Showing papers by "Medical Research Council published in 2004"
TL;DR: Women with violent or controlling male partners are at increased risk of HIV infection and it is postulate that abusive men are more likely to have HIV and impose risky sexual practices on partners.
1,358 citations
TL;DR: It is concluded that severe acute respiratory syndrome and smallpox are easier to control using these simple public health measures and should be a priority during an outbreak of a novel infectious agent.
Abstract: The aim of this study is to identify general properties of emerging infectious agents that determine the likely success of two simple public health measures in controlling outbreaks, namely (i) isolating symptomatic individuals and (ii) tracing and quarantining their contacts. Because these measures depend on the recognition of specific disease symptoms, we investigate the relative timing of infectiousness and the appearance of symptoms by using a mathematical model. We show that the success of these control measures is determined as much by the proportion of transmission occurring prior to the onset of overt clinical symptoms (or via asymptomatic infection) as the inherent transmissibility of the etiological agent (measured by the reproductive number R0). From published studies, we estimate these quantities for two moderately transmissible viruses, severe acute respiratory syndrome coronavirus and HIV, and for two highly transmissible viruses, smallpox and pandemic influenza. We conclude that severe acute respiratory syndrome and smallpox are easier to control using these simple public health measures. Direct estimation of the proportion of asymptomatic and presymptomatic infections is achievable by contact tracing and should be a priority during an outbreak of a novel infectious agent.
1,093 citations
Vanderbilt University1, University of Southern California2, University of Texas MD Anderson Cancer Center3, University of Wisconsin-Madison4, University of California, Los Angeles5, National Center for Genome Resources6, Portland VA Medical Center7, University of Colorado Boulder8, University of Pennsylvania9, Hannover Medical School10, Johns Hopkins University11, Oregon Health & Science University12, Cornell University13, University of Michigan14, University of Tennessee Health Science Center15, Washington University in St. Louis16, University of Toronto17, University of Memphis18, Medical Research Council19, University of Massachusetts Medical School20, Hebrew University of Jerusalem21, Université de Montréal22, Purdue University23, University of California, Davis24, Academy of Sciences of the Czech Republic25, University at Buffalo26, Emory University27, University of Cincinnati28, University of Texas Southwestern Medical Center29, New York University30, University of Groningen31, Rutgers University32, Stanford University33, Max Planck Society34, National Institutes of Health35, University of Alabama at Birmingham36, International Livestock Research Institute37, Heidelberg University38, Medical College of Wisconsin39, Icahn School of Medicine at Mount Sinai40, Oak Ridge National Laboratory41, Charité42, University of Antwerp43, RWTH Aachen University44, Paul Sabatier University45, University of California, San Francisco46, McGill University47, Pasteur Institute48, University of Western Australia49, Yale University50, University of Oxford51, Case Western Reserve University52, Roswell Park Cancer Institute53, University of Kentucky54, University of Helsinki55, University of Nebraska–Lincoln56, Harvard University57, Merck & Co.58, King's College London59, Northwestern University60, Shriners Hospitals for Children61, Thomas Jefferson University62, Novartis63, University of North Carolina at Chapel Hill64, Southern Illinois University Carbondale65, University of Rochester66
TL;DR: The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way the authors approach human health and disease.
Abstract: The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.
1,040 citations
TL;DR: A whole-genome comparison between humans and the pufferfish, Fugu rubripes, is used to identify nearly 1,400 highly conserved non-coding sequences, which are likely to form part of the genomic circuitry that uniquely defines vertebrate development.
