenic environmental changes, with nonnative species introductions being a leading cause. The recent establishment of coyotes (Canis latrans) into the southeastern USA has the potential to change white-tailed deer (Odocoileus virginianus) population dynamics through direct predation and behavioral adaptation. We used movement rate and bedsite characteristics of radiocollared neonates to evaluate their antipredator strategies in the context of novel predation risk in a structurally homogeneous, fire-maintained ecosystem. Neonate bedsites had greater plant cover values compared with random sites (t = 30.136; p < 0.001), indicating bedsite selection was consistent with the hider strategy used to avoid predation. We determined selection gradients of coyote predation on neonate movement rate and plant cover and diversity at bedsites during the first 10 days of life. Interestingly, neonates that moved less and bedded in denser cover were more likely to be depredated by coyotes, meaning that greater neonate movement rate and bedsites located in less dense cover were favored by natural selection. These results are counter to expected antipredator strategies in white-tailed deer and exemplify how an adaptive response could be maladaptive in novel contexts. 相似文献
9.
Fangli Chen Emilia Licarete Xue Wu Daniela Petrusca Callista Maguire Max Jacobsen Austyn Colter George E. Sandusky Magdalena Czader Maegan L. Capitano James P. Ropa H. Scott Boswell Fabrizio Carta Claudiu T. Supuran Brian Parkin Melissa L. Fishel Heiko Konig 《Journal of cellular and molecular medicine》2021,25(24):11039-11052
Acute myeloid leukaemia (AML) is an aggressive form of blood cancer that carries a dismal prognosis. Several studies suggest that the poor outcome is due to a small fraction of leukaemic cells that elude treatment and survive in specialised, oxygen (O2)-deprived niches of the bone marrow. Although several AML drug targets such as FLT3, IDH1/2 and CD33 have been established in recent years, survival rates remain unsatisfactory, which indicates that other, yet unrecognized, mechanisms influence the ability of AML cells to escape cell death and to proliferate in hypoxic environments. Our data illustrates that Carbonic Anhydrases IX and XII (CA IX/XII) are critical for leukaemic cell survival in the O2-deprived milieu. CA IX and XII function as transmembrane proteins that mediate intracellular pH under low O2 conditions. Because maintaining a neutral pH represents a key survival mechanism for tumour cells in O2-deprived settings, we sought to elucidate the role of dual CA IX/XII inhibition as a novel strategy to eliminate AML cells under hypoxic conditions. Our findings demonstrate that the dual CA IX/XII inhibitor FC531 may prove to be of value as an adjunct to chemotherapy for the treatment of AML. 相似文献
10.
M. Colter Chitwood Marcus A. Lashley John C. Kilgo Kenneth H. Pollock Christopher E. Moorman Christopher S. DePerno 《PloS one》2015,10(3)
Coyotes recently expanded into the eastern U.S. and potentially have caused localized white-tailed deer population declines. Research has focused on quantifying coyote predation on neonates, but little research has addressed the potential influence of bedsite characteristics on survival. In 2011 and 2012, we radiocollared 65 neonates, monitored them intensively for 16 weeks, and assigned mortality causes. We used Program MARK to estimate survival to 16 weeks and included biological covariates (i.e., sex, sibling status [whether or not it had a sibling], birth weight, and Julian date of birth). Survival to 16 weeks was 0.141 (95% CI = 0.075-0.249) and the top model included only sibling status, which indicated survival was lower for neonates that had a sibling. Predation was the leading cause of mortality (35 of 55; 64%) and coyotes were responsible for the majority of depredations (30 of 35; 86%). Additionally, we relocated neonates for the first 10 days of life and measured distance to firebreak, visual obstruction, and plant diversity at bedsites. Survival of predation to 10 days (0.726; 95% CI = 0.586-0.833) was weakly associated with plant diversity at bedsites but not related to visual obstruction. Our results indicate that neonate survival was low and coyote predation was an important source of mortality, which corroborates several recent studies from the region. Additionally, we detected only weak support for bedsite cover as a covariate to neonate survival, which indicates that mitigating effects of coyote predation on neonates may be more complicated than simply managing for increased hiding cover. 相似文献