2,621 research outputs found
The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma
The cell's repertoire of transfer RNAs (tRNAs) has been linked to cancer. Recently, levels of the initiator methionine tRNA (tRNAiMet) in stromal fibroblasts have been shown to influence extracellular matrix (ECM) secretion to drive tumour growth and angiogenesis. Here we show that increased tRNAiMet within cancer cells does not influence tumour growth, but drives cell migration and invasion via a mechanism that is independent from ECM synthesis and dependent on α5β1 integrin and levels of the translation initiation ternary complex. In vivo and ex vivo migration (but not proliferation) of melanoblasts is significantly enhanced in transgenic mice which express additional copies of the tRNAiMet gene. We show that increased tRNAiMet in melanoma drives migratory, invasive behaviour and metastatic potential without affecting cell proliferation and primary tumour growth, and that expression of RNA polymerase III-associated genes (which drive tRNA expression) are elevated in metastases by comparison with primary tumours. Thus specific alterations to the cancer cell tRNA repertoire drive a migration/invasion programme that may lead to metastasis
Changes in dietary patterns and body composition within 12 months of liver transplantation
Background: Cardiometabolic risk factors are increasing in liver transplant recipients (LTR). Influencing dietary factors have not been assessed. The aim of this observational study was to assess changes in weight, metabolic function, dietary intake and eating behaviours in the first year after orthotopic liver transplantation (OLT). Methods: Consecutive recruitment of 17 patients (14 males) awaiting OLT at a single tertiary hospital. Dietary intake, food behaviours and anthropometry were recorded at baseline, and 6 and 12 months posttransplant. Results: By 12 months, patients had gained on average 7.3% of body weight. The prevalence of overweight or obesity increased from baseline 53% to 77% (P=0.001). By 6 months, 65% (n=11/17) of patients had altered glucose metabolism. Dietary intake was consistent with a Western-style dietary pattern with high saturated fat. Over half of the patients (69%, n=11/16) reported low to no depressive feelings and rated their self-esteem as good (53%, n=9/16). The Power of Food Scale increased between pre and post-transplant, indicating a stronger appetitive drive. Conclusions: Weight gain occurs early post-transplant, with significant metabolic dysfunction present within 6 months, however is not associated with significant psychological distress. Early dietary intervention designed to limit weight gain and target cardiometabolic health is recommended for this unique patient population
The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis
Summary:
Expression of the initiator methionine tRNA (tRNAi
Met)
is deregulated in cancer. Despite this fact, it is not
currently known how tRNAi
Met expression levels influence
tumor progression. We have found that tRNAi
Met
expression is increased in carcinoma-associated
fibroblasts, implicating deregulated expression of
tRNAi
Met in the tumor stroma as a possible contributor
to tumor progression. To investigate how elevated
stromal tRNAi
Met contributes to tumor progression,
we generated a mouse expressing additional copies
of the tRNAi
Met gene (2+tRNAi
Met mouse). Growth
and vascularization of subcutaneous tumor allografts
was enhanced in 2+tRNAi
Met mice compared with
wild-type littermate controls. Extracellular matrix
(ECM) deposited by fibroblasts from 2+tRNAi
Met
mice supported enhanced endothelial cell and fibroblast
migration. SILAC mass spectrometry indicated
that elevated expression of tRNAi
Met significantly
increased synthesis and secretion of certain types of
collagen, in particular type II collagen. Suppression
of type II collagen opposed the ability of tRNAi
Metoverexpressing
fibroblasts to deposit pro-migratory
ECM. We used the prolyl hydroxylase inhibitor ethyl-
3,4-dihydroxybenzoate (DHB) to determine whether
collagen synthesis contributes to the tRNAi
Met-driven
pro-tumorigenic stroma in vivo. DHB had no effect
on the growth of syngeneic allografts in wild-type
mice but opposed the ability of 2+tRNAi
Met mice to
support increased angiogenesis and tumor growth.
Finally, collagen II expression predicts poor prognosis
in high-grade serous ovarian carcinoma. Taken
together, these data indicate that increased tRNAi
Met
levels contribute to tumor progression by enhancing
the ability of stromal fibroblasts to synthesize and
secrete a type II collagen-rich ECM that supports
endothelial cell migration and angiogenesis
Family and home correlates of television viewing in 12–13 year old adolescents: The Nepean Study
BACKGROUND: Few young people meet television viewing guidelines. PURPOSE: To determine the association between factors in the family and home environment and watching television, including videos and DVDs, in early adolescence. METHODS: Cross-sectional, self-report survey of 343 adolescents aged 12–13 years (173 girls), and their parents (338 mothers, 293 fathers). Main measures were factors in the family and home environment potentially associated with adolescents spending ≥ 2 hours per day in front of the television. Factors examined included family structure, opportunities to watch television/video/DVDs, perceptions of rules and regulations on television viewing, and television viewing practices. RESULTS: Two-thirds of adolescents watched ≥ 2 hours television per day. Factors in the family and home environment associated with adolescents watching television ≥ 2 hours per day include adolescents who have siblings (Adjusted Odds Ratio [95%CI] AOR = 3.0 [1.2, 7.8]); access to pay television (AOR = 2.0 [1.1, 3.7]); ate snacks while watching television (AOR = 3.1 [1.8, 5.4]); co-viewed television with parents (AOR = 2.3 [1.3, 4.2]); and had mothers who watched ≥ 2 hours television per day (AOR = 2.4 [1.3, 4.6]). CONCLUSION: There are factors in the family and home environment that influence the volume of television viewed by 12–13 year olds. Television plays a central role in the family environment, potentially providing a means of recreation among families of young adolescents for little cost. Interventions which target family television viewing practices and those of parents, in particular, are more likely to be effective than interventions which directly target adolescent viewing times
Clinical stakeholders' opinions on the use of selective decontamination of the digestive tract in critically ill patients in intensive care units : an international Delphi study
Peer reviewedPublisher PD
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Thermodynamic mapping of effector protein interfaces with RalA and RalB.
