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Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Antisense oligonucleotide gene therapy for treating Huntington's disease 20/03/24, 18:10 Last updated: A potential gene therapy Huntington’s disease (HD) is an inherited neurodegenerative disease caused by a CAG extension in exon 1 of the huntingtin gene. An extended polyglutamine tract in the huntingtin protein is developed due to the expanded alleles, resulting in intracellular signalling defects. Antisense Oligonucleotide (ASO) gene therapy is currently being pioneered to treat HD. In this therapy, oligonucleotides are inserted into cells and bind to the target huntingtin mRNA. Thus, inhibiting the formation of the huntingtin protein by either physically blocking the translation of mRNA (figure 1) or by utilising RNase H to degrade the mRNA. Previous ASO gene therapy experiments conducted on R6/2 mice that express the human huntingtin gene have been successful. In HD research, the R6/2 mouse model is commonly used to replicate HD symptoms and is therefore useful for testing potential treatments. The transgenic R6/2 mouse has an N-terminally mutant Huntingtin gene with a CAG repeat expansion within exon 1. In this successful experiment, scientists treated one group of R6/2 mice with the ASO treatment that suppresses the production of human huntingtin mRNA, and saline solution was administered to the control group of mice. This experiment aimed to confirm if ASO therapy improves the survival rate in the R6/2 mice. The results showed that human huntingtin mRNA levels of the mice treated with ASO therapy were lower than the control group. Furthermore, the mice treated with ASO therapy had a higher percentage of survival and lived longer (21 weeks), in comparison to the control group mice that survived until 19 weeks. Thus, it could be concluded that if less human huntingtin mRNA was present in the ASO group, then less human huntingtin mRNA would be translated, and so there would be less synthesis of the huntingtin protein, in contrast to the control group. The results of this study are enormously informative in understanding how gene therapy can be used in the future to treat other neurological diseases. However, before ASO therapy is approved for clinical use, further trials will need to be conducted in humans to verify the same successful outcomes as the R6/2 mice. If approved, then the symptoms of HD, including dystonia could be safely controlled with ASO therapy. Furthermore, scientists need to consider that an increased survival rate of only an additional two weeks, as shown in the experiment does not always correlate to an increased quality of life for the patient. Therefore, it needs to be established if the benefits of ASO gene therapy will outweigh the risks associated with it. Furthermore, the drug PBT2, which influences copper interactions between abnormal proteins, is currently being studied as a potential treatment option for HD. Some studies have inferred that the aggregation of mutant huntingtin proteins could be due to interactions with metals, including copper. Therefore, this drug is designed to chelate metals and consequently, decrease abnormal protein aggregations in the body. This treatment has been shown to improve motor tasks and increase the lifespan in R6/2 mice. However, as this treatment has a lot of shortcomings, further studies need to be conducted over a large period of time to confirm a successful outcome of this drug on HD patients. Written by Maria Z Kahloon References: Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pytel KA, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron. 2012;74(6):1031–44. Valcárcel-Ocete L, Alkorta-Aranburu G, Iriondo M, Fullaondo A, García-Barcina M, Fernández-García JM, et al. Exploring genetic factors involved in Huntington disease age of onset: E2F2 as a new potential modifier gene. PLoS One. 2015;10(7):e0131573. Liou S. Antisense gene therapy [Internet]. Stanford.edu . 2010 [cited 2021 Aug 6]. Available from: https://hopes.stanford.edu/antisense-gene-therapy/ Huntington's disease research study in R6/2 MOUSE model: Charles River [Internet]. Charles River Labs. [cited 2021 Aug 26]. Available from: https://www.criver.com/products-services/discovery-services/pharmacology-studies/neuroscience-models-assays/huntingtons-disease-studies/r62-mouse?region=3696 Frank S. Treatment of Huntington's disease. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. Springer US; 2014;11(1):153-160. Potkin KT, Potkin SG. New directions in therapeutics for HUNTINGTON DISEASE. Future neurology. 2018;13(2):101-121. Project Gallery

Go back Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Influence of different environmental factors on exercise Last updated: 07/11/24 The characteristics of environmental factors: - Chemical safety - Air pollution - Climate change and natural disasters - Diseases caused by microbes - Lack of access to health care - Infrastructure issues - Poor water quality - Global environmental issues What are the impacts of these environmental influences on physical activity? An individual may be restricted to a certain range of physical activities which they can participate in. Individuals are usually reliant on the surrounding environment and the maintenance of facilities. If they are not kept well maintained, individuals are usually discouraged. The physiological effect on training: Climate change will disproportionately affect the most vulnerable in our populations, including the very young, the very old, and those with pre-existing health conditions. Training adjustments to compensate for the influence of environmental factors on training: - Treatments for heat stress- stop exercising / move to a shaded or air-conditioned area / remove excess clothing or equipment / drink cold beverages / sit in front of a fan / put a cool piece of cloth around neck / place entire body in cool water e.g. cool bath or shower - Treatments for cold stress- move to a warm environment / remove cold and wet clothes / find access to warm air such as heaters, or fireplace / use electric or non-electric blankets / drink warm beverages Written by Kushwant Nathoo Related article: Impacts of negligent exercise on physiology

Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Rare zoonotic diseases 05/12/24, 12:23 Last updated: Lesser-known illnesses Introduction From COVID-19 possibly coming from livestock in Wuhan market to HIV resulting from numerous transmissions between African primates, it seems that zoonotic diseases are difficult to control. They occur when pathogenic microorganisms are spread from animals to humans or vice-versa. Their impact on human civilization is alarming because they are responsible for 2.5 billion cases of illness and 2.7 million deaths in humans annually around the world. Although there is a lot of information regarding more familiar zoonotic diseases such as rabies and malaria, this article focuses on those that may be less discussed as they could become more problematic in the future. Crimean-Congo haemorrhagic fever (virus) To begin, Crimean-Congo haemorrhagic fever (CCHF) is a viral disease, which spreads when humans are bitten by ticks carrying the virus along with farmers killing infected livestock. It is endemic in more than 30 European, African and Asian countries with the exact factors contributing to the increased cases of CCHF being a mystery. Diagnosing the disease involves detecting the virus through Enzyme-linked immunosorbent assay (ELISA), real time polymerase chain reaction (RT-PCR) along with detecting IgM and IgG antibodies using ELISA. As for the treatment options for CCHF, they are finite as there are no available vaccines and the only antiviral drug used against the virus is ribavirin, which prevents replication of various DNA and RNA viruses in-vitro. Given all this information, it is evident that extensive research is necessary to better understand the disease holistically and design drugs that can stop more fatalities associated with CCHF. Trichinellosis (parasite) The next zoonotic disease to address is trichinellosis or trichinosis , which is caused by Trichinella spiralis and so it is a parasitic infection. It can spread by eating poorly prepared meat such as pork and mammals like horses and wild carnivores are typically the reservoirs of infection. Its epidemiology in humans seems to be limited because it has 10,000 cases and 0.2% death rate annually. Moreover, an important factor that can contribute to the spread of trichinellosis is culture because certain communities have dishes containing raw meat. For example, a review referenced more than 600 outbreaks, 38,797 infections and 336 deaths in humans between 1964 and 2011 in China. As for diagnosing trichinellosis, it is challenging because it has general signs. With this in mind, the common method to spot the disease is detecting IgG antigens that work against Trichinella spiralis . On the other hand, its major drawback is getting a false negative in early trichinellosis infection. Like CCHF, trichinellosis is not as prevalent compared to other zoonotic diseases but it can have devastating impacts on specific countries, so increasing the supply of antiparasitic drugs like albendazole and/or mebendazole would be beneficial to stop the spread of Trichinella spiralis. Brucellosis (bacteria) The next zoonotic disease which is caused by a bacterial pathogen is brucellosis and is common worldwide, though certain places have higher prevalence of the disease compared to others. The pathogen can be transmitted through various ways such as direct contact with infected animal tissue on broken skin and consuming contaminated meat or dairy. Interestingly, it has been linked to childhood pulmonary infections as 18 out of 98 brucellosis patients have experienced such symptoms, but this is rare. The graph above indicates that when brucellosis occurs in animals, it has a high likelihood of being passed onto humans. For example, the years 2004-2007 could be when brucellosis cases were most frequent. This could have been alleviated through specific antibiotics used to treat brucellosis that include rifampin, doxycycline and streptomycin. Similar to trichinellosis, brucellosis diagnosis can be difficult because the symptoms can vary and are not exclusive to one disease, suggesting that different laboratory techniques are needed to find brucellosis in patients. Conclusion It looks like there is a recurring pattern of the zoonotic diseases outlined in this article occurring in developing countries as opposed to developed countries. As such, there have to be more effective interventions to prevent their ramifications on populations living in these countries. For this to occur, there has to be sufficient information, awareness, and education of these rarer zoonotic diseases to begin with. Furthermore, the current treatments for CCHF, trichinellosis and brucellosis may be unsuccessful due to the threat of antimicrobial resistance, hence finding alternative treatments for the aforementioned zoonotic diseases is vital in the future. Written by Sam Jarada Relate articles: Rabies / Canines and cancer Project Gallery

Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Correlation between wealthy countries and COVID-19 mortality rate 24/09/24, 10:56 Last updated: Linking a country's HDI with its COVID-19 mortality rate Investigation title: Could there have been a correlation between very rich countries and COVID-19 mortality rate? Investigation period: December 2019- November 2020 (Approx. 1 year) Background The World Health Organisation (WHO) were first alerted about coronavirus, on the 31st December 2019, by a lot of pneumonia cases in Wuhan, China which have a population of 11 million. Furthermore, by 15th January 2020 there were precisely 289 cases recorded in countries such as: Thailand, Japan, S.Korea and other places in China. And of the original cases there were 6 deaths, 51 severe cases - 12 of which were in critical condition. Meanwhile, the virus responsible for the cases was isolated and its genome mapped and was shared on 12th January. HDI represents the measurement of development. This is a composite of Gross National Income (GNI) per capita, mean years of education and life expectancy at birth to measure the development of a country. It is calculated between a scale of 0 (least developed) to 1 (most developed) and all its values are to 3 significant figures. HDI values of 2019 and countries of HDI greater than 0.800 were used, as these are all regarded as very high HDI countries so were in the scope of this investigation. Therefore, this aimed to determine the impact of human development on the number of mortalities caused by SARS-CoV-2; where human development is measured by HDI, and the number of mortalities per hundred thousand from December 2019 to November 2020. Method Stratified sampling produced 12 countries, in descending order of HDI value: - Australia, Netherlands, UK, Austria, Spain, Estonia, UAE, Portugal, Bahrain, Kazakhstan, Romania, Malaysia See Table 4 . Results See Chart 2 . r= 0.321 (3 s.f.) – Pearson’s test ∴ There is a moderate positive linear correlation between HDI and mortality rate due to SARS-CoV-2 per 100,000. Further stats testing- Spearman’s Rank ∑D^2 = 216 n = 12 Rs = 1 - (6 ∑D^2 )/ n(n^2 – n) = 