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The Future
Published in James Sherifi, General Practice Under the NHS, 2023
The NHS was created in 1948 in response to the healthcare needs of British society of the time. It has continued to evolve sine then to meet those needs. The place of general practice in the future delivery of healthcare will depend on what society dictates. Whatever that may be, the role of the general practitioner will remain demanding and frustrating but ultimately there are few jobs in life that are more emotionally, intellectually, and financially rewarding!
The Contribution of Pets to Human and Veterinary Medicine
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Verdinexor and selinexor are examples of compounds where data from canine clinical trials informed the development of similar human therapy (News 2014). In 2018, a research team found the orally bioavailable nuclear export protein Exportin 1 inhibitor, Verdinexor, to be safe and effective in a relevant, spontaneous canine model of cancer. This inhibition prevents the export of tumor suppressor proteins and leads to their accumulation in the nucleus, which reinitiates and amplifies their natural apoptotic function. Nuclear localized tumor suppressor proteins detect cancer-associated DNA damage, leading to the selective apoptosis of cancer cells; normal cells, which do not have significant DNA damage, are spared (Sadowski et al. 2018). The US Food and Drug Administration’s Center for Veterinary Medicine has found the effectiveness and safety technical sections for Verdinexor complete to support conditional approval under a New Animal Drug Application (NADA) for the treatment of canine lymphoma. The use of Verdinexor to treat canine lymphoma has been designated a “minor use” in accordance with the Minor Use Minor Species (MUMS) Act. This makes the product eligible for conditional approval similar to orphan drug/accelerated approvals used for submissions of human therapeutics. The utilization of this animal model helped lay the groundwork for evaluation of these same selective inhibitor of nuclear export (SINE) compounds in human cancer (London et al. 2014).
Genetics of Human Obesities: Introductory Notes
Published in Claude Bouchard, The Genetics of Obesity, 2020
A properly assessed phenotype is a sine qua non condition for a valid and productive genetic study. The data summarized in Table 3 indicate why the BMI is only a partially acceptable surrogate measure of body fat content. The common variance between BMI and percent body fat derived from underwater weighing in large samples of adult men and women ranging from 35 to 54 years of age attains only about 40%. At the extremes of the body fat content distribution, BMI is more closely associated with percent body fat; that is, the common variance may reach 60% and more. This is not entirely satisfactory as genetic studies deal with individual differences in the phenotype of interest and, for them to be successful, the phenotype of complex multifactorial trait must be measured with a reasonable degree of precision.
Genomic diversity and differentiation of Alu insertion polymorphisms in a native British and four South Asian migrant populations
Published in Annals of Human Biology, 2023
Rebekah Beaumont, Liz Akam, Puneetpal Singh, Jasvinder Singh Bhatti, Sarabjit Mastana
Alu insertion (characterised by the presence of AluI restriction site) DNA sequences of around 300 bp in length are highly abundant (> 1 million repeats) in the human genome, contributing to roughly 11% of the DNA sequence (Batzer and Deininger 1991; Batzer et al. 1994; Deininger 2011). Alu insertions are identical by descent and are members of a larger group of transposable elements called Short Interspersed Nuclear Elements (SINEs) and they randomly distribute themselves throughout the genome (Chadli et al. 2009). However, Alus lack removal mechanisms so, once they have been inserted, they propagate in the genome through generations. Alu insertions are stable, bi-allelic, and primate-specific, this makes them a useful marker for studying genetic variation, migration patterns, forensics, paternity, and evolutionary heritage (Stoneking et al. 1997; Batzer and Deininger 2002; Mastana et al. 2003; Watkins et al. 2003; Deininger 2011; Laybourn et al. 2016; Singh et al. 2016; Mastana et al. 2017). Indian populations often have endogamous marriages and strict religious and cultural traditions that restrict the diversity within native and migrant populations (Pemberton et al. 2012; Mastana 2014; Sankaran et al. 2017; Brearley et al. 2020). The purpose of this study is to investigate the levels of genetic variation in a sample of four migrant South Asian and one native White British/European population using a panel of selected Alu polymorphisms and investigate the usefulness of the Alus for genomic variation and genetic differentiation among populations.
RNA A-to-I editing, environmental exposure, and human diseases
Published in Critical Reviews in Toxicology, 2021
Retrotransposons (or “jumping genes,” via RNA intermediates) comprise almost half of the human genome. They are the discrete sequences of DNA that can move from region to region across genomes under environmental stress. By affecting human genomic structures, transposable elements contribute to genomic evolution. Besides, they modify the risks for various diseases, including cancer, by generating chromosome mutations (insertion/deletion), genomic instability, and disorder in gene expression. Retrotransposons include the widely studied LINE-1 and Alu elements that are defined as short interspersed nuclear elements (SINEs) and common in the primate genome (Bazak et al. 2014). In Alu elements, intramolecular double strand RNA occurs in introns and 3′ untranslated region which are subject to RNA editing (Nishikura 2016). Recent advances in deep sequencing accelerate our understanding of how RNA editing is common in Alu double stranded RNAs. Now, we have substantial evidence from various studies that RNA editing sites are commonly available in Alu elements. Approximately 1.6 million RNA editing sites were demonstrated in Alu elements which are much higher than is anticipated (Bazak et al. 2014). In another human transcriptome study, the authors reported that A-to-I RNA editing was common in human mRNAs containing 14,500 sites and located in untranslated regions and introns (Athanasiadis et al. 2004; Levanon et al. 2004).
Selinexor for the treatment of multiple myeloma
Published in Expert Opinion on Pharmacotherapy, 2020
Klaus Podar, Jatin Shah, Ajai Chari, Paul G Richardson, Sundar Jagannath
With the increasing and earlier use of novel agents, a growing number of MM patients are refractory to PIs, IMiDs, and daratumumab (TCR). Indeed, MM patients penta-refractory against bortezomib, carfilzomib, lenalidomide, pomalidomide, and CD38-targeting antibodies such as daratumumab as well as alkylating agents and corticosteroids have limited therapeutic options with a particularly poor prognosis. Selinexor is an oral, first-in-class SINE compound, targeting XPO-1. Of note, given its capacity to cross the blood-brain barrier makes selinexor a promising candidate for the treatment of central nervous and meningeal manifestation of MM. Based on the STORM trial Sd represents the first FDA-approved selinexor-containing therapy with clear activity in patients with penta-refractory MM, who have exhausted approved therapies; the EMA approval is still pending. Ongoing studies investigate the efficiency and tolerability of other selinexor-containing combinations in MM. These additional studies are instrumental to prove that SINE compounds are a valuable addition to our current therapeutic armamentarium.