RalA and RalB are members of the Ras family of small G proteins and are activated downstream of Ras via RalGEFs. The RalGEF-Ral axis represents one of the major effector pathways controlled by Ras and as such is an important pharmacological target. RalA and RalB are approximately 80% identical at the amino acid level; despite this, they have distinct roles both in normal cells and in the disease state. We have used our structure of RalB-RLIP76 to guide an analysis of Ral-effector interaction interfaces, creating panels of mutant proteins to probe the energetics of these interactions. The data provide a physical mechanism that underpins the effector selective mutations commonly employed to dissect Ral G protein function. Comparing the energetic landscape of the RalB-RLIP76 and RalB-Sec5 complexes reveals mutations in RalB that lead to differential binding of the two effector proteins. A panel of RLIP76 mutants was used to probe the interaction between RLIP76 and RalA and -B. Despite 100% sequence identity in the RalA and -B contact residues with RLIP76, differences still exist in the energetic profiles of the two complexes. Therefore, we have revealed properties that may account for some of the functional separation observed with RalA and RalB at the cellular level. Our mutations, in both the Ral isoforms and RLIP76, provide new tools that can be employed to parse the complex biology of Ral G protein signaling networks. The combination of these thermodynamic and structural data can also guide efforts to ablate RalA and -B activity with small molecules and peptides.Captain Stephanos FoundationThis is the author accepted manuscript. The final version is available from the American Chemical Society via http://dx.doi.org/10.1021/bi501530
Fertilisers for wine grapes : an information package to promote efficient fertiliser practices
https://researchlibrary.agric.wa.gov.au/bulletins/1278/thumbnail.jp
A qualitative study exploring the acceptability of the McNulty-Zelen design for randomised controlled trials evaluating educational interventions
Background: Traditional randomised controlled trials evaluating the effect of educational interventions in general practice may produce biased results as participants know they are being evaluated. We aimed to explore the acceptability of a McNulty-Zelen Cluster Randomised Control Trial (CRT) design which conceals from educational participants that they are in a RCT. Consent is obtained from a trusted third party considered appropriate to give consent on participants’ behalf, intervention practice staff then choose whether to attend the offered education as would occur with normal continuing professional development.
Methods:We undertook semi structured telephone interviews in England with 16 general practice (GP) staff involved in a RCT evaluating an educational intervention aimed at increasing chlamydia screening tests in general practice using the McNulty-Zelen design, 4 Primary Care (PC) Research Network officers, 5 Primary Care Trust leads in Public or sexual health, and one Research Ethics committee Chair. Interviews were undertaken by members of the original intervention evaluation McNulty-Zelen design RCT study team. These experienced qualitative interviewers used an agreed semi-structured interview schedule and were careful not to lead the participants. To further mitigate against bias, the data analysis was undertaken by a researcher (CR) not involved in the original RCT.
Results: We reached data saturation and found five main themes;
Support for the design: All found the McNulty-Zelen design acceptable because they considered that it generated
more reliable evidence of the value of new educational interventions in real life GP settings.
Lack of familiarity with study design: The design was novel to all. GP staff likened the evaluation using the McNulty–Zelen
design to audit of their activities with feedback, which were to them a daily experience and therefore acceptable.
Ethical considerations:Research stakeholders considered the consent procedure should be very clear and that these trial designs should go through at least a proportionate ethical review. GP staff were happy for the PCT leads to give consent
on their behalf.
GP research capacity and trial participation: GP staff considered the design increased generalisability, as staff who would not normally volunteer to participate in research due to perceived time constraints and paperwork might do so.
Design ‘worth it’: All interviewees agreed that the advantages of the “more accurate” or “truer” results and information gained about uptake of workshops within Primary Care Trusts (PCTs) outweighed any disadvantages of the consent procedure.
Discussion:Our RCT was evaluating the effect of an educational intervention to increase chlamydia screening tests in
general practices where there was routine monitoring of testing rates; our participants may have been less enthusiastic
about the design if it had been evaluating a more controversial educational area, or if data monitoring was not routine.
Implications:The McNulty-Zelen design should be considered for the evaluation of educational interventions, but these
designs should have clear consent protocols and proportionate ethical review.
Trial registration: The trial was registered on the UK Clinical Research Network Study Portfolio database. UKCRN9722
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NMR resonance assignments for the active and inactive conformations of the small G protein RalA
Abstract: The Ral proteins (RalA and RalB) are small G proteins of the Ras family that have been implicated in exocytosis, endocytosis, transcriptional regulation and mitochondrial fission, as well as having a role in tumourigenesis. RalA and RalB are activated downstream of the master regulator, Ras, which causes the nucleotide exchange of GDP for GTP. Here we report the 1H, 15 N and 13C resonance assignments of RalA in its active form bound to the GTP analogue GMPPNP. We also report the backbone assignments of RalA in its inactive, GDP-bound form. The assignments give insight into the switch regions, which change conformation upon nucleotide exchange. These switch regions are invisible in the spectra of the active, GMPPNP bound form but the residues proximal to the switches can be monitored. RalA is also an important drug target due to its over activation in some cancers and these assignments will be extremely useful for NMR-based screening approaches
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