Abstract: In addition to protein coding sequence, the human genome contains a significant amount of regulatory DNA, the identification of which is proving somewhat recalcitrant to both in silico and functional methods. An approach that has been used with some success is comparative sequence analysis, whereby equivalent genomic regions from different organisms are compared in order to identify both similarities and differences. In general, similarities in sequence between highly divergent organisms imply functional constraint. We have used a whole-genome comparison between humans and the pufferfish, Fugu rubripes, to identify nearly 1,400 highly conserved non-coding sequences. Given the evolutionary divergence between these species, it is likely that these sequences are found in, and furthermore are essential to, all vertebrates. Most, and possibly all, of these sequences are located in and around genes that act as developmental regulators. Some of these sequences are over 90% identical across more than 500 bases, being more highly conserved than coding sequence between these two species. Despite this, we cannot find any similar sequences in invertebrate genomes. In order to begin to functionally test this set of sequences, we have used a rapid in vivo assay system using zebrafish embryos that allows tissue-specific enhancer activity to be identified. Functional data is presented for highly conserved non-coding sequences associated with four unrelated developmental regulators (SOX21, PAX6, HLXB9, and SHH), in order to demonstrate the suitability of this screen to a wide range of genes and expression patterns. Of 25 sequence elements tested around these four genes, 23 show significant enhancer activity in one or more tissues. We have identified a set of non-coding sequences that are highly conserved throughout vertebrates. They are found in clusters across the human genome, principally around genes that are implicated in the regulation of development, including many transcription factors. These highly conserved non-coding sequences are likely to form part of the genomic circuitry that uniquely defines vertebrate development.
952 citations
TL;DR: Delineation of the structural elements in GnRH and the receptor, which facilitate differential signaling, will contribute to the development of novel interventive GnRH analogs.
Abstract: GnRH and its analogs are used extensively for the treatment of hormone-dependent diseases and assisted reproductive techniques. They also have potential as novel contraceptives in men and women. A thorough delineation of the molecular mechanisms involved in ligand binding, receptor activation, and intracellular signal transduction is kernel to understanding disease processes and the development of specific interventions. Twenty-three structural variants of GnRH have been identified in protochordates and vertebrates. In many vertebrates, three GnRHs and three cognate receptors have been identified with distinct distributions and functions. In man, the hypothalamic GnRH regulates gonadotropin secretion through the pituitary GnRH type I receptor via activation of G(q). In-depth studies have identified amino acid residues in both the ligand and receptor involved in binding, receptor activation, and translation into intracellular signal transduction. Although the predominant coupling of the type I GnRH receptor in the gonadotrope is through productive G(q) stimulation, signal transduction can occur via other G proteins and potentially by G protein-independent means. The eventual selection of intracellular signaling may be specifically directed by variations in ligand structure. A second form of GnRH, GnRH II, conserved in all higher vertebrates, including man, is present in extrahypothalamic brain and many reproductive tissues. Its cognate receptor has been cloned from various vertebrate species, including New and Old World primates. The human gene homolog of this receptor, however, has a frame-shift and stop codon, and it appears that GnRH II signaling occurs through the type I GnRH receptor. There has been considerable plasticity in the use of different GnRHs, receptors, and signaling pathways for diverse functions. Delineation of the structural elements in GnRH and the receptor, which facilitate differential signaling, will contribute to the development of novel interventive GnRH analogs.
731 citations
TL;DR: It is demonstrated that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake, and that AMPK is identified as a novel target for anti-obesity drugs.
724 citations
TL;DR: As of 2018, most scientists accept Watson and Crick ́s model of DNA presented in the article, which connected the concept of genes to heredity, growth, and development.
657 citations
University of Oxford1, Utrecht University2, University of Cambridge3, Institut Gustave Roussy4, Aalborg University5, German Cancer Research Center6, Harvard University7, National and Kapodistrian University of Athens8, University of Naples Federico II9, University of Turin10, University of Tromsø11, Lund University12, Umeå University13, Medical Research Council14, International Agency for Research on Cancer15
TL;DR: Excess breast cancer risk with HRT was particularly evident among lean women, and general obesity is a significant predictor of breast cancer, while abdominal fat assessed as waist–hip ratio or waist circumference was not related to excess risk when adjusted for BMI.
Abstract: The evidence for anthropometric factors influencing breast cancer risk is accumulating, but uncertainties remain concerning the role of fat distribution and potential effect modifiers. We used data from 73,542 premenopausal and 103,344 postmenopausal women from 9 European countries, taking part in the EPIC study. RRs from Cox regression models were calculated, using measured height, weight, BMI and waist and hip circumferences; categorized by cohort-wide quintiles; and expressed as continuous variables, adjusted for study center, age and other risk factors. During 4.7 years of follow-up, 1,879 incident invasive breast cancers were identified. In postmenopausal women, current HRT modified the body size-breast cancer association. Among nonusers, weight, BMI and hip circumference were positively associated with breast cancer risk (all ptrend 30) had a 31% excess risk compared to women with BMI < 25. Among HRT users, body measures were inversely but nonsignificantly associated with breast cancer. Excess breast cancer risk with HRT was particularly evident among lean women. Pooled RRs per height increment of 5 cm were 1.05 (95% CI 1.00-1.16) in premenopausal and 1.10 (95% CI 1.05-1.16) in postmenopausal women. Among premenopausal women, hip circumference was the only other measure significantly related to breast cancer (ptrend = 0.03), after accounting for BMI. In postmenopausal women not taking exogenous hormones, general obesity is a significant predictor of breast cancer, while abdominal fat assessed as waist-hip ratio or waist circumference was not related to excess risk when adjusted for BMI. Among premenopausal women, weight and BMI showed nonsignificant inverse associations with breast cancer.
