Controversies in radioiodine therapy: relation to ophthalmopathy,the possible radioprotective effect of antithyroid drugs,and use in large goitres

In routine use for more than 50 years, radioiodine ((131)I) is generally considered safe and devoid of major side effects. Therefore, it is surprising that relatively many aspects of radioiodine therapy are controversial, as illustrated by recent international questionnaire studies. Our review aims at highlighting three of these areas - namely, the influence of (131)I on the course of Graves' ophthalmopathy, the possible radioprotective effects of antithyroid drugs, and the use of (131)I in large goitres. (131)I therapy carries a small (but definite) risk of causing progression of Graves' ophthalmopathy. Identification of risk factors (thyroid dysfunction, high level of thyroid-stimulating hormone (TSH) receptor antibodies, cigarette smoking) allows the identification of patients at risk and the institution of concomitant glucocorticoid treatment, thereby hindering progression of eye disease. On the basis, largely, of retrospective data, it appears that carbimazole (or methimazole), if stopped 3-5 days before treatment, does not influence the outcome of (131)I therapy. Simultaneous thyrostatic medication most probably reduces the efficacy of (131)I, as does restarting it within 7 days. Propylthiouracil seems to have a more prolonged radioprotective effect than carbimazole. Surgery is the treatment of first choice in patients with a large goitre. However, in the case of patient ineligibility or preference, (131)I therapy may be an option. The treatment has a favourable effect on tracheal compression and inspiratory capacity, but the reduction in thyroid volume is only 30-40%. Inpatient treatment, necessitated by the large doses, makes the treatment cumbersome. Controversy related to radioiodine therapy is mainly based on the lack of adequate prospective randomised studies comparing efficacy, side effects, cost and patient satisfaction.     

Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective

OBJECTIVE: Because differentiated (follicular and papillary) thyroid cancer (DTC) may recur years after initial treatment, the follow-up of patients with DTC is long term. However, this population has changed, with more individuals being discovered at an earlier stage of the disease, so that previous follow-up protocols based mostly on data from high-risk patients no longer apply. We sought to develop an improved protocol for the follow-up of low-risk patients with DTC based on the findings of recent studies. METHODS: We analysed recent literature on the follow-up of DTC. RESULTS: Recent large studies have produced three important findings: (i) in patients with low-risk DTC with no evidence of disease up to the 6- to 12-month follow-up, diagnostic whole-body scan adds no information when serum thyroglobulin (Tg) is undetectable and interference from anti-Tg antibodies is absent; (ii) use of recombinant human thyroid-stimulating hormone to aid Tg measurement is effective and provides greater safety, quality-of-life and work productivity than does levothyroxine withdrawal with its attendant hypothyroidism; and (iii) ultrasonography performed by an experienced operator is the most sensitive means of detecting neck recurrences of DTC. CONCLUSIONS: We present a revised follow-up protocol for low-risk patients taking into account the above findings. This protocol should help clinicians enter a new era of monitoring characterized by greater safety, simplicity, convenience and cost savings.     

Preservation of genetic and regulatory robustness in ancient gene duplicates of Saccharomyces cerevisiae