1 - (6 x 216) 1584 = 0.182 (3 d.p.) Rs = 0.245 ＜ Critical Value (0.0.587591) ∴ There is no correlation between HDI and mortality rate due to coronavirus per 100,000. Conclusion The null hypothesis was accepted: there is no correlation between a country’s HDI and its mortality rate due to SARS-CoV-2. A biogeographical reason for this is that the more developed countries (such as those in my investigation for example the UK) have a higher level of immigration from latitudes closer to the equator therefore there is a section of their society with increased susceptibility to SARS-CoV-2 due to vitamin D deficiency. It is known that low vitamin D levels have a negative impact on immune function and that low vitamin D levels are common in the immigrant population. Therefore, it is likely that there is a link between vitamin D deficiency and mortality rate per 100,000, however this could be overstated due to confounding factors such as socioeconomic status, residence and employment. This would explain why countries at higher latitudes like the Netherlands have higher mortality rates per 100,000 (41.80) which is the 3rd highest in this investigation. Another explanation for this non-correlation could be that the less developed countries could be more used to dealing with a pandemic or stress on a healthcare system due to previous experience. For example, after the SARS outbreak, many countries decided to prepare in case of a pandemic, however some large HDI countries such as the UK chose not to and even ignored other warnings on the effect of a pandemic (like the exercise signs simulation). Moreover, studies have shown that as a very high HDI country becomes more developed its healthcare system continues to develop until it reaches a peak where its effectiveness is undermined by economic benefit or interest. This would explain why the UK had a death rate of 68.00 per 100,000 and a total death count of over 45,000 (as of December 2020). Implications Since there is no correlation between a country’s HDI index and its mortality rate of COVID-19, this may apply to other diseases that became pandemics such as 1918’s Spanish Flu, or more recent ones like the SARS outbreak in the early 21st century. As for tropical diseases (malaria, dengue, chikungunya and others) and other illnesses such as the common cold and the flu, these diseases present in only certain geographies. This means that the countries with these ailments will be of a similar HDI and economical status; therefore there would be a correlation between a country’s HDI index and its mortality rate of these diseases, to a certain extent. Investigation conducted and written by Roshan Gill Tables, charts, stats and calculations by Roshan Gill This summary by Manisha Halkhoree ‘Implications’ section by Manisha Halkhoree Project Gallery

Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link The Biggest Innovations in Biosciences 10/05/24, 10:34 Last updated: CRISPR-Cas9, CAR T-cells, incretins, and iPSCs We are in the era of innovation and cutting-edge technology in biosciences and health. This article goes through some of the most remarkable technologies slowly conquering the world of biosciences. Gene editing and CRISPR-Cas9 Gene editing is based on the idea that correcting the genetic mistake that causes a disease offers a permanent result than curing the symptoms. This technique allows scientists to alter the DNA of cells by deleting, adding or modifying genes. There are numerous ways to edit a gene. The most widely used and revolutionary method for gene editing is CRISPR-Cas9, which stands for Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR- associated protein 9. The process begins with the design of a synthetic RNA molecule, known as guide RNA (gRNA) that matches the target gene sequence. The gRNA, combined with the Cas9 protein, forms a complex that is then introduced into the target cells. Cas9 acts like scissors, guided by the gRNA, to locate the precise location on the DNA where the genetic modification is intended. Once the target site is identified, Cas9 induces a break in the DNA strand. The cell's natural DNA repair mechanisms then come into play. The non- homologous end joining pathway introduces insertions and deletions at the site, resulting in gene knockout or inactivation. On the other hand, once a DNA template with homology to the sequences is present, the homology-directed repair pathway allows the incorporation of a desired genetic sequence, facilitating gene insertion or replacement. Several other gene-editing techniques have been developed, each with unique approaches. Zinc Finger Nucleases (ZFNs) and Transcription Activator-Like Effector Nucleases (TALENs) are two examples. These methods also use proteins that act as molecular scissors to cut the DNA at specific locations. ZFNs use zinc finger proteins to bind to target DNA sequences, while TALENs use transcription activator-like effector proteins. As the field of gene editing rapidly advances, these diverse methods contribute to the expanding toolkit available for researchers and hold promise for addressing a wide array of applications, from medical treatments to agricultural improvements. CAR T-cells Chimeric antigen receptor T-cells (CAR T-cells) are a new type of immunotherapy, considered to be the new fighters in the war on cancer. In general, immunotherapies use the patient’s immune system to fight the cancer. This therapy promises more specificity than traditional therapies and more permanent results. T-cells naturally exist in the human organism, supporting the adaptive immune system. They are a group of lymphocytes in the blood or lymph tissue that target or kill specific pathogens. Each type of T-cell recognises specific pathogens. T-cells have proteins on their outer surface, called receptors and these receptors recognize specific proteins on the outer surface of the pathogen. Depending on the type of T-cell, after recognizing the specific pathogen, they are either killing the pathogen (killer T-cells) or signaling to other elements of immune system to attack the pathogen (helper T-cells). CAR T-cell therapy involves modifying a patient’s own T-cells to express a specific CAR on their surface. The receptor is designed to recognise antigens commonly found on the surface of cancer cells. To introduce CARs on the outer surface of T-cells, the patient’s T-cells are genetically modified in the lab. A viral vector is often used to knock out the original T-cell receptors and express the CAR construct. The newly created CAR-T-cells are introduced into the patients, where they target and destroy cancer cells expressing the specific antigen for which the CAR