583 citations
TL;DR: It is concluded that transactional sex may place women at increased risk for HIV, and is associated with gender-based violence, substance use and socio-economic disadvantage.
580 citations
TL;DR: The ASTRAL Compendium provides several databases and tools to aid in the analysis of protein structures, particularly through the use of their sequences, and all SCOP domains are now made available as PDB-style coordinate files as well as sequences.
Abstract: The ASTRAL Compendium provides several databases and tools to aid in the analysis of protein structures, particularly through the use of their sequences. Partially derived from the SCOP database of protein structure domains, it includes sequences for each domain and other resources useful for studying these sequences and domain structures. The current release of ASTRAL contains 54,745 domains, more than three times as many as the initial release 4 years ago. ASTRAL has undergone major transformations in the past 2 years. In addition to several complete updates each year, ASTRAL is now updated on a weekly basis with preliminary classifications of domains from newly released PDB structures. These classifications are available as a stand-alone database, as well as integrated into other ASTRAL databases such as representative subsets. To enhance the utility of ASTRAL to structural biologists, all SCOP domains are now made available as PDB-style coordinate files as well as sequences. In addition to sequences and representative subsets based on SCOP domains, sequences and subsets based on PDB chains are newly included in ASTRAL. Several search tools have been added to ASTRAL to facilitate retrieval of data by individual users and automated methods. ASTRAL may be accessed at http://astral.stanford. edu/.
578 citations
TL;DR: It is proposed that fumonisins are potential risk factors for NTD, craniofacial anomalies, and other birth defects arising from neural crest cells because of their apparent interference with folate utilization.
Abstract: Fumonisins are a family of toxic and carcinogenic mycotoxins produced by Fusarium verticillioides (formerly Fusarium moniliforme), a common fungal contaminant of maize. Fumonisins inhibit ceramide synthase, causing accumulation of bioactive intermediates of sphingolipid metabolism (sphinganine and other sphingoid bases and derivatives) as well as depletion of complex sphingolipids, which interferes with the function of some membrane proteins, including the folate-binding protein (human folate receptor alpha). Fumonisin causes neural tube and craniofacial defects in mouse embryos in culture. Many of these effects are prevented by supplemental folic acid. Recent studies in LMBc mice found that fumonisin exposure in utero increases the frequency of developmental defects and administration of folate or a complex sphingolipid is preventive. High incidences of neural tube defects (NTD) occur in some regions of the world where substantial consumption of fumonisins has been documented or plausibly suggested (Guatemala, South Africa, and China); furthermore, a recent study of NTD in border counties of Texas found a significant association between NTD and consumption of tortillas during the first trimester. Hence, we propose that fumonisins are potential risk factors for NTD, craniofacial anomalies, and other birth defects arising from neural crest cells because of their apparent interference with folate utilization.
TL;DR: A mutation in the gene encoding the protein kinase AKT2/PKBβ in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus is described, demonstrating the central importance of AKT signaling to insulin sensitivity in humans.
Abstract: Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBbeta in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.
TL;DR: The results of the present study support a rational rather than random approach to the selection of antiplasmodial screening candidates, and identify a number of promising taxa for further investigation as plant-based antimalarial agents.
TL;DR: How antioxidants targeted to mitochondria, or selective mitochondrial uncoupling, may be potential therapies for diabetes are discussed and the background to these strategies is outlined.