Biological systems remain robust against certain genetic and environmental challenges. Robustness allows the exploration of ecological adaptations. It is unclear what factors contribute to increasing robustness. Gene duplication has been considered to increase genetic robustness through functional redundancy, accelerating the evolution of novel functions. However, recent findings have questioned the link between duplication and robustness. In particular, it remains elusive whether ancient duplicates still bear potential for innovation through preserved redundancy and robustness. Here we have investigated this question by evolving the yeast Saccharomyces cerevisiae for 2200 generations under conditions allowing the accumulation of deleterious mutations, and we put mechanisms of mutational robustness to a test. S. cerevisiae declined in fitness along the evolution experiment, but this decline decelerated in later passages, suggesting functional compensation of mutated genes. We resequenced 28 genomes from experimentally evolved S. cerevisiae lines and found more mutations in duplicates—mainly small-scale duplicates—than in singletons. Genetically interacting duplicates evolved similarly and fixed more amino acid–replacing mutations than expected. Regulatory robustness of the duplicates was supported by a larger enrichment for mutations at the promoters of duplicates than at those of singletons. Analyses of yeast gene expression conditions showed a larger variation in the duplicates’ expression than that of singletons under a range of stress conditions, sparking the idea that regulatory robustness allowed a wider range of phenotypic responses to environmental stresses, hence faster adaptations. Our data support the persistence of genetic and regulatory robustness in ancient duplicates and its role in adaptations to stresses.Biological systems are inherently robust to perturbations, maintaining the same phenotypes in the face of environmental and genetic challenges (Gu et al. 2003; Stelling et al. 2004; Wagner 2005b). Robustness is key to the emergence of biological complexity and diversification as more robust systems can explore a larger set of phenotypes, allowing greater potential for evolving novel adaptations (Draghi et al. 2010; Payne and Wagner 2014). Determining the factors that provide systems with robustness would pave the way for a more complete understanding of the origin of adaptations and biological complexity. However, despite major efforts in understanding robustness (Wagner 2012), the factors that increase robustness of biological systems and their characterization remain to be determined.Gene duplication has been considered to have a major role in genetic robustness (Lynch and Conery 2000), as the presence of two copies performing identical or overlapping functions confers immunity to the deleterious effects of mutations occurring in one of the gene copies. Additionally, gene duplication has been credited with great importance in generating evolutionary novelties (Ohno 1999) because the selection-free exploration of the genotype space, due to genetic redundancy, allows one gene copy to probe a wider range of phenotypes (Payne and Wagner 2014). Arguably, gene duplication provides an invaluable opportunity to explore the link between genetic robustness and evolvability. Indeed, a number of studies have shown that major gene duplication events, such as whole-genome duplication (WGD) in angiosperms (Wendel 2000; Blanc and Wolfe 2004a) and animals (Otto and Whitton 2000; Hoegg et al. 2004), are concomitant with the emergence of morphological, metabolic, and physiological innovations (Otto and Whitton 2000; Holub 2001; Lespinet et al. 2002; Hoegg et al. 2004; Kim et al. 2004; Maere et al. 2005).Despite the apparent causal link between gene duplication and evolutionary innovation, the neutral exploration of genotype space by a duplicated gene requires the persistence of both gene copies for long periods. This clashes with the evolutionary instability of genetic redundancy, illustrated by the fact that 92% of duplicates in Saccharomyces cerevisiae, originated through WGD roughly 100 million years ago (Mya) (Wolfe and Shields 1997), have returned to single gene copies in extant S. cerevisiae. The rate of preservation of genes in duplicate varies, however, among organisms, with some exhibiting up to 30% of their genes in duplicate (Blanc and Wolfe 2004b; Cui et al. 2006). Genetic robustness, along with other factors such as selection for increasing gene dosage (Conant and Wolfe 2008) and gene balance (Birchler et al. 2005; Freeling and Thomas 2006), has been proposed to allow the persistence of genes in duplicate for longer periods of time, thereby providing opportunity for innovation through mutation (Gu et al. 2003; Fares et al. 2013). This claim is supported by larger fitness effects associated with the deletion of singletons compared to duplicates in yeast (Gu et al. 2003), functional compensation of deleted gene copies (VanderSluis et al. 2010), higher robustness of duplicates to transient gene knockdowns in Caenorhabditis elegans (Conant and Wagner 2004), and the contribution of gene duplicates to provide functional back-up against deleterious human mutations (Hsiao and Vitkup 2008). Recent studies have challenged, however, the link between gene duplication and genetic robustness, revealing a more complex relationship between duplicate preservation, genetic redundancy, and robustness. For example, using synthetic lethality genetic maps, Ihmels et al. (2007) found that duplicates, although exhibiting functional compensation, account for only 25% of the mutational robustness of a system. Furthermore, Wagner (2000) analyzed a number of duplicated genes and found no evidence of compensatory effects for null mutations between gene copies with high sequence or expression similarities. Moreover, a recent study has shown that in natural populations of yeast, close duplicates are unlikely to provide substantial functional compensation (Plata and Vitkup 2013). Thus, it is unresolved whether gene duplication provides mutational robustness through genetic redundancy. Since genetic redundancy and robustness are directly linked to evolvability, finding whether or not gene duplication provides sufficient genetic robustness to overcome the energetic and metabolic cost of maintaining additional genetic material is crucial to link gene duplication with the evolution of novel traits. Also, finding appreciable genetic redundancy between the copies of ancient duplicates would support their potential for future biological innovations.The studies conducted so far to probe the link between gene duplication, genetic redundancy, and mutational robustness have been obscured by the complex mixture of the genomic signatures of natural selection and genetic drift. These mixed signatures make it difficult to disentangle the role of genetic redundancy and mutational robustness in the emergence of novel functions from that of selection favoring adaptive mutations. Moreover, most studies ignore the role of the mechanism of duplication, WGD versus small-scale duplication (SSD), in providing mutational robustness and thus opportunity for innovation (Carretero-Paulet and Fares 2012; Fares et al. 2013). It is expected that the present genetic robustness and incomplete functional compensation of today’s duplicates are the remainders of an ancient larger genetic robustness that emerged at the time of gene duplication. Owing to the functional diversification of duplicates, quantification of preserved genetic robustness is complex and requires a direct test of the robustness of current, long-term preserved duplicates to deleterious mutations. Therefore, a definitive resolution of the controversy of whether ancient gene duplicates provide genetic robustness must come from testing the impact of deleterious mutations on duplicates in comparison with singletons. In this study, we resolved the controversy by conducting an experiment that allows the accumulation of deleterious mutations in the genome of S. cerevisiae. Using experimental evolution allows disentangling adaptive mutations from deleterious and neutral mutations and testing hypotheses under tightly controlled experimental conditions, which are not possible in comparative genomics studies. We test, for the first time, whether duplicates tolerate more deleterious mutations in their coding and regulatory regions than expected under the assumption of no genetic robustness.     

