276 research outputs found
A well-conserved Plasmodium falciparum var gene shows an unusual stage-specific transcript pattern
No full textThe var multicopy gene family encodes Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variant antigens, which, through their ability to adhere to a variety of host receptors, are thought to be important virulence factors. The predominant expression of a single cytoadherent PfEMP1 type on an infected red blood cell, and the switching between different PfEMP1 types to evade host protective antibody responses, are processes thought to be controlled at the transcriptional level. Contradictory data have been published on the timing of var gene transcription. Reverse transcription-polymerase chain reaction (RT-PCR) data suggested that transcription of the predominant var gene occurs in the later (pigmented trophozoite) stages, whereas Northern blot data indicated such transcripts only in early (ring) stages. We investigated this discrepancy by Northern blot, with probes covering a diverse var gene repertoire. We confirm that almost all var transcript types were detected only in ring stages. However, one type, the well-conserved varCSA transcript, was present constitutively in different laboratory parasites and does not appear to undergo antigenic variation. Although varCSA has been shown to encode a chondroitin sulphate A (CSA)-binding PfEMP1, we find that the presence of full-length varCSA transcripts does not correlate with the CSA-binding phenotype
2019 European Thyroid Association Guidelines for the Treatment and Follow-Up of Advanced Radioiodine-Refractory Thyroid Cancer
No full textThe vast majority of thyroid cancers of follicular origin (TC) have a very favourable outcome, but 5-10% of cases will develop metastatic disease. Around 60-70% of this subset, hence less than 5% of all patients with TC, will become radioiodine refractory (RAI-R), with a significant negative impact on prognosis and a mean life expectancy of 3-5 years. Since no European expert consensus or guidance for this challenging condition is currently available, a task force of TC experts was nominated by the European Thyroid Association (ETA) to prepare this document based on the principles of clinical evidence. The task force started to work in September 2018 and after several revision rounds, prepared a list of recommendations to support the treatment and follow-up of patients with advanced TC. Criteria for advanced RAI-R TC were proposed, and the most appropriate diagnostic tools and the local, systemic and palliative treatments are described. Systemic therapy with multikinase inhibitors is fully discussed, including recommendations on how to start it and at which dosage, on the duration of treatment, and on the management of side effects. The appropriate relationship between the specialist and the patient/family as well as ethical issues are covered. Based on the available studies and on personal experience, the experts provided 39 recommendations aimed to improve the management of advanced RAI-R TCs. Above all of them is the indication to treat and follow these patients in a specialized setting which allows the interaction between several specialists in a multidisciplinary team
Vandetanib in advanced medullary thyroid cancer: Review of adverse event management strategies
No full textINTRODUCTION:
Vandetanib has recently demonstrated clinically meaningful benefits in patients with unresectable, locally advanced or metastatic medullary thyroid cancer (MTC). Given the potential for long-term vandetanib therapy in this setting, in addition to treatment for disease-related symptoms, effective management of related adverse events (AEs) is vital to ensure patient compliance and maximize clinical benefit with vandetanib therapy.
METHODS:
This expert meeting-based review aims to summarize published data on AEs associated with vandetanib therapy and to provide clinicians with specific practical guidance on education, monitoring, and management of toxicities induced in patients treated with vandetanib in advanced and metastatic MTC. The content of this review is based on the expert discussions from a multidisciplinary meeting held in October 2012.
RESULTS:
Characteristics, frequency, and risk data are outlined for a number of dermatological, cardiovascular, gastrointestinal, and general AEs related to vandetanib treatment. Preventive strategies, practical treatment suggestions, and points for clinical consideration are provided.