Abstract: Hyperglycemia causes many of the pathological consequences of both type 1 and type 2 diabetes. Much of this damage is suggested to be a consequence of elevated production of reactive oxygen species by the mitochondrial respiratory chain during hyperglycemia. Mitochondrial radical production associated with hyperglycemia will also disrupt glucose-stimulated insulin secretion by pancreatic beta-cells, because pancreatic beta-cells are particularly susceptible to oxidative damage. Therefore, mitochondrial radical production in response to hyperglycemia contributes to both the progression and pathological complications of diabetes. Consequently, strategies to decrease mitochondrial radical production and oxidative damage may have therapeutic potential. This could be achieved by the use of antioxidants or by decreasing the mitochondrial membrane potential. Here, we outline the background to these strategies and discuss how antioxidants targeted to mitochondria, or selective mitochondrial uncoupling, may be potential therapies for diabetes.
TL;DR: A functional magnetic resonance imaging study with 27 healthy volunteers to examine whether amygdala responsivity to unattended threat-related stimuli varies with individual differences in state anxiety suggests that anxiety may interact with attentional focus to determine the magnitude of the amygdala response to threat- related stimuli.
Abstract: Findings from fear-conditioning studies in rats and functional neuroimaging with human volunteers have led to the suggestion that the amygdala is involved in the preattentive detection of threat-related stimuli However, some neuroimaging findings point to attentional modulation of the amygdala response The clinical-cognitive literature suggests that the extent to which the processing of threat-related stimuli is modulated by attention is crucially dependent on participants' anxiety levels Here, we conducted a functional magnetic resonance imaging study with 27 healthy volunteers to examine whether amygdala responsivity to unattended threat-related stimuli varies with individual differences in state anxiety Pairs of houses and faces (both fearful or neutral in expression) were presented, and participants attended to either the faces or the houses and matched these stimuli on identity “Low-anxious” participants showed a reduced amygdala response to unattended versus attended fearful faces, but “high-anxious” participants showed no such reduction, having an increased amygdala response to fearful versus neutral faces regardless of attentional focus These findings suggest that anxiety may interact with attentional focus to determine the magnitude of the amygdala response to threat-related stimuli
TL;DR: Observed rates of superoxide generation by rat skeletal muscle mitochondria under a variety of conditions suggest that quinone-binding site inhibitors can make complex I adopt the highly radical-producing state that occurs during reverse electron transport.
TL;DR: The conclusions are that the effect of protonmotive force was mostly direct, and not indirect through changes in the redox state of the ubiquinone pool, and that the production of superoxide by complex I during reverse electron transport was at least 3-fold more sensitive to the pH gradient than to the membrane potential.
Abstract: The relationship between protonmotive force and superoxide production by mitochondria is poorly understood To address this issue, the rate of superoxide production from complex I of rat skeletal muscle mitochondria incubated under a variety of conditions was assessed By far, the largest rate of superoxide production was from mitochondria respiring on succinate; this rate was almost abolished by rotenone or piericidin, indicating that superoxide production from complex I is large under conditions of reverse electron transport The high rate of superoxide production by complex I could also be abolished by uncoupler, confirming that superoxide production is sensitive to protonmotive force It was inhibited by nigericin, suggesting that it is more dependent on the pH gradient across the mitochondrial inner membrane than on the membrane potential These effects were examined in detail, leading to the conclusions that the effect of protonmotive force was mostly direct, and not indirect through changes in the redox state of the ubiquinone pool, and that the production of superoxide by complex I during reverse electron transport was at least 3-fold more sensitive to the pH gradient than to the membrane potential
TL;DR: Protein-depleted membranes demonstrated changes in thickness of up to 5 Å, suggesting that (i) membrane proteins rather than cholesterol modulate the average bilayer thickness of eukaryotic cell membranes, and (ii) proteins and lipids are not naturally hydrophobically matched in some biological membranes.