Adult acute lymphoblastic leukaemia in Denmark. A national population‐based retrospective study on acute lymphoblastic leukaemia in Denmark 1998–2008

Since July 2008, children and adults 1–45 years, diagnosed with acute lymphoblastic leukaemia (ALL) in Denmark have been treated according to the common Nordic Society for Paediatric Haematology and Oncology ALL2008 protocol. To explore whether this strategy will improve survival compared with historical controls, we performed a retrospective national population‐based study of adult ALL between 1998 and 2008. Patients were identified through the Danish Patobank and the Danish Cancer Registry; data was collected from patient files, and included 277 patients (median age, 47 years, range 15–91 years). The 5‐year projected event‐free survival (pEFS_5y) and overall survival (pOS_5y) for the whole cohort was 27·5% [95% confidence interval (CI) 22·4–33·6] and 34·1% (95% CI 28·7–40·4), respectively. No patient above 65 years survived beyond 5 years from diagnosis. For patients receiving curatively intended treatment, the pEFS_5y and pOS_5y were 36·6% and 44·1%, respectively, with a significantly higher pOS_5y for patients 15–35 years compared with patients 36–65 years (50·7% vs. 38·9%, P = 0·006). Cox multiple regression analysis identified age (Hazard Ratio = 1·7, P < 0·006) as a statistically significant predictor of EFS. The cure rates, not least for the elderly, are unacceptably low, and call for new strategies in the treatment of adult ALL in all age groups.     

Mode of regulation of natural killer cell activity by interferon

Whereas xenogeneic tumors such as baby hamster kidney or HeLa cells grow in nude mice, the same cells persistently infected with a variety of viruses are rejected. Spleen cells from normal nude mice were found to be induced to produce interferon and to exert natural killer (NK) activity on virus persistently infected (PI) tumor cells, and not on uninfected parental cells in vitro. The phenotype of the interferon-producing cells and the NK effector cells was found to be the same namely, Qa 5(+), Ly 5(+), ganglio-N- tetraosylceramide, with 35 percent of the NK cells also expressing Thy 1.2. NK activity against virus PI tumor cell lines could be nonspecifically augmented both in vivo and in vitro by prior contact with virus PI tumor cells. It was unambiguously demonstrated with chemically homogeneous mouse interferon that interferon, and not a contaminant, was responsible for the augmentation of NK activity in vitro. Studies on the mode of interferon action in augmenting NK activity revealed that the target cell for interferon action was serologically distinct from the NK effector cell. Anti-Ly 5 + complement (C)-treated spleen cells were depleted of NK activity and the ability to produce interferon, but, upon incubation with interferon for 1-3 h, regained both NK activity and susceptibility to anti-Ly 5 + C. Treatment with anti-Qa 5 + C eliminated NK activity, which could not be restored by the addition of interferon. We conclude that interferon produced by Ly 5(+) cells in response to virus PI tumor cells acts on Ly 5(-) precursor cells and induces their differentiation into functional Ly 5(+) NK effector cells.     

On clustering fMRI time series

Analysis of fMRI time series is often performed by extracting one or more parameters for the individual voxels. Methods based, e.g., on various statistical tests are then used to yield parameters corresponding to probability of activation or activation strength. However, these methods do not indicate whether sets of voxels are activated in a similar way or in different ways. Typically, delays between two activated signals are not identified. In this article, we use clustering methods to detect similarities in activation between voxels. We employ a novel metric that measures the similarity between the activation stimulus and the fMRI signal. We present two different clustering algorithms and use them to identify regions of similar activations in an fMRI experiment involving a visual stimulus.