CONCLUSIONS:
Good patient and team communication is necessary for the prevention, early detection, and management of AEs of vandetanib. Physicians, nurses, and other healthcare providers play a critical role in providing AE management and patient support to optimize outcomes with vandetanib in MTC
Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
No full textThis ESMO Clinical Practice Guidelines provide updated state-of-the-art recommendations on management of thyroid cancer (diagnosis, treatment and follow-up), compiled by a multidisciplinary author panel and accompanied by level of evidence and grade of recommendation, depending on the strength of supporting data and magnitude of benefit from particular intervention
Microbial community organisation and functioning under ocean acidification conditions
No full textSince industrialisation global CO2 emissions have increased, and as a consequence oceanic pH is predicted to drop by 0.3-0.4 units before the end of the century - a process coined ‘ocean acidification’ (OA). There is significant interest therefore in how pH changes will affect the oceans’ biota and integral processes. This thesis investigates community organisation and functioning in response to predicted end of century CO2 concentrations using an elevated CO2 (~750ppm), large volume (11,000 L) contained seawater mesocosm. This thesis utilises RNA stable isotope probing (SIP) technologies, in conjunction with quantitative reverse transcriptase PCR (RT-qPCR), to investigate the functional consequences of ocean acidification upon microbial communities. This thesis finds little evidence of changes occurring in bacterial abundance or community composition with elevated CO2, under both phytoplankton pre-bloom/bloom and post-bloom conditions. It is proposed that they represent a community resistant to the changes imposed. In contrast, significant differences were observed between treatments for a number of key eukaryote community members. These findings were investigated in the context of functional change, using the uptake of two key substrates (bicarbonate and glucose) as analogues for photosynthesis and respiration respectively. Unlike community abundance, distinct changes in carbon assimilation were detected in dominant members of the picoplankton. In conclusion the data presented suggests that although current microbial communities hold the capacity to respond to elevated CO2, future responses will likely be taxa specific and controlled by wider community dynamics
Optimisation of treatment with lenvatinib in radioactive iodine-refractory differentiated thyroid cancer
No full textLenvatinib has been approved for the treatment of advanced differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) following the results of the SELECT trial which demonstrated a significant increase in progression-free survival and a high response rates. The data reported for lenvatinib in RAI-refractory DTC (RAI-R DTC) are the most significant to date in this patient population, with a RECIST objective response rate above 60% and almost 80% reduction in the risk of disease progression. Because the first indication in oncology for lenvatinib is specifically in RAI-R DTC, a period of familiarisation with its safety and efficacy profile is required. This review includes a series of specific recommendations for optimising the management of RAI-R DTC with lenvatinib, as well as specific guidelines for minimising the incidence and severity of adverse events (AEs), which enable dose intensity to be increased and this way maximise the benefits of the drug in the patient population treated. These recommendations were defined at a meeting of experts of different specialities, reviewing available scientific evidence on the drug, as well as their own direct personal experience in daily clinical practice. For toxicity to be properly managed, a multidisciplinary approach is required in which the different medical services, nursing staff and the patient and their careers are all involved. It is essential to assess the suitability of patients who are candidates for lenvatinib, as well as their clinical and physiological status prior to treatment. They must then be closely monitored to prevent and detect possible AEs. The main objective should be to maintain the dose that obtains the maximum therapeutic effect, discontinuing the treatment only if the toxicity becomes unmanageable or there is no clinical benefit
Erythrocyte complement receptor 1 (CR1) expression level is not associated with polymorphisms in the promoter or 3' untranslated regions of the CR1 gene
No full textComplement receptor 1 (CR1) expression level on erythrocytes is genetically determined and is associated with high (H) and low (L) expression alleles identified by a HindIII restriction fragment-length polymorphism (RFLP) in intron 27 of the CR1 gene. The L allele confers protection against severe malaria in Papua New Guinea, probably because erythrocytes with low CR1 expression, are less able to form pathogenic rosettes with Plasmodium falciparum-infected erythrocytes. Despite the biological importance of erythrocyte CR1, the genetic mutation controlling CR1 expression level remains unknown. We investigated the possibility that mutations in the upstream or 3' untranslated regions of the CR1 gene could control erythrocyte CR1 level. We identified several novel polymorphisms; however, the mutations did not segregate with erythrocyte CR1 expression level or the H and L alleles. Therefore, high and low erythrocyte CR1 levels cannot be explained by polymorphisms in transcriptional control elements in the upstream or 3' untranslated regions of the CR1 gene
CR1 Knops blood group alleles are not associated with severe malaria in the Gambia
No full textThe Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McC(a)/McC(b), we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1,365/1,706) and McC(b) (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McC(a) allele observed in all populations, the African Sl 2/McC(b) allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e.=1.77, P-valu
Retirement 20/20: Innovation in Pension Design
No full textToday, both the United States and Canada are experiencing a decline in Single-Employer Sponsored Defined Benefit (DB) Pension plans. In some instances, they are being replaced by Defined Contribution (DC) or Individual Account [e.g., 401(k)] plans; in other cases, by nothing. It appears that traditional sponsors of DB plans have concluded that their cost (or its variability) is larger than the rewards (e.g., a loyal work force). At the same time, two stock market meltdowns in less than a decade have indicated to all the frailties of Individual Account DC systems. What we need is a new pension system that brings most of the advantages of the DB and DC plans to the participants, while minimizing their disadvantages. We must also recognize the skill set of the participants (e.g., do not expect a blue collar worker to be an investment professional) and not anticipate or require anomalous markets (e.g., ever-stronger equity returns). Size matters. Larger plans can run at lower per unit expense ratios, and can also achieve entry into a wide variety of investment products (e.g., private placements) not available to a small plan. Larger funds also benefit from risk sharing through “Law of Large Numbers”. The model proposed is a “Jointly Governed Target Benefit Pension plan”. Such plans would have many features in common with today’s Ontario Multi-Employer Pension Plans (MEPPs), the Canada/Quebec Pension Plans (C/QPP), TIAA-CREF in the United States and the Dutch national plan. For the plan sponsor, this is a DC plan. Inherent in the concept are that smaller plans (and even individual plans) could commingle their assets to achieve “size” (e.g. a minimum investment portfolio of $10B). Investment management would be at arm’s length from the plan itself.Target Benefit, Joint Governance, Commingled Assets
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