is designed. Incretins The scientific journal “Science” proclaimed glucagon-like peptide-1 (GLP-1) receptor agonists The Breakthrough of 2023. These medications, originally approved for type 2 diabetes, demonstrated remarkable weight-loss benefits. GLP-1 is a natural hormone produced in the intestines that plays a role in regulating blood sugar levels. When we eat a meal, incretins, GLP-1 and Glucose-dependent insulinotropic polypeptide (GIP), are released into the bloodstream. They bind to specific receptors on the beta cells of the pancreas, triggering insulin release. Incretins also suppress the release of glucagon, a hormone that increases blood sugar levels by promoting the breakdown of stored glucose. GLP-1 receptor agonists are medications that mimic the effects of GLP-1. They bind to the GLP-1 receptors on pancreatic beta cells, promoting insulin secretion and suppressing glucagon release. By mimicking the actions of GLP-1, these medications help to lower sugar levels, improve glucose control, and reduce the risk of hypoglycemia. At the same time, they seem to regulate the appetite and delay gastric emptying. iPSCs Induced pluripotent stem cells (iPSCs) are becoming a new powerful weapon in lab research. They are a type of stem cell that can be generated from adult cells, such as skin or blood cells, through reprogramming. The process of creating iPSCs involves introducing a set of specific genes into the adult cells. These reprogramming factors reset the adult cells' developmental clock, turning them back into a pluripotent state, similar to embryonic stem cells. Once iPSCs are generated, they can be expanded indefinitely in the laboratory and induced to differentiate into various cell types. iPSCs are a valuable tool for studying human development and disease, as well as for drug discovery and regenerative medicine. iPSCs can be derived from patients with genetic diseases or other conditions, allowing researchers to study disease mechanisms in a dish. By differentiating iPSCs into the relevant cell types affected by the disease, researchers can observe how the disease develops and test potential treatments. Moreover, iPSC-derived cells can screen potential drugs for safety and efficacy. Because iPSCs can differentiate into many different cell types, they provide a more accurate model of human biology than traditional cell culture methods. Finally, because iPSCs can be derived from individual patients, they offer the potential for personalised therapies. iPSCs could be used to generate patient-specific cells for transplantation or to test drugs for individual patients. Conclusion These cutting-edge technologies offer unprecedented opportunities for targeted interventions in the treatment of genetic disorders, cancer, diabetes, and a myriad of other diseases. However alongside their immense promise, these biotechnological techniques and therapies also raise important ethical, social and regulatory considerations. The implications of gene editing on human germline cells, the accessibility of advanced therapies, and the long-term safety of these interventions are critical areas that warrant careful attention and thoughtful deliberation. Embracing these innovative techniques with diligence holds the key to unlocking a future where previously incurable conditions become manageable, and where the boundaries of medical possibility are continually expanded. Written by Matina Laskou Related article: Medical biotechnology Project Gallery

Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Germline gene therapy (GGT): its potential and problems 06/01/25, 13:38 Last updated: A Scientia News Biology and Genetics collaboration Introduction Genetic diseases arise when there are alterations or mutations to genes or genomes. In most acquired cases, mutations occur in somatic cells. However, when these mutations happen in germline cells (i.e. sperm and egg cells), they are incorporated into the genome of every cell. In other words, should this mutation be deleterious, all cells will have this issue. Furthermore, this mutation becomes inheritable. This is partly why most genetic diseases are complicated to treat and cure. Gene therapy is a concept that has been circulating among geneticists for some time. Indeed, addressing a disease directly from the genes that caused or promoted it has been an attractive and appealing avenue of therapies. The first successful attempt at gene therapy dates back to 1990, using retrovirus-derived vectors to transduce the T-lymphocytes of a 4-year-old girl with X-linked severe combined immunodeficiency disease (SCID-X1) with enzyme adenosine deaminase (ADA) deficiency. The trial was a great success, eliminating the girl's disease and marking a great milestone in the history of genetics. Furthermore, the success of viral vectors also opened new avenues to gene editing, such as zinc finger nucleases and the very prominent CRISPR-Cas9. For example, in mid-November 2023, the UK Medicines and Healthcare products Regulatory Agency or MHRA approved the CRISPR-based gene therapy, Casgevy, for sickle cell disease and β-thalassemia. It is clear that the advent of gene therapies significantly shaped the treatment landscape and our approach to genetic disorders. However, for most of gene therapy history, it is done almost exclusively on somatic cells or some stem cells, not germline cells. How it works As mentioned, inherited genetic disease-associated mutations are also present in germline cells or gametes. The current approach to gene therapy targets genes of some or very specific somatic or multipotent stem cells. For example, in the 1990 trial, the ADA-deficient SCID-X1 T-lymphocytes were targeted, and in recently approved Casgevy, the BCL11A erythroid-specific enhancer in hematopoietic stem cells. The methods involved in gene therapies also vary, each with advantages and limitations and carrying some therapeutic risks. Nevertheless, when aiming to treat genetic diseases, gene therapy should answer two things: how to do it and where. There are a few elucidated strategies of gene therapies. Unlike some popular beliefs, gene therapies do not always directly change or edit mutated genes. Instead, some gene therapies target enhancers or regulatory regions that control the expression of mutated genes. In other cases, such as in Casgevy, enhancers of a different subtype are targeted. By targeting or reducing BCL11A expression, Casgevy aims to induce the production of foetal haemoglobin (HbF), which contains the γ-globin chain as opposed to the defective β-chain in the adult haemoglobin (HbA) of sickle cell disease or β-thalassemia. Some gene therapies can also be done ex vivo