Abstract: A biological membrane is conceptualized as a system in which membrane proteins are naturally matched to the equilibrium thickness of the lipid bilayer. Cholesterol, in addition to lipid composition, has been suggested to be a major regulator of bilayer thickness in vivo because measurements in vitro have shown that cholesterol can increase the thickness of simple phospholipid/cholesterol bilayers. Using solution x-ray scattering, we have directly measured the average bilayer thickness of exocytic pathway membranes, which contain increasing amounts of cholesterol. The bilayer thickness of membranes of the endoplasmic reticulum, the Golgi, and the basolateral and apical plasma membranes, purified from rat hepatocytes, were determined to be 37.5 ± 0.4 A, 39.5 ± 0.4 A, 35.6 ± 0.6 A, and 42.5 ± 0.3 A, respectively. After cholesterol depletion using cyclodextrins, Golgi and apical plasma membranes retained their respective bilayer thicknesses whereas the bilayer thickness of the endoplasmic reticulum and the basolateral plasma membrane decreased by 1.0 A. Because cholesterol was shown to have a marginal effect on the thickness of these membranes, we measured whether membrane proteins could modulate thickness. Protein-depleted membranes demonstrated changes in thickness of up to 5 A, suggesting that (i) membrane proteins rather than cholesterol modulate the average bilayer thickness of eukaryotic cell membranes, and (ii) proteins and lipids are not naturally hydrophobically matched in some biological membranes. A marked effect of membrane proteins on the thickness of Escherichia coli cytoplasmic membranes, which do not contain cholesterol, was also observed, emphasizing the generality of our findings.
TL;DR: Simple Monte Carlo methods are derived that extend the use of EVSI calculations to medical decision applications with multiple sources of uncertainty, with particular attention to the form in which epidemiological data and research findings are structured.
Abstract: There has been an increasing interest in using expected value of information (EVI) theory in medical decision making, to identify the need for further research to reduce uncertainty in decision and as a tool for sensitivity analysis. Expected value of sample information (EVSI) has been proposed for determination of optimum sample size and allocation rates in randomized clinical trials. This article derives simple Monte Carlo, or nested Monte Carlo, methods that extend the use of EVSI calculations to medical decision applications with multiple sources of uncertainty, with particular attention to the form in which epidemiological data and research findings are structured. In particular, information on key decision parameters such as treatment efficacy are invariably available on measures of relative efficacy such as risk differences or odds ratios, but not on model parameters themselves. In addition, estimates of model parameters and of relative effect measures in the literature may be heterogeneous, reflecting additional sources of variation besides statistical sampling error. The authors describe Monte Carlo procedures for calculating EVSI for probability, rate, or continuous variable parameters in multi parameter decision models and approximate methods for relative measures such as risk differences, odds ratios, risk ratios, and hazard ratios. Where prior evidence is based on a random effects meta-analysis, the authors describe different ESVI calculations, one relevant for decisions concerning a specific patient group and the other for decisions concerning the entire population of patient groups. They also consider EVSI methods for new studies intended to update information on both baseline treatment efficacy and the relative efficacy of 2 treatments. Although there are restrictions regarding models with prior correlation between parameters, these methods can be applied to the majority of probabilistic decision models. Illustrative worked examples of EVSI calculations are given in an appendix.
TL;DR: The objective of this review was to investigate the malarial situation before and after the introduction of indoor residual insecticide spraying in South Africa, Swaziland, Botswana, Namibia, Zimbabwe and Mozambique using historical malarial data and related information collected from National Malaria Control Programmes, national archives and libraries, as well as academic institutions in the respective countries.
Abstract: Indoor residual house-spraying (IRS) mainly with dichlorodiphenyltrichloroethane (DDT) was the principal method by which malaria was eradicated or greatly reduced in many countries in the world between the 1940s and 1960s. In sub-Saharan Africa early malarial eradication pilot projects also showed that malaria is highly responsive to vector control by IRS but transmission could not be interrupted in the endemic tropical and lowland areas. As a result IRS was not taken to scale in most endemic areas of the continent with the exception of southern Africa and some island countries such as Reunion, Mayotte, Zanzibar, Cape Verde and Sao Tome. In southern Africa large-scale malarial control operations based on IRS with DDT and benzene hexachloride (BHC) were initiated in a number of countries to varying degrees. The objective of this review was to investigate the malarial situation before and after the introduction of indoor residual insecticide spraying in South Africa, Swaziland, Botswana, Namibia, Zimbabwe and Mozambique using historical malarial data and related information collected from National Malaria Control Programmes, national archives and libraries, as well as academic institutions in the respective countries. Immediately after the inception of IRS with insecticides, dramatic reductions in malaria and its vectors were recorded. Countries that developed National Malaria Control Programmes during this phase and had built up human and organizational resources made significant advances towards malarial control. Malaria was reduced from hyper- to meso-endemicity and from meso- to hypo-endemicity and in certain instances to complete eradication. Data are presented on the effectiveness of IRS as a malarial control tool in six southern African countries. Recent trends in and challenges to malarial control in the region are also discussed.
TL;DR: The results suggest that children of all ages with clinical features of HIV infection should receive co-trimoxazole prophylaxis in resource-poor settings, irrespective of local resistance to this drug.
TL;DR: Based on the strength of available evidence regarding diet and lifestyle in the prevention of type 2 diabetes, it is recommended that a normal weight status in the lower BMI range and regular physical activity be maintained throughout adulthood; abdominal obesity be prevented; and saturated fat intake be less than 7% of the total energy intake.
Abstract: Objectives: The overall objective of this study was to evaluate and provide evidence and recommendations on current published literature about diet and lifestyle in the prevention of type 2 diabetes. Design: Epidemiological and experimental studies, focusing on nutritional intervention in the prevention of type 2 diabetes are used to make disease-specific recommendations. Long-term cohort studies are given the most weight as to strength of evidence available. Setting and subjects: Numerous clinical trials and cohort studies in low, middle and high income countries are evaluated regarding recommendations for dietary prevention of type 2 diabetes. These include, among others, the Finnish Diabetes Prevention Study, US Diabetes Prevention Program, Da Qing Study; Pima Indian Study; Iowa Women’s Health Study; and the study of the US Male Physicians. Results: There is convincing evidence for a decreased risk of diabetes in adults who are physically active and maintain a normal body mass index (BMI) throughout adulthood, and in overweight adults with impaired glucose tolerance who lose weight voluntarily. An increased risk for developing type 2 diabetes is associated with overweight and obesity; abdominal obesity; physical inactivity; and maternal diabetes. It is probable that a high intake of saturated fats and intrauterine growth retardation also contribute to an increased risk, while non-starch polysaccharides are likely to be associated with a decreased risk. From existing evidence it is also possible that omega3 fatty acids, low glycaemic index foods and exclusive breastfeeding may play a protective role, and that total fat intake and trans fatty acids may contribute to the risk. However, insufficient evidence is currently available to provide convincing proof. Conclusions: Based on the strength of available evidence regarding diet and lifestyle in the prevention of type 2 diabetes, it is recommended that a normal weight status in the lower BMI range (BMI 21‐23) and regular physical activity be maintained throughout adulthood; abdominal obesity be prevented; and saturated fat intake be less than 7% of the total energy intake.
TL;DR: This trial has failed to observe a survival benefit with adjuvant chemotherapy following complete resection of stage I-III NSCLC, but the hazard ratio and 95% confidence intervals are consistent with the previously reported meta-analysis and two large recently reported trials, which suggest a small survival Benefit with cisplatin-based chemotherapy.
Abstract: Objectives: The non-small cell lung cancer (NSCLC) meta-analysis suggested a survival benefit for cisplatin-based chemotherapy when given in addition to surgery, radical radiotherapy or 'best supportive care'. However, it included many small trials and trials with differing eligibility criteria and chemotherapy regimens. The aim of the Big Lung Trial was therefore to run a large pragmatic trial to confirm the survival benefits seen in the meta-analysis. Methods: In the surgery setting, a total of 381 patients were randomised to chemotherapy (C, 192 patients) or no chemotherapy (NoC, 189 patients). C was three 3-weekly cycles of cisplatin/vindesine, mitomycin/ifosfamide/cisplatin, mitomycin/vinblastine/cisplatin or vinorelbine/cisplatin. Results: Chemotherapy was given before surgery in 3% of patients whilst 97% received adjuvant chemotherapy. Baseline characteristics were: median age 61 years, 69% male, 48% squamous cell, 93% WHO PS 0-1, 27% stage I, 38% stage II, and 34% stage III. Complete resection was achieved in approximately 95% of patients. In the C group, 13% received no chemotherapy, 21% one or two cycles, and 64% all three cycles of their prescribed chemotherapy (60% of the latter with no delays or modification). 30% had grade 3/4 toxicity, mainly haematological, nausea/vomiting and neutropenic fever, and six patients were reported as having a treatment-related death. 198 (52%) of patients have died, but there is currently no evidence of a benefit in overall survival to the C group: HR 1.02 (95% CI 0.77-1.35), P = 0.90). Conclusions: This trial has failed to observe a survival benefit with adjuvant chemotherapy following complete resection of stage I-III NSCLC. However, the hazard ratio and 95% confidence intervals are consistent with the previously reported meta-analysis and two large recently reported trials, which suggest a small survival benefit with cisplatin-based.
TL;DR: The patterns of hypermutation in antibodies and retroviruses owe much to the intrinsic sequence preferences of the AID/APOBEC family of DNA deaminases: analogous biases might also contribute to the spectra of cancer-associated mutation.
TL;DR: It is confirmed that reliable Phi values can be derived from the recommended mutations in suitable proteins with 0.6 < DeltaDeltaG(D-N) < 1.7 kcal/mol, and there are many reliable high Phi values.
Abstract: Phi values are used to map structures of protein-folding transition states from changes in free energies of denaturation (DeltaDeltaG(D-N)) and activation on mutation. A recent reappraisal proposed that Phi values for DeltaDeltaG(D-N) 1.7 kcal/mol are often found for large side chains that make dispersed tertiary interactions, especially in hydrophobic cores that are in the process of being formed in the transition state. Conversely, specific local interactions that probe secondary structure tend to have DeltaDeltaG(D-N) approximately 0.5-2 kcal/mol. Discarding Phi values from lower-energy changes discards the crucial information about local interactions and makes transition states appear uniformly diffuse by overemphasizing the dispersed tertiary interactions. The evidence for the 1.7 kcal/mol cutoff was based on mutations that had been deliberately designed to be unsuitable for Phi-value analysis because they are structurally disruptive. We confirm that reliable Phi values can be derived from the recommended mutations in suitable proteins with 0.6 > 2 kcal/mol and that protein-folding transition states do move on the energy surface on mutation.
TL;DR: There is concurrent, VEGF-A-dependent hem- and lymphangiogenesis after normal-risk keratoplasty within the preoperatively avascular recipient bed, establishing early postoperative hem-and- lymphANGiogenesis as novel risk factors for graft rejection even in low-risk eyes.
Abstract: PURPOSE. To evaluate the occurrence and time course of hem-and lymphangiogenesis after normal-risk corneal transplantation in the mouse model and to test whether pharmacologic strategies inhibiting both processes improve long-term graft survival. METHODS. Normal-risk allogeneic (C57BL/6 to BALB/c) and syngeneic (BALB/c to BALB/c) corneal transplantations were performed and occurrence and time course of hem- and lymphangiogenesis after keratoplasty was observed, by using double immunofluorescence of corneal flatmounts (with CD31 as a panendothelial and LYVE-1 as a lymphatic vascular endothelium-specific marker). A molecular trap designed to eliminate VEGF-A (VEGF Trap R1R2 ; 12.5 mg/kg) was tested for its ability to inhibit both processes after keratoplasty and to promote long-term graft survival (intraperitoneal injections on the day of surgery and 3, 7, and 14 days later). RESULTS. No blood or lymph vessels were detectable immediately after normal-risk transplantation in either donor or host cornea, but hem- and lymphangiogenesis were clearly visible at day 3 after transplantation. Both vessel types reached donor tissue at 1 week after allografting and similarly after syngeneic grafting. Early postoperative trapping of VEGF-A significantly reduced both hem- and lymphangiogenesis and significantly improved long-term graft survival (78% vs. 40%; P < 0.05). CONCLUSIONS. There is concurrent, VEGF-A-dependent hem- and lymphangiogenesis after normal-risk keratoplasty within the preoperatively avascular recipient bed. Inhibition of hem- and lymphangiogenesis (afferent and efferent arm of an immune response) after normal-risk corneal transplantation improves long-term graft survival, establishing early postoperative hem-and lymphangiogenesis as novel risk factors for graft rejection even in low-risk eyes.
TL;DR: It is shown that BRCA2 deficiency impairs the completion of cell division by cytokinesis, which link cytokinetic abnormalities to a hereditary cancer syndrome characterized by chromosomal instability and may help to explain why BRCa2-deficient tumors are frequently aneuploid.
Abstract: Germ-line mutations inactivating BRCA2 predispose to cancer. BRCA2-deficient cells exhibit alterations in chromosome number (aneuploidy), as well as structurally aberrant chromosomes. Here, we show that BRCA2 deficiency impairs the completion of cell division by cytokinesis. BRCA2 inactivation in murine embryo fibroblasts (MEFs) and HeLa cells by targeted gene disruption or RNA interference delays and prevents cell cleavage. Impeded cell separation is accompanied by abnormalities in myosin II organization during the late stages in cytokinesis. BRCA2 may have a role in regulating these events, as it localizes to the cytokinetic midbody. Our findings thus link cytokinetic abnormalities to a hereditary cancer syndrome characterized by chromosomal instability and may help to explain why BRCA2-deficient tumors are frequently aneuploid.
TL;DR: Interventions that aim to protect adolescents from engaging in risk behaviours by increasing their self-esteem are likely to be most effective and cost-efficient if they are aimed at the family and school domains.
Abstract: Background: This study investigated associations among adolescents' self-esteem in 6 domains (peers, school, family, sports/athletics, body image and global self-worth) and risk behaviours related to substance use, bullying, suicidality and sexuality. Method: A multistage stratified sampling strategy was used to select a representative sample of 939 English-, Afrikaans- and Xhosa-speaking students in Grades 8 and 11 at public high schools in Cape Town, South Africa. Participants completed the multidimensional Self-Esteem Questionnaire (SEQ; DuBois, Felner, Brand, Phillips, & Lease, 1996) and a self-report questionnaire containing items about demographic characteristics and participation in a range of risk behaviours. It included questions about their use of tobacco, alcohol, cannabis, solvents and other substances, bullying, suicidal ideation and attempts, and risky sexual behaviour. Data was analysed using a series of logistic regression models, with the estimation of model parameters being done through generalised estimation equations. Results: Scores on each self-esteem scale were significantly associated with at least one risk behaviour in male and female adolescents after controlling for the sampling strategy, grade and race. However, specific self-esteem domains were differentially related to particular risk behaviours. After taking the correlations between the self-esteem scales into account, low self-esteem in the family and school contexts and high self-esteem in the peer domain were significantly independently associated with multiple risk behaviours in adolescents of both sexes. Low body-image self-esteem and global self-worth were also uniquely associated with risk behaviours in girls, but not in boys. Conclusions: Overall, the findings suggest that interventions that aim to protect adolescents from engaging in risk behaviours by increasing their self-esteem are likely to be most effective and cost-efficient if they are aimed at the family and school domains.
TL;DR: The method should be useful for making aggregation-resistant proteins and for helping to identify features that promote or prevent protein aggregation, including those responsible for misfolding diseases.
Abstract: We describe a method for selecting aggregation-resistant proteins by heat denaturation. This is illustrated with antibody heavy chain variable domains (dAbs), which are prone to aggregate. The dAbs were displayed multivalently at the infective tip of filamentous bacteriophage, and heated transiently to induce unfolding and to promote aggregation of the dAbs. After cooling, the dAbs were selected for binding to protein A (a ligand common to these folded dAbs). Phage displaying dAbs that unfold reversibly were thereby enriched with respect to those that do not. From a repertoire of phage dAbs, six dAbs were characterized after selection; they all resisted aggregation, and were soluble, well expressed in bacteria and could be purified in good yields. The method should be useful for making aggregation-resistant proteins and for helping to identify features that promote or prevent protein aggregation, including those responsible for misfolding diseases.
TL;DR: It is concluded that the UUG codon-specific translational defect of the mutant mt tRNAs(Leu(UUR)) is the primary cause of MELAS at the molecular level.
Abstract: Point mutations in the mitochondrial (mt) tRNALeu(UUR) gene are responsible for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a subgroup of mitochondrial encephalomyopathic diseases. We previously showed that mt tRNALeu(UUR) with an A3243G or T3271C mutation derived from patients with MELAS are deficient in a normal taurine-containing modification (τm5U; 5-taurinomethyluridine) at the anticodon wobble position. To examine decoding disorder of the mutant tRNA due to the wobble modification deficiency independent of the pathogenic point mutation itself, we used a molecular surgery technique to construct an mt tRNALeu(UUR) molecule lacking the taurine modification but without the pathogenic mutation. This “operated” mt tRNALeu(UUR) without the taurine modification showed severely reduced UUG translation but no decrease in UUA translation. We thus concluded that the UUG codon–specific translational defect of the mutant mt tRNAsLeu(UUR) is the primary cause of MELAS at the molecular level. This result could explain the complex I deficiency observed clinically in MELAS.