or in vivo . Ex vivo strategies involve extracting cells from the body and modifying them in the lab, whilst in vivo strategies directly modify the cell without extraction (e.g. using viral/ non-viral vectors to insert genes). In essence, the list of strategies for gene therapies is growing, each with limitations and a promising prospect of tackling genetic diseases. These methods aim to “cure” genetic diseases in patients. However, the strategies mentioned above have all been researched using and, perhaps, made therapeutically for somatic or multipotent stem cells. Germline gene therapy (GGT), involves directly editing the genetic materials of germline cells or the egg and sperm cells before fertilisation. This means if it is done successfully, fertilisation of these cells will eliminate the disease phenotype from all cells of the offspring instead of only effector cells. Potentially, GGT may eradicate a genetic disease for all future generations. Therefore, it is an appealing alternative to human embryo editing, as it achieves similar or the same result without the need to modify an embryo. However, due to its nature, its advantage may also be its limitation. Ethical issues GGT has the potential to cure genetic disorders within families. However, because it involves editing either the egg or sperm cells before fertilisation, there are prominent ethical issues associated with this method, like the use of embryos for research and many more. Firstly, GGT gives no room for error. Mistakes during the gene modification process could cause systemic side effects or a harsher disease than the one initially targeted, leading to a multigenerational effect. For example, if parents went to a clinic to check if one/both their germ cells have a gene coding for proteins implicated in cystic fibrosis, an off-target mistake during GGT may lead to their child developing Prader-Willi Syndrome or other hereditary disorders caused by editing out significant genes for development. Secondly, an ecological perspective asserts that the current human gene pool, an outcome of many generations of natural selection, could be weakened by germline gene editing. Also, there is the religious perspective, where editing embryos goes against the natural order of how god created living creatures as they should be, where their natural phenotypes are “assigned” for when they are alive. Another reason GGT may be unethical is it leads to eugenics or creating “designer babies”. These are controversial ideas dating back to the late 19th century, where certain traits are “better” than others. This implies they should appear in human populations while individuals without them should be sterilised/killed off. For instance, it is inconceivable to forget the Nazi Aktion T4 program, which sought to murder disabled people because they were seen as “less suitable” for society. Legal and social issues Eugenics is notorious today because of its history. Genetic counselling may be seen like this as one possible outcome may be parents who end pregnancies if their child inherits a genetic disease. Moreover, understanding GGT’s societal influences is crucial, so clinical trial designs must consider privacy, self-ownership, informed consent and social justice. In China, the public’s emotional response to GGT in 2018 was mainly neutral, as shown in Figure 1, but some of the common “hot words” when discussed were ‘mankind’, ‘ethics’, and ‘law’. With this said, regulations are required with other nations for a wider social consensus on GGT research. In other countries, there are stricter rules for GGT. it is harder to conduct experiments using purposely formed/altered human embryos with inheritable mutations in the United States because the legal outcomes can include prison time and $100,000 fines. Furthermore, when donors are required, they must be fairly compensated, and discussing methodologies is crucial because there are issues on how they can impact men and women. South Africa has two opposing thoughts on GGT or gene editing. Bioconservatism has worries about genetic modification and asserts its restrictions, while bioliberalism is receptive to this technology because of the possible benefits. Likewise, revisions to the current regulations are suggested, such as rethinking GGT research or a benefit-risk analysis for the forthcoming human. Conclusion Overall, gene therapies have transformed the therapeutic landscape for genetic diseases. GGT is nevertheless a unique approach that promises to completely cure a genetic disease for families without the need to edit human embryos. However, GGT’s prospects may do more harm than good because its therapeutic effects are translated systemically and multigenerationally. On top of that, controversial ideas such as designer babies can arise if GGT is pushed too far. Additionally, certain countries have varying regulations due to cultural attitudes towards particular scientific innovations and the beginning of life. Reflecting on the ethical, legal and social issues, GGT is still contentious and probably would not be a prominent treatment option anytime soon for genetic diseases. Written by Sam Jarada and Stephanus Steven Introduction, and How it works by Stephanus Ethical issues, and Legal and social issues by Sam Conclusion by Sam and Stephanus Related article: Monkey see, monkey clone References: Cavazzana-Calvo, M. et al. (2000) ‘Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease’, Science , 288(5466), pp. 669–672. doi:10.1126/science.288.5466.669. Demarest, T.G. and Biferi, M.G. (2022) ‘Translation of gene therapy strategies for amyotrophic lateral sclerosis’, Trends in Molecular Medicine , 28(9), pp. 795–796. doi:10.1016/j.molmed.2022.07.001. Frangoul, H. et al. (2021) ‘CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia’, New England Journal of Medicine , 384(3), pp. 252–260. doi:10.1056/nejmoa2031054. AGAR, N. (2018). Why We Should Defend Gene Editing as Eugenics. Cambridge Quarterly of Healthcare Ethics, 28(1), pp.9–19. doi: https://doi.org/10.1017/s0963180118000336 . de Miguel Beriain, I., Payán Ellacuria, E. and Sanz, B. (2023). Germline Gene Editing: The Gender Issues. Cambridge Quarterly of Healthcare Ethics, 32(2), pp.1–7. doi: https://doi.org/10.1017/s0963180122000639 . Genome.gov . (2021). Eugenics: Its Origin and Development (1883 - Present). [online] Available at: https://www.genome.gov/about-genomics/educational-resources/timelines/eugenics#:~:text=Discussions%20of%20eugenics%20began%20in . Johnston, J. (2020). Budgets versus Bans: How U.S. Law Restricts Germline Gene Editing. Hastings Center Report, 50(2), pp.4–5. doi: https://doi.org/10.1002/hast.1094 . Kozaric, A., Mehinovic, L., Stomornjak-Vukadin, M., Kurtovic-Basic, I., Catibusic, F., Kozaric, M., Mesihovic-Dinarevic, S., Hasanhodzic, M. and Glamuzina, D. (2016). Diagnostics of common microdeletion syndromes using fluorescence in situ hybridization: single center experience in a developing country. Bosnian Journal of Basic Medical Sciences, [online] 16(2). doi: https://doi.org/10.17305/bjbms.2016.994 . Luque Bernal, R.M. and Buitrago BejaranoR.J. (2018). Assessoria genética: uma prática que estimula a eugenia? Revista Ciencias de la Salud, 16(1), p.10. doi: https://doi.org/10.12804/revistas.urosario.edu.co/revsalud/a.6475 . Nielsen, T.O. (1997). Human Germline Gene Therapy. McGill Journal of Medicine, 3(2). doi: https://doi.org/10.26443/mjm.v3i2.546 . Niemiec, E. and Howard, H.C. (2020). Germline Genome Editing Research: What Are Gamete Donors (Not) Informed About in Consent Forms? The CRISPR Journal, 3(1), pp.52–63. doi: https://doi.org/10.1089/crispr.2019.0043 . Peng, Y., Lv, J., Ding, L., Gong, X. and Zhou, Q. (2022). Responsible governance of human germline genome editing in China. Biology of Reproduction, 107(1). doi: https://doi.org/10.1093/biolre/ioac114 . Shozi, B. (2020). A critical review of the ethical and legal issues in human germline gene editing: Considering human rights and a call for an African perspective. South African Journal of Bioethics and Law, 13(1), p.62. doi: https://doi.org/10.7196/sajbl.2020.v13i1.00709 . Thaldar, D., Botes, M., Shozi, B., Townsend, B. and Kinderlerer, J. (2020). Human germline editing: Legal-ethical guidelines for South Africa. South African Journal of Science, 116(9/10). doi: https://doi.org/10.17159/sajs.2020/6760 . Zhang, D. and Lie, R.K. (2018). Ethical issues in human germline gene editing: a perspective from China. Monash Bioethics Review, 36(1-4), pp.23–35. doi: https://doi.org/10.1007/s40592-018-0091-0 . Project Gallery

Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Apocrine carcinoma: a rare form of breast cancer 02/11/24, 11:57 Last updated: Key facts This is article no. 1 in a series on Rare Diseases. Next article: Pseudo-Angelman Syndrome . Apocrine carcinoma (AC) is a rare form of breast cancer, accounting for approximately 1-4% of all breast cancer cases worldwide. It affects a wide range of patients from 19 to 92 years of age, with the reported mean age varying from 53 to 62 years. AC of the skin - primary cutaneous apocrine carcinoma - is the only other known cancer that arises from apocrine cells. This is a very rare cancer with limited research. AC is commonly classified into two subtypes: triple-negative AC (TNAC) and HER2+ AC. Another receptor not included in the ‘triple negative’ name is the androgen receptor (AR). A ‘pure’ apocrine carcinoma is ER-negative, PR-negative, but AR-positive. Among triple negative ACs, ones that are AR-positive have a better prognosis. AC is often associated with triple-negative breast cancers (TNBC), meaning that it does not express oestrogen receptors (ER) and progesterone receptors (PR), and produces very little to no HER2– all of which play key roles in the reproductive system. AC arises from apocrine metaplastic cells that are commonly located in the lobules of the breast. This disease can be aggressive and can metastasise to the lymph nodes and distant organs (eg. lungs, liver, and bone). What makes AC different is the appearance of cells which have abundant granular eosinophilic or cytoplasm with fine empty vacuoles. Despite its rarity, focal apocrine differentiation is relatively common (reported in approximately 60% of not otherwise specified [NOS] invasive ductal carcinoma) and shows clinical presentation and radiographic findings similar to that of invasive ductal carcinoma NOS. TNBCs are generally aggressive and present a poor prognosis. However, studies show apocrine breast cancer to have a better prognosis and low proliferative nature, despite its poor response to neoadjuvant chemotherapy. Treatment of AC may include surgery, radiation therapy, chemotherapy, hormone therapy, or targeted therapy. The problem with TNACs is that therapies targeting the hormone receptors are ineffective. Conversely, targeted therapy is seen to work relatively well with HER2-positive ACs despite them being more aggressive than TNACs. ACs can be diagnosed through a series of tests—usually a mammogram, ultrasound, biopsy, and finally immunohistochemistry. The latter makes it possible to know the status of the ERs and PRs. As with most breast cancers the earlier the detection and treatment implementation, the better the prognosis for the patient. ACs can be hard to diagnose due to its rarity and non-specific presentation. AC has a low proliferative nature, which is shown in its low Ki-67 index. Ki-67 has a higher presentation in cells that have a high division rate. Slower division rates result in slower growth rates of the tumour, and may imply that there is a better prognosis. This could be one of the reasons why apocrine triple-negative breast cancers have a better prognosis than other types of TNBCs. There is promise in the future for AC, however this is not without its challenges. Due to its rarity there are limited patients to participate in clinical trials which are essential in new treatment development. Written by Henrietta Owen & Sherine A Latheef Related article: Epitheliod hemangioendothelioma REFERENCES Apple, S.K., Bassett, L.W. and Poon, C.M. (2011) ‘Invasive ductal carcinomas’, Breast Imaging, pp. 423–482. doi:10.1016/b978-1-4160-5199-2.00022-9. Bcrf (2024) Types of breast cancer: BCRF, Breast Cancer Research Foundation. Available at: https://www.bcrf.org/blog/types-of-breast-cancer/ (Accessed: 05 June 2024). Hu, T. et al. (2022) ‘Triple-negative apocrine breast carcinoma has better prognosis despite poor response to neoadjuvant chemotherapy’, Journal of Clinical Medicine, 11(6), p. 1607. doi:10.3390/jcm11061607. Suzuki, C., Yamada, A., Kawashima, K., Sasamoto, M., Fujiwara, Y., Adachi, S., Oshi, M., Wada, T., Yamamoto, S., Shimada, K., Ota, I., Narui, K., Sugae, S., Shimizu, D., Tanabe, M., Chishima, T., Ichikawa, Y., Ishikawa, T., & Endo, I. (2023). Clinicopathological Characteristics and Prognosis of Triple-Negative Apocrine Carcinoma: A Case-Control Study. World Journal of Oncology, 14(6), 551-557. Vranic, S., Feldman, R. and Gatalica, Z. (2017) ‘Apocrine carcinoma of the breast: A brief update on the molecular features and targetable biomarkers’, Bosnian Journal of Basic Medical Sciences, 17(1), pp. 9–11. doi:10.17305/bjbms.2016.1811 Xiao, X., Jin, S., Zhangyang, G., Xiao, S., Na, F. and Yue, J. (2022). Tumor-infiltrating lymphocytes status, programmed death-ligand 1 expression, and clinicopathological features of 41 cases of pure apocrine carcinoma of the breast: a retrospective study based on clinical pathological analysis and different immune statuses. Gland Surgery, 11(6), pp.1037–1046. doi:https://doi.org/10.21037/gs-22-248. Project Gallery

Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Are PCOS and endometriosis sisters? 28/03/24, 11:16 Last updated: You can have endometriosis and PCOS at the same time The label of PCOS or Endometriosis can have physical and emotional consequences for women. It is important for both male and females to gain a better understanding of such conditions, the symptoms and the challenges they pose. Such knowledge can act as physical and emotional support in times of need. It creates a safe space where the person with PCOS is comfortable discussing their experiences, feelings and concerns knowing they are being heard and supported by the right people. With research fast developing there is a plethora of information out there so WHAT do you believe in and WHAT do you ignore and WHOM do you believe and WHOM do you ignore? Endometriosis and polycystic ovary syndrome (PCOS) both affect females and can have similar symptoms. However, the causes and some key symptoms are different. Endometriosis is a painful disorder in which tissue that normally lines the inside of your uterus grows outside the uterus. (Read more on Endometriosis breakthrough ). PCOS is an endocrine system disorder where small fluid-filled sacs develop in the ovaries. You can have endometriosis and PCOS at the same time. A 2015 study found that women with PCOS had a higher risk for a diagnosis of endometriosis. Another 2014 study determined that there is a strong link between endometriosis and PCOS with pelvic pain and trouble getting pregnant. What is a normal menstrual cycle? Let’s polish up the basics! The brain, ovaries and uterus work together to prepare the body per month for pregnancy. Follicle-stimulating Hormone (FSH) and Luteinising Hormone (LH) are made by the pituitary gland and progesterone and oestrogen are made in the ovaries. Many females with PCOS do not ovulate regularly and it may take these females longer to become pregnant. Irregular periods results in months where ovulation does not occur. Where the ovaries do not produce progesterone the lining of the uterus becomes thicker but shedding is very irregular which can lead to heavy and prolonged bleeding. PCOS affects 1 in 10 women in the UK. Women with PCOS experience irregular menstrual cycles, acne, excess hair growth, infertility, pregnancy complications and cardiovascular disease. PCOS can be associated with weight gain and obesity in approximately one-half of females. Females with PCOS can also be at increased risk of other problems that can impact quality of life. These include depression and anxiety, sexual dysfunction and eating disorders. Although PCOS is not ‘completely’ reversible there are many ways you can minimise the symptoms. Most females can lead a normal life and are able to conceive without significant complications. A pelvic examination is requested by your GP to assess the ovaries for a diagnosis to be made. Imaging tests for examining the ovaries are pelvic and intravaginal ultrasonography, however, the latter may be extremely uncomfortable if sexually inactive. Please be aware this article acts to capture your attention, encouraging you to delve further into the subject and continue your self-education on this topic and by no means is everything about PCOS. It is essential to consult with a healthcare professional if you suspect you may have symptoms of either PCOS or endometriosis. Proper diagnosis and management can help address specific concerns and improve overall reproductive health. Written by Khushleen Kaur Related articles: Endometriosis breakthrough / Underreporting in endometriosis REFERENCES R. Hart and D. A. Doherty, Fertility Specialists of Western Australia (R.H.), Bethesda Hospital, 6008. K. J. Holoch, R. F. Savaris, D. A. Forstein, P. B. Miller, H. Lee Higdon, C. E. Likes and B. A. Lessey, https://doi.org/10.5301/je.5000181 , 2014, 6, 79–83. R. J. Norman, D. Dewailly, R. S. Legro and T. E. Hickey, The Lancet, 2007, 370, 685– 697. Project Gallery

Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link Can Tetris help treat Post Traumatic Stress Disorder? 02/11/24, 11:47 Last updated: PTSD and Tetris This is the last part (Part II) in the two-part series on PTSD and intrusive memories, discussing how a common and well-loved visuospatial game, Tetris, can reduce the presence of the core clinical symptom. Previous article: Boom, and you're back! As discussed in an earlier article , psychological trauma resulting from threat to life or serious injury from events such as vehicle accidents or assault, among others, can result in development of post traumatic stress disorder (PTSD). The core clinical feature is intrusive memories, where memories of the event involuntarily intrude into a person’s consciousness after being triggered by environmental cues, resulting in extreme emotional distress. Two of the most common and effective treatments for PTSD include trauma-focused cognitive behavioural therapy (CBT) and eye movement desensitisation and reprocessing (EMDR) therapy. These approaches address an individual’s memory of the event alongside their emotional understanding of the experience. Unfortunately, there is a lack of qualified therapists and patients are often wary of delving into the event details. This results in many patients not receiving sufficient treatment. Following an event, the memory must be consolidated into long-term memory for it to be remembered at a later date. Memory consolidation theory states that the memory is flexible several hours following the event, meaning it can be interfered with. Engaging in a visuospatial task during this period may weaken the consolidation of the traumatic memory because the tasks compete with limited cognitive resources. Therefore, completing tasks with high visuospatial demands in the consolidation period may reduce the occurrence of intrusive memories. Many studies have looked into this, using Tetris to disrupt the memory up to six hours post exposure, and have found positive results. One study took this outside of the laboratory, recruiting patients in an emergency department following serious vehicle accidents. The intervention involved two steps, first patients were asked to remember the accident and state the most traumatising experience they observed. Following this they played Tetris for a minimum of 10 minutes, which competed with the visual memories they had just produced. It was found that 62% of those in the Tetris intervention group had a reduction in intrusive memories in the subsequent week, compared to those in the control group. However, it is not always practical to play a video game in the direct aftermath of the event. The memory consolidation theory also states that memories become flexible to change when they are remembered and subsequently must be reconsolidated into long-term memory. Therefore, other studies have investigated using Tetris as an intervention for those already experiencing PTSD. In this case, combining Testis game play with EMDR therapy has been found useful. After completion of therapy, both control and Tetris groups were found to have a reduction in symptoms at 6-months. However, only the Tetris group had reductions in anxiety and depression. Remember in the previous article we spoke about the neuroanatomy of PTSD and how that related to intrusive memories. Research has shown those with PTSD have reductions in hippocampus and ventromedial prefrontal cortex volume, with the reduced hippocampal volume correlating to symptom severity. In fact, studies investigating the use of Tetris have shown that playing this during psychological therapy increases the hippocampal volume, and this increase correlates to the reduced symptoms 6-months following treatment. Currently, the interventions for PTSD have limitations surrounding the longevity of symptom improvements. Therefore, combining Tetris playing with psychotherapies may maintain the symptom improvements long term by increasing the hippocampal volume. Not only this, but videogames with high visuospatial demands like Tetris, may provide some utility as preventative interventions, which are currently lacking. Considering patients involved in vehicle accidents wait upto four hours in emergency departments in the UK, there is an opportunity to reach patients within the memory consolidation window. This approach is not only cost-effective and requires straightforward training for implementation but has been found acceptable in clinical populations. Notably, the earlier study found 48% of patients engaged in this approach, surpassing participation rates of 10% in a psychotherapy trial and 8% in a pharmacological trial within the same emergency department. Overall, interfering with memory consolidation using Tetris could provide a good treatment option for intrusive memories in PTSD. So, where are we currently? Research is still being undertaken, with some even investigating the effects of other visuospatial games such as Candy Crush. Written by Alice Jayne Greenan Project Gallery

Facebook X (Twitter) WhatsApp LinkedIn Pinterest Copy link How to prevent tooth decay 17/03/24, 18:00 Last updated: The science behind tooth decay Dental caries, commonly referred to as tooth decay, manifests as a gradual process and progressive disease affecting the dental hard tissues, resulting in the breakdown of tooth structure and the potential for pain and infection within the oral cavity. Understanding the mechanisms behind tooth decay is crucial for adopting effective preventative measures, to stop or reverse the carious process and prevent cavity formation. Several factors contribute to dental caries, including bacteria, time, fermentable carbohydrates, and a susceptible tooth surface. In the absence of regular toothbrushing, a plaque biofilm is allowed to form on the tooth surface—a sticky, colourless film that serves as a breeding ground for bacteria such as Streptococcus mutans and Lactobacillus species. Once these bacterial species encounter fermentable carbohydrates and sugars from our diet, they begin to metabolise them, producing acids as a by-product. These acids contribute to an acidic environment in the mouth. When enamel, the outermost layer of tooth structure, is exposed to an acidic pH below 5.5, its mineral structure weakens, initiating the dissociation of hydroxyapatite crystals. Frequent acid attacks from dietary sugars result in a net mineral loss in teeth, leading to cavity formation, dental pain, and potential infections. The initial stage of decay involves the demineralisation of enamel. At this point, the damage can be reversible with good oral hygiene practices and through remineralising agents. Saliva has the capacity to remineralise initial carious lesions, and fluoride application through fluoridated toothpaste can also aid in reversing the initial stages of dental caries. However, if left untreated and allowed to progress, the decay can develop further into the tooth structure reaching the softer dentine beneath enamel. Dentin decay occurs more rapidly than enamel and can contribute to increased sensitivity and discomfort. As the decay advances, it may reach the dental pulp, which is the nerve of the tooth. Infection of the pulp can trigger severe pain and may necessitate root canal treatment in attempt to save the tooth. Persistent infections can lead to abscess formation—a pocket of pus causing swelling, pain, and systemic health issues, should the infection spread throughout the body. Tooth decay can be preventing through regular brushing with a fluoride toothpaste. The consistent disturbance to the plaque biofilm formation through brushing it away will not allow the caries process to continue, and hence prevent cavity formation. The fluoride aspect will help to strengthen the enamel and remineralise any mineral loss found in early lesions; this can stop and even reverse the carious process, thus preventing dental decay A healthy diet with limited consumption of sugary foods and drinks can significantly reduce the risk of tooth decay; with less sugars in the oral environment there is a lower rate of bacterial metabolization to create the acids which contribute to the decay process. Regular dental check up appointments enable early detection and intervention of any initial lesions, preventing the progression of decay before reaching an irreversible status. Tooth decay is a preventable yet prevalent oral health issue. Instigated by the action of oral bacteria metabolising sugars in the mouth, our natural tooth structure can be destructed and decayed if the plaque biofilm is not controlled. By understanding the causes and progression of tooth decay, individuals can adopt proactive measures to maintain good oral hygiene, preserve enamel, and safeguard their smiles for a lifetime. Regular dental check- ups and a commitment to a healthy lifestyle play pivotal roles in preventing the onset and progression of tooth decay. Written by Isha Parmar Reference (Banerjee & Watson, 2015): Banerjee, A. and Watson, T.F. (2015) Pickard’s Guide to Minimally Invasive Operative Dentistry, King’s College London